Total synthesis of (+)-decarbamoylsaxitoxin and (+)-gonyautoxin 3

Article abstract of DOI:10.1021/ol1006696

Figure presented Facile construction of the complex saxitoxin (STX) skeleton is carried out by using a novel, conformationally controlled, guanidine cyclization process that relies on the use of neighboring group participation. The utility of this methodology is verified by its employment in syntheses of both natural and unnatural STX derivatives.

Full text of DOI:10.1021/ol1006696

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2150-2153
Total Synthesis of
(+)-Decarbamoylsaxitoxin and
(+)-Gonyautoxin 3
Osamu Iwamoto and Kazuo Nagasawa*
Department of Biotechnology and Life Science, Tokyo UniVersity of Agriculture and
Technology (TUAT), 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan
knaga@cc.tuat.ac.jp
Received March 21, 2010
ABSTRACT
Facile construction of the complex saxitoxin (STX) skeleton is carried out by using a novel, conformationally controlled, guanidine cyclization
process that relies on the use of neighboring group participation. The utility of this methodology is verified by its employment in syntheses
of both natural and unnatural STX derivatives.
Saxitoxin (STX, 1) and its analogues (Figure 1), the causative
agents of paralytic shellfish poisoning (PSP), are potent
neurotoxins produced by dinoflagellates.1 PSP is attributed
to the potent affinities of STXs against voltage gated sodium
channels (NaChs), where binding strongly blocks the influx
of sodium ions and inhibits neuronal cell depolarization
processes. Owing to their characteristic pharmacological
profiles, STXs have been used as biological tools to
investigate the properties of NaChs.
STXs have a unique tricyclic bis-guanidine structure
containing a quaternary C4 N,N-aminal carbon. The two
guanidium ions in STXs serve as the sodium cation mimics.
X-ray crystallographic analysis of STXs clearly show that
Figure 1. (+)-Saxitoxin (1) and its analogues (2-5).
(1) Review for STX and its analogues: (a) Llewellyn, L. E. Nat. Prod.
Rep. 2006, 23, 200–222, and references therein. For recent isolation of new
both the C5 and C6 substituents are oriented in an anti-di-
STXs: (b) Lim, P.-T.; Sato, S.; Thuoc, C. V.; Tu, P. T.; Huyen, N. T. M.;
axial arrangement.2 As a result of unique, highly polar, and
heteroatom-rich structural features, STXs have attracted the
Takata, Y.; Yoshida, M.; Kobiyama, A.; Koike, K.; Ogata, T. Harmful Algae
2007, 6, 321–331.
(2) (c) Dell’Aversano, C.; Walter, J. A.; Burton, I. W.; Stirling, D. J.;
interest of synthetic groups that have accomplished four total
syntheses of members of this alkaloid family. Kishi and co-
workers were the first to describe total syntheses of (()-
STX (1) and (-)-decarbamoylsaxitoxin (dcSTX) (ent-3) in
Fattorusso, E.; Quilliam, M. A. J. Nat. Prod. 2008, 71, 1518–1523. (a)
Bordner, J.; Thiessen, W. E.; Bates, H. A.; Rapoport, H. J. Am. Chem.
Soc. 1975, 97, 6008–6012. (b) Schantz, E. J.; Ghazarossian, V. E.; Schnoes,
H. K.; Strong, F. M.; Springer, J. P.; Pezzanite, J. O.; Clardy, J. J. Am.
Chem. Soc. 1975, 97, 1238–1239.
10.1021/ol1006696  2010 American Chemical Society
Published on Web 03/31/2010

1977 and 1992, respectively.3 Jacobi and co-workers also
developed a strategy for the synthesis of (()-STX (1) that
is based on an azomethine imine cycloaddition process.4
More recently, Du Bois and co-workers devised routes for
the preparation of (+)-STX (1) and (+)-gonyautoxin 3 (GTX
3) (5) that employ a Rh-catalyzed amination strategy.5
We recently completed total syntheses of (-)- and (+)-
decarbamoyloxysaxitoxin (doSTX) (ent-2 and 2) and a formal
synthesis of (+)-STX (1) that utilize a 1,3-dipolar cycloaddition
process and a unique IBX oxidation reaction.6 Below, we
describe the results of our continuing studies in this area, which
have resulted in total syntheses of (+)-dcSTX (3) and (+)-
GTX 3 (5) that rely on divergent approaches involving a
protected saxitoxinol intermediate and a newly developed
guanidine ring constructing methodology.
removal of the Cbz guanidine protecting groups. By using
this approach, we were able to prepare (-)-doSTX (2).6a
The development of a mild method to promote the key
cyclization remains as a significant challenge in employing
the strategy we have devised for the preparation of a variety
of STX derivatives. In considering possible reasons why
cyclization of 6 is problematic, we assumed that two key
processes must take place in order for this reaction to occur
efficiently. First, the iminium cation B must be generated
from the precursor A (Scheme 2). Second, a conformational
Scheme 2. Hypothesis of Guanidine Cyclization Reaction
In routes for syntheses of highly polar and water-soluble
natural product targets like those found in guanidine-
containing alkaloid families, deprotection step(s) are usually
carried out at final stages in order to avoid solubility and
purification problems.7 In our early work on the synthesis
of (-)-doSTX (ent-2), attempts to construct the STX skeleton
in the protected form 7 by acid treatment of the bis-guanidine
precursor 6 met with failure (Scheme 1). In contrast,
Scheme 1. Early Attempts To Prepare Protected Saxitoxinol 7
change must take place to transform B to C, in which the
guanidinium moiety is correctly oriented for stereoelectroni-
cally governed axial addition to the iminum cation. We
believed that in the case of 6, the electron withdrawing Cbz
group on the endocyclic guanidine moiety suppresses imi-
nium ion formation even under acidic conditions. In addition,
the conformational change required to create the bis-
pseudoaxial C5 conformer C would be difficult owing to
the presence of bulky substituents in B. If this reasoning is
correct, activation of the leaving group at C4 in A and
stabilization of conformer C would facilitate the cyclization
process. In order to circumvent both problems, we planned
to install a leaving group at C4 in order to accelerate iminium
ion generation (A to E, Scheme 2) and an acyloxy neighbor-
ing group at C12 that would generate a bridged acyloxonium
ion intermediate F, in which the C5 and C6 substituents are
oriented in an anti-di-axial manner. On the basis of this
analysis, we anticipated that cyclization of F would proceed
to generate the protected saxitoxinol D.
cyclization involving the guanidine and aminal moieties in
6 could be carried out under strongly acidic conditions after
(3) (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc.
1977, 99, 2818–2819. (b) Kishi, Y. Heterocycles 1980, 14, 1477–1495. (c)
Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1992, 114, 7001–7006. Kishi
reported synthetic studies on GTX 2 and 3; see: (d) Hannick, S. M.; Kishi,
Y. J. Org. Chem. 1983, 48, 3833–3835.
(4) (a) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc.
1984, 106, 5594–5598. (b) Martinelli, M. J.; Brownstein, A. D.; Jacobi,
P. A.; Polanc, S. Croat. Chem. Acta 1986, 59, 267–295. (c) Jacobi, P. A.
Strategies and Tactics in Organic Synthesis; Lindberg, T., Ed.; Academic
Press: New York, 1989; Vol. 2, pp 191-219.
(5) (a) Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926–
3927. (b) Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem.
Soc. 2007, 129, 9964–9975. (c) Mulcahy, J. V.; Du Bois, J. J. Am. Chem.
Soc. 2008, 130, 12630–12631. Recently Du Bois reported derivatization of
STX: (d) Andresen, B. M.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 12524–
12525.
(6) (a) Iwamoto, O.; Koshino, H.; Hashizume, D.; Nagasawa, K. Angew.
Chem., Int. Ed. 2007, 46, 8625–8628. (b) Iwamoto, O.; Shinohara, R.;
Nagasawa, K. Chem. Asian J. 2009, 4, 277–285.
(7) Recent review for guanidine alkaloids: (a) Berlinck, R. G. S.;
Burtoloso, A. C. B.; Kossuga, M. H. Nat. Prod. Rep. 2008, 25, 919–954.
Selected articles: (b) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003,
125, 11510–11511. (c) Urabe, D.; Nishikawa, T.; Isobe, M. Chem Asian J.
2006, 1-2, 125–135. (d) Wang, S.; Romo, D. Angew. Chem., Int. Ed. 2008,
47, 1284–1286. (e) Imaoka, T.; Iwamoto, O.; Noguchi, K.; Nagasawa, K.
Angew. Chem., Int. Ed. 2009, 48, 3799–3801.
These proposals were explored by using the bis-guanidines
9a-d, derived from alcohol 8 that was synthesized in
multigram quantities (Scheme 3).6b Cyclization reactions of
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was converted into the carbamate 14 by treatment with
trichloroacetyl isocyanate, followed by stepwise methanolysis
to remove the trichloroacetyl and acetyl groups. Finally,
ꢀ-saxitoxinol (15) was produced by removal of the four Boc
groups from 14 with trifluoroacetic acid in near quantitative
yield (Path A, Scheme 4). The R-isomer 16 was also
Scheme 3. Synthesis of Protected Saxitoxinols (10 and 12)
Scheme 4
.
Synthesis of R- and ꢀ-Saxitoxinols (15 and 16) and
Azide Derivative (17)
9a-d were promoted by methanesulfonyl chloride induced
formation of the corresponding amido methanesulfonates. In
the cases of 9a and 9b, cyclization reaction takes place
smoothly under these conditions to afford the respective
protected saxitoxinols 10a (94%) and 10b (95%) as N7
methanesulfonamide derivatives.8 In contrast, treatment of
9c and 9d, containing MOM and TMS C12 hydroxyl
protecting groups, with methanesulfonyl chloride did not
effect this cyclization. Encouraged by these results, more
selective conditions to promote the cyclization reaction but
avoid formation of methansulfonamide products were ex-
plored. We observed that reaction of bis-guanidine 8 with
acetic anhydride in the presence of catalytic DMAP led to
generation of the C4,12-diacetate 11, which when treated
with zinc(II) chloride in dichloromethane at -20 °C yielded
the tricyclic acetate 12 (98% from 8), a protected saxitoxi-
nol.9 Notably, this two-step cyclization reaction could be
performed in one pot on a practical scale.
produced from 14 via a three-step route (65%, Path B)
involving alcohol oxidation followed by stereoselective
reduction of resulting ketone with NaBH4 and treatment with
trifluoroacetic acid. The C13 azide 17, an unnatural nitrogen-
substituted STX derivative, was also easily prepared by
reaction of the alcohol 13 under Mitsunobu conditions.
The chemistry described above clearly demonstrates that
C12- and C13-functionalized derivatives of saxitoxinol can
be readily prepared from the protected saxitoxinol 12. The
advantageous features of this approach are further exempli-
fied by routes we have developed for syntheses of the
naturally occurring STX derivatives (+)-dcSTX (3) and (+)-
GTX 3 (5) (Scheme 5). The sequences were initiated by
removal of the acetyl group in 12 by methanolysis and
oxidation of the resulting alcohol with the Dess-Martin
reagent to generate the ketone 18 (92%, 2 steps). Simulta-
neous removal of the Boc and MPM ether protecting groups
by treatment of 18 with HCl generated (+)-dcSTX (3) in
quantitative yield. (+)-GTX 3 (5) is also prepared from 18
In order to demonstrate the synthetic utility of the
cyclization strategy we have developed, the protected sax-
itoxinol 12 was converted into the R- and ꢀ-saxitoxinols 15
and 16.10 The MPM ether protecting group on the C6 side
chain alcohol in 12 was removed by reacting with NBS and
Et3B as the radical initiator,11 and the resulting alcohol 13
(8) The di-axial conformation of 13b at C5,6 was confirmed with X-ray
analysis, and its dihedral angle was estimated. See Supporting Information.
(9) To investigate details of this cyclization reaction, control experiments,
i.e., treatment of 9a with ZnCl2 or reaction of 9c with Ac2O and DMAP
followed by treatment with ZnCl2, were conducted. In these cases, no
corresponding cyclized products were obtained. Thus, both C4- and C12-
OAc groups were revealed to be mandatory for this cyclization by activation
and neighboring effect, respectively.
(11) Standard conditions (DDQ, CAN or Pd/C-H2, etc.) did not give
13, and Boc groups in 12 were deprotected. To the best of our knowledge,
NBS-Et3B or other radical initiators mediated deprotection of the MPM
group has not been reported, although only the NBS condition can be seen
in literature.12 Meanwhile, treatment of 12 with NBS, NaHCO3 solution in
wet CH2Cl2 gave desired 13 with no reproducibility.
(10) Koehn, F. E.; Ghazarossian, V. E.; Schantz, E. J.; Schnoes, H. K.;
Strong, F. M. Bioorg. Chem. 1981, 10, 412–428.
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The studies described above have led to the total synthesis
of (+)-dcSTX (3) and (+)-GTX 3 (5) from the protected
saxitoxinol 12, which was prepared by employing a protocol
that is based on a newly devised conformationally controlled
guanidine cyclization process. These syntheses of (+)-dcSTX
(3) and (+)-GTX 3 (5) were performed in 15 steps with 24%
and 19 steps with 2.9% overall yield from chiral nitrone,
respectively.15 Since the substitution or transformation at
C11-13 and N7 was successfully performed from the single
intermediate 12, this methodology should serve as the
foundation for a general strategy for the syntheses of diverse
natural and unnatural STX derivatives. Further studies on
the synthesis of STX type NaCh modulators are in progress.
Scheme 5. Synthesis of (+)-dcSTX (3) and (+)-GTX 3 (5)
Acknowledgment. Financial support of this work was
provided in part by a Grant-in-Aid for Scientific Research
(B) from JSPS (No. 20310130). O.I. is grateful for financial
support from the education program “Human Resource
Development Program for Scientific Powerhouse” provided
through the TUAT and the JSPS Predoctoral Fellowships
for Young Scientists. We are grateful to Prof. Kei-ichi
Noguchi (TUAT) for measurement of X-ray crystallographic
data of key compounds.
Supporting Information Available: Experimental details
and analytical data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
through reaction with NaHMDS and TIPSCl, followed by
oxidation with mCPBA to produce the siloxy epoxide 19.13
Following transformation of the hydroxyl group in 19 to the
corresponding carbamate in 20 (24% from 18), the Boc and
TIPS ether groups were removed by using TFA to give 11
ꢀ-hydroxysaxitoxin. Finally, the synthesis of (+)-GTX 3 (5)
was accomplished by sulfation of the C11 alcohol in 20 by
utilizing the method developed by Du Bois.5c Both synthetic
(+)-dcSTX (3) and (+)-GTX 3 (5) were identical to natural
products.14
OL1006696
(14) For preparation of (+)-dcSTX (3) by hydrolysis of natural STX
(1), see: (a) Ghazarossian, V. E.; Schantz, E. J.; Schnoes, H. K.; Strong,
F. M. Biochem. Biophys. Res. Commun. 1976, 68, 776–780. For first
identification of (+)-dcSTX (3) as a natural product, see: (b) Harada, T.;
Oshima, Y.; Yasumoto, T. Agric. Biol. Chem. 1983, 47, 191–193. For
isolation of (+)-GTX 3 (5), see: (c) Shimizu, Y.; Buckley, L. J.; Alam,
M.; Oshima, Y.; Fallon, W. E. J. Am. Chem. Soc. 1976, 98, 5414–5416.
(d) Boyer, G. L.; Schantz, E. J.; Schoes, H. K. J. Chem. Soc., Chem.
Commun. 1978, 889–890. (e) Onodera, H.; Satake, M.; Oshima, Y.;
Yasumoto, T.; Carmichael, W. W. Nat. Toxins 1997, 5, 146–151. Also see
Supporting Information.
(15) (a) Goti, A.; Cacciarini, M.; Cardona, F.; Brandi, A. Tetrahedron
Lett. 1999, 40, 2853–2856. (b) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero,
F. M.; Goti, A. Chem.sEur. J. 2009, 15, 7808–7821. Details of the
preparation of intermediate 8 from chiral nitrone were summarized; see
Supporting Information.
(12) Classon, B.; Garegg, P. J.; Samuelsson, B. Acta Chem. Scand. 1984,
B38, 419–422.
(13) In this condition, MPM ether was oxidatively cleaved and overoxidized
byproduct was generated in 27% yield. See Supporting Information.
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