Synthesis of Saxitoxin and Its Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c03281

The chiral synthesis of (+)-saxitoxin and its derivatives is described. Two consecutive carbon-nitrogen bonds at C-5 and C-6 in saxitoxin were effectively installed by the sequential Overman rearrangement of an allylic vicinal diol derived from d-malic acid. The bicyclic guanidine unit was constructed by the intramolecular aminal formation of an acyclic bis-guanidine derivative possessing a ketone carbonyl at C-4. From the bicyclic aminal intermediate, (+)-saxitoxin, (+)-decarbamoyl-β-saxitoxinol [(+)-dc-β-saxitoxinol], and the unnatural skeletal isomer, (-)-iso-dc-saxitoxinol, were synthesized.

Full text of DOI:10.1021/acs.orglett.0c03281

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Letter
Synthesis of Saxitoxin and Its Derivatives
Yuya Okuyama, Ryosuke Okamoto, Shori Mukai, Kyoko Kinoshita, Takaaki Sato, and Noritaka Chida*
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ABSTRACT: The chiral synthesis of (+)-saxitoxin and its
derivatives is described. Two consecutive carbon−nitrogen bonds
at C-5 and C-6 in saxitoxin were effectively installed by the sequential
Overman rearrangement of an allylic vicinal diol derived from D-
malic acid. The bicyclic guanidine unit was constructed by the
intramolecular aminal formation of an acyclic bis-guanidine
derivative possessing a ketone carbonyl at C-4. From the bicyclic
aminal intermediate, (+)-saxitoxin, (+)-decarbamoyl-β-saxitoxinol
[(+)-dc-β-saxitoxinol], and the unnatural skeletal isomer, (−)-iso-
dc-saxitoxinol, were synthesized.
axitoxin (STX, 1), a paralytic shellfish poison whose
channels.9 Nagasawa reported that the skeletal isomer of STX
(FD-STX: N-9 is connected to C-12 instead of C-4) possessed
moderate activity.6h Therefore, a novel method to give access
to STX (1) and its analogues including unnatural skeletal
isomers would be an important task for the development of
novel voltage-gated sodium channel inhibitors. In this letter,
we report the synthesis of (+)-STX (1), (+)-decarbamoyl-β-
saxitoxinol [(+)-dc-β-saxitoxinol: 2], and the unnatural skeletal
isomer of 2, (−)-iso-dc-saxitoxinol (3), starting from D-malic
acid.
Our synthetic plan for (+)-STX (1) is illustrated in Scheme
1. The sequential Overman rearrangement of allylic vicinal diol
4 derived from D-malic acid would install two consecutive
carbon−nitrogen bonds stereoselectively through chirality
transfer.10 The rearranged product 5 was planned to be
converted to an acyclic bis-guanidine derivative 6 possessing a
ketone carbonyl at C-4 (STX numbering). Removal of the N-
Cbz groups on the guanidines in 6 would induce the
intramolecular aminal formation to afford bicyclic aminal
derivative 7.11 Bond formation between N-3 and C-10 by N-
alkylation in 7 would construct a pyrrolidine ring to provide
the tricyclic ring system of STX. On the other hand, the N−C
bond formation between N-9 and C-10 in 7 would generate
the unnatural skeletal isomer of STX, the iso-saxitoxinol core,
which is expected to show inhibitory effects on voltage-gated
sodium channels and/or other interesting biological activities.
1
Sstructure was determined in 1975,
specifically inhibits
voltage-gated sodium channels at low concentration.2
Structurally, STX (1) has a bicyclic guanidine unit containing
two consecutive carbon−nitrogen bonds at C-5 and C-6, and a
pyrrolidine ring with a hydrated form of the C-12 carbonyl
group. This fascinating structure as well as the intriguing
biological activity attracted considerable interest from the
synthetic community. The first total synthesis of racemic 1 was
reported by Kishi in 1977,3 in which a bicyclic six-membered
thiourea was utilized as the pivotal intermediate. After another
report from Jacobi’s laboratory4 on the racemic synthesis of 1
employing the intramolecular 1,3-dipolar cycloaddition of
azomethine imine as the key reaction, a number of total
syntheses and synthetic studies of 1 have been reported.3c,5
When synthesizing 1, the main issue is the construction of the
tricyclic core composed of a bis-guanidine and a pyrrolidine
ring. Du Bois5a,b successfully constructed the tricyclic core by
the intramolecular aminal formation of a nine-membered bis-
guanidine derivative possessing a ketone at C-4. Nagasawa5c−e
synthesized the tricyclic core via the iminium cation generated
by the dehydration of the hemiaminal derivative. Nishikawa5f,g,j
reported the construction of the tricyclic core by the Br+-
triggered cascade cyclization of an alkyne bearing a guanidine
unit as the key reaction. Looper5h employed a cascade Ag(I)-
catalyzed cyclization of an alkynyl bis-guanidine for the
construction of the tricycle. A number of STX congeners
have been isolated from natural sources,2 and syntheses of STX
analogues have been reported from many groups.6 The
biological assessment of STX analogues revealed that some
analogues including naturally occurring C-11 alkylated
derivatives (11-saxitoxinethanoic acid7 and zetekitoxin AB8)
also showed potent inhibitory effects on voltage-gated sodium
Received: September 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03281
© XXXX American Chemical Society
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Scheme 1. Synthetic Plan for STX and Its Skeletal Isomer
Scheme 3. Sequential Overman Rearrangement
Scheme 4. Synthesis of a Substrate for Cyclization
Our synthesis of 1 commenced with the known silyl ether
912 derived in three steps from commercially available D-malic
acid (8) (Scheme 2). DIBAL-H reduction of 9, followed by the
Scheme 2. Preparation of Allylic Vicinal Diols
lation reagent 13.16 Without isolation, dihydroxylation of 14
provided diol 1515 in a one-pot process (44% yield from 5, the
diastereomer of 15 was also isolated in 6% yield from 5).17 For
the selective protection of the C-12 hydroxy group, diol 15 was
subjected to various acylation conditions. After several
attempts, it turned out that borinic acid catalyzed benzoylation
reported by Taylor18 gave good results, affording the desired
12-benzoate 1615 in 80% yield.19 TPAP oxidation of the
secondary alcohol smoothly provided ketone 615 in 90% yield.
With ketone 6 in hand, the crucial step, construction of the
bicyclic guanidine unit by intramolecular aminal formation,
was investigated (Scheme 5). Removal of the two Cbz groups
in 6 by hydrogenolysis in MeOH in the presence of 10% Pd/C,
however, resulted in the formation of a complex mixture
composed of unidentified highly polar compounds, and no
desired bicyclic compound 17 was obtained. We then tried
stepwise access to the bicyclic compound. Hydrogenolysis of 6
in EtOAc under atmospheric pressure of H2 with 10% Pd/C at
room temperature for 2 h gave five-membered hemiaminal
1915 and six-membered hemiaminal 1815 in 31% yield as an
inseparable mixture (19:18 = ca. 1.5:1.0). Since the starting
material 6 was recovered in 67% yield, hemiaminals 19 and 18
were obtained in 94% yield based on the recovered starting
material.20
addition of magnesium acetylide 10 to the resulting lactol, gave
propargylic diols, syn-11 and anti-11, in 78% yield over two
steps (syn-11:anti-11 = 1.9:1.0). Semihydrogenation of syn-11
provided syn-4 bearing a Z-olefin, while Red-Al reduction of
anti-11 gave anti-4 with an E-olefin.13 Both syn-4 and anti-4
were converted to the same bis-amide 5 as follows (Scheme 3).
Treatment of syn-4 with CCl3CN in the presence of DBU gave
bis-imidate syn-12. The sequential Overman rearrangement of
syn-12 at 200 °C in the presence of Na2CO3 provided desired
bis-amide 5 in 97% yield from syn-4. The reaction proceeded
in a highly stereoselective manner, and 5 was isolated as the
sole product. By the same procedure, anti-4 was converted to
the identical bis-amide 5 as a single isomer (92% yield over
two steps).13
After successful construction of the two consecutive
carbon−nitrogen bonds, preparation of ketone 6, a substrate
for the cyclization of the bis-guanidine, was investigated
(Scheme 4). Treatment of 5 with DIBAL-H removed the
trichloroacetyl groups in 5 to give a bis-amine,14 which was
converted to bis-guanidine 1415 by the action of guanidiny-
To construct the bicyclic aminal structure, hemiaminals 19
and 18 were subjected to various reaction conditions. We were
pleased to find that the reaction of a mixture of 19 and 18 with
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in (CH2Cl)2 af-
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Scheme 5. Synthesis of Bicyclic Aminal 21
Scheme 7. Synthesis of dc-β-Saxitoxinol (2) and STX (1)
forded bicyclic aminal 20.21 Compound 20 was isolated as
cyclic carbamate 21 in 48% yield after the removal of the
TBDPS group from the mixture of 19 and 18.
A plausible mechanism of the formation of 20 is shown in
Scheme 6. Treatment of 19 with TBD would cause the
isocyanate, followed by methanolysis in the presence of
K2CO3, to afford a primary carbamate.5a,d,9d Under the
methanolysis conditions, the ethyl carbonate was also cleaved.
Finally, removal of the remaining Boc groups with aq HCl
provided a 77% yield (from 26) of (+)-β-saxitoxinol (27),
which is known to be converted into (+)-STX (1) by oxidation
at C-12.5a,6a All the spectroscopic data and the [α]D value of
synthetic 27 were consistent with those reported by other
groups.5a,b,d,h,6a
Scheme 6. Plausible Mechanism of the Formation of 20
We subsequently embarked on the synthesis of novel STX
derivatives possessing a different skeleton, which are expected
to show similar inhibitory effects on the voltage-gated sodium
channels as STX and/or other interesting biological activities.
For this purpose, synthesis of iso-dc-saxitoxinol (3) from the
intermediate 21 was carried out (Scheme 8). Reaction of 21
Scheme 8. Synthesis of iso-dc-Saxitoxinol (3)
migration of the benzoyl group to the C-4 position to give
tertiary benzoate 22. Next, the elimination of the benzoate
would generate the electrophilic acylimine (or acyliminium)
intermediate 23. Cyclization between N-3 and C-4 (23 → 24),
followed by cyclic carbonate formation between the C-12
hydroxy group and the Cbz group, would provide tricyclic 20.
TLC monitoring of the reaction suggested that the reaction of
19 to 20 was fast, whereas the aminal formation of 18 was
sluggish, and decomposition of 18 was observed during the
reaction.22
With bicyclic aminal 21 in hand, transformation of 21 to dc-
β-saxitoxinol (2) and STX (1) was investigated (Scheme 7).
Toward this end, the cyclic carbamate in 21 was converted to
ethyl carbonate 25 by the action of EtOH.23 Reaction of 25
with TsCl, DMAP, and Et3N in CH2Cl2 induced the
pyrrolidine ring formation to provide tricyclic STX core 26
in 57% yield over two steps. Deprotection of the protecting
groups in 26 in three steps cleanly gave (+)-dc-β-saxitoxinol
(2) in 67% yield from 26. The spectral data (1H and 13C
NMR) as well as the [α]D value of synthetic 2 were in good
accordance with those reported by the Du Bois group.5b We
then turned our attention to the synthesis of STX (1). The
BOM group in 26 was removed by hydrogenolysis to give a
primary alcohol, which was treated with trichloroacetyl
with TsCl successfully constructed the pyrrolidine ring, and
subsequent basic ethanolysis of the cyclic carbamate afforded
tricyclic compound 28 in 82% yield. Removal of the protecting
groups provided the unnatural skeletal isomer of STX, (−)-iso-
dc-saxitoxinol (3), in 66% yield. The NMR experiments of 3
supported the assigned structure (see the Supporting
Information).
In summary, we have achieved the synthesis of (+)-STX (1)
and (+)-dc-β-saxitoxinol (2) employing the sequential Over-
man rearrangement and the intramolecular aminal formation of
an acyclic bis-guanidine as the key transformations. Utilizing
the synthetic intermediate 21, the unnatural skeletal isomer,
(−)-iso-dc-saxitoxinol (3), was also synthesized. This work
C
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In Strategies and Tactics in Organic Synthesis; Lindberg, T., Ed.;
Academic Press: New York, 1989, Vol. 2, pp 191−219.
demonstrated that the sequential Overman rearrangement is a
powerful tool for the stereoselective one-step construction of a
diamino moiety in complex natural products. The intra-
molecular aminal formation approach to the bicyclic guanidine
structure allowed us to prepare not only STX but also a skeletal
isomer of STX. Synthesis of iso-saxitoxin derivatives and their
biological assessment are underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03281.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
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Ghazarossian, V. E.; Schantz, E. J.; Schnoes, H. K.; Strong, F. M.
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AUTHOR INFORMATION
Corresponding Author
■
Noritaka Chida − Department of Applied Chemistry, Faculty of
Science and Technology, Keio University, Yokohama 223-8522,
Japan; orcid.org/0000-0003-3074-6914; Email: chida@
applc.keio.ac.jp
Authors
Yuya Okuyama − Department of Applied Chemistry, Faculty of
Science and Technology, Keio University, Yokohama 223-8522,
Japan
Ryosuke Okamoto − Department of Applied Chemistry, Faculty
of Science and Technology, Keio University, Yokohama 223-
8522, Japan
Shori Mukai − Department of Applied Chemistry, Faculty of
Science and Technology, Keio University, Yokohama 223-8522,
Japan
Kyoko Kinoshita − Department of Applied Chemistry, Faculty
of Science and Technology, Keio University, Yokohama 223-
8522, Japan
(7) Arakawa, O.; Nishio, S.; Noguchi, T.; Shida, Y.; Onoue, Y.
Toxicon 1995, 33, 1577−1584.
(8) Yotsu-Yamashita, M.; Kim, Y.-H.; Dudley, S. C.; Choudhary, G.;
Pfahnl, A.; Oshima, Y.; Daly, J. W. Proc. Natl. Acad. Sci. U. S. A. 2004,
101, 4346−4351.
Takaaki Sato − Department of Applied Chemistry, Faculty of
Science and Technology, Keio University, Yokohama 223-8522,
Japan; orcid.org/0000-0001-5769-3408
(9) For synthesis and synthetic study of C-11-alkylated STX
derivatives, see: (a) Nishikawa, T.; Wang, C.; Akimoto, T.; Koshino,
H.; Nagasawa, K. Asian J. Org. Chem. 2014, 3, 1308−1311. (b) Wang,
C.; Oki, M.; Nishikawa, T.; Harada, D.; Yotsu-Yamashita, M.;
Nagasawa, K. Angew. Chem., Int. Ed. 2016, 55, 11600−11603.
(c) Walker, J. R.; Merit, J. E.; Thomas-Tran, R.; Tang, D. T. Y.; Du
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R.; James, C. K.; Looper, R. E. Org. Lett. 2019, 21, 7999−8002.
(e) Adachi, K.; Yamada, T.; Ishizuka, H.; Oki, M.; Tsunogae, S.;
Shimada, N.; Chiba, O.; Orihara, T.; Hidaka, M.; Hirokawa, T.;
Odagi, M.; Konoki, K.; Yotsu-Yamashita, M.; Nagasawa, K. Chem. -
Eur. J. 2020, 26, 2025−2033.
(10) (a) Momose, T.; Hama, N.; Higashino, C.; Sato, H.; Chida, N.
Tetrahedron Lett. 2008, 49, 1376−1379. (b) Hama, N.; Matsuda, T.;
Sato, T.; Chida, N. Org. Lett. 2009, 11, 2687−2690. (c) Kitamoto, K.;
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Eur. J. Org. Chem. 2012, 2012, 4217−4231. (d) Nakayama, Y.; Sekiya,
R.; Oishi, H.; Hama, N.; Yamazaki, M.; Sato, T.; Chida, N. Chem. -
Eur. J. 2013, 19, 12052−12058.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03281
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by a JSPS Research Fellowships
for Young Scientists to Y.O. (19J12788).
■
REFERENCES
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(19) Conventional benzoylation of 15 (BzCl, Et3N, and DMAP)
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35% and 56% yields, respectively (see the Supporting Information).
(20) Prolonged hydrogenolysis of 6 (8 h) resulted in the formation
of unidentified byproducts, and the yield of 18 and 19 was not
improved (28%, 19:18 = ca. 2.7:1). Due to the low recovery (17%) of
the starting material 6, the brsm yield of 19 and 18 dropped
significantly (34%). Use of other catalysts such as Lindlar cat., Pd/
C(en), and Rh/C did not improve the results (see the Supporting
Information).
(21) Use of other organic bases such as Et3N, TMG (1,1,3,3-
tetramethylguanidine), and DBN (1,5-diazabicyclo[4.3.0]non-5-ene)
gave no desired bicyclic aminal 20 (see the Supporting Information).
Attempted acid-promoted cyclization of 6 by the removal of N-Boc
groups with TFA−CH2Cl2 resulted in the formation of a complex
mixture, and the corresponding bicyclic aminal was not obtained.
(22) Analyses of aliquots of the reaction mixture by NMR and ESI-
MS revealed that six-membered hemiaminal 18 gradually changed to a
cyclic enamine. We assume that the decomposition of 18 would be
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formation had been reported by Pearson and Williams (see ref 5i).
(23) The addition of base such as i-Pr2NEt caused the migration of
the ethoxycarbonyl group to give a primary carbonate.
E
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