A stereocontrolled synthesis of (+)-saxitoxin

Article abstract of DOI:10.1021/ja2098063

A concise stereoselective total synthesis of (+)-saxitoxin is described. A silver(I)-initiated hydroamination cascade constructs the bicyclic guanidinium ion core from a alkynyl bisguanidine. This sequence creates two C-N bonds, one C-O bond, and three ri

Full text of DOI:10.1021/ja2098063

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A Stereocontrolled Synthesis of (+)-Saxitoxin
Vasudev R. Bhonde and Ryan E. Looper*
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
S Supporting Information
b
ABSTRACT: A concise stereoselective total synthesis of
(+)-saxitoxin is described. A silver(I)-initiated hydroamina-
tion cascade constructs the bicyclic guanidinium ion core
from a alkynyl bisguanidine. This sequence creates two
CÀN bonds, one CÀO bond, and three rings and forms a
single stereoisomer in a single synthetic transformation.
This process enabled us to complete the synthesis of (+)-
saxitoxin in 14 steps from N-Boc-L-serine methyl ester.
nraveling the molecular basis for the toxicity of paralytic
shellfish poisoning agents has proven indispensible in under-
U
standing the complex biology of voltage-gated sodium (Nav)
channels.1 Paralytic shellfish toxins (PSTs) represent a family
of at least 35 different chemical entities and are generally
characterized by the presence of one or more cyclic guanidinium
ion(s).2 The flag bearer for the PSTs is undoubtedly (+)-
saxitoxin (STX), whose significant toxicity has led to its use
not only as an ion channel probe but also as a chemical warfare
agent.3 STX has received a great deal of attention from the
synthetic community concerning the significant challenges asso-
ciated with the chemical synthesis of such a polar, heteroatom-
rich, and densely functionalized natural product. Advances in
synthetic technology to access this natural product architecture
hold promise for the further development of isoform-specific
small-molecule inhibitors of Nav channels with both improved
potency and selectivity toward therapeutically relevant Nav
isoforms.4 With these goals in mind, we engaged the synthesis
of STX.
Figure 1. A strategy for (+)-saxitoxin.
to give B, but we were concerned that the 6-exo-dig process to
give C would be kinetically competitive. It is likely that the
7-endo pathway would be much slower relative to the other three
modes of cyclization. In the event that the 5-exo and 6-exo
pathways are indeed competitive, both B and C should be viable
intermediates for the oxidative cyclization to give A. Although
this might deliver a mixture of epimers at C12, it would be
inconsequential as the oxidation state of C12 would later be
adjusted. Thu, both intermediates should provide the correct
stereochemistry at C4 provided that the oxidative cyclization is
thermodynamically controlled by the stereochemistry at C5.
With this synthetic redundancy in mind, we embraced this
strategy for accessing STX.
As exemplified by Du Bois in his second-generation synthesis
of STX, Merino’s stereoselective addition of acetylides to aldoni-
trones provides a straightforward and readily scalable access to
the requisite propargyldiamine and thus became a natural entry
point for our campaign also (Scheme 1).7b,12 Addition of the
magnesiated homopropargyl benzyl ether to L-serine aldonitrone
(1) gave the desired N-hydroxydiamine 2 in good chemical yield
and diastereoselectivity for the anti isomer (86%, 9:1 d.r.).
Reductive cleavage of the NÀO bond and acidic removal of
both the silyl and carbamate protecting groups gave the diamine
To date, STX has succumbed to synthetic campaigns by
Kishi,5 Jacobi,6 Du Bois,7 and Nagasawa.8 Numerous other
accounts have detailed approaches to related natural products,
including a recent report by Nishikawa exploiting a halonium-
induced propargylguanidine cyclization conceptually related to
that detailed below.4g,9 Our group has been interested in the
metal-catalyzed hydroaminations of propargylguanidines, in par-
ticular from the vantage of controlling the selectivity in these
cyclizations between the 5-exo and 6-endo manifolds.10,11 Armed
with the ability to control these processes, we became interested
in STX as an intriguing skeletal system for further probing of
hydroamination selectivity. As shown in Figure 1, we envisaged
that the pyrrolidine ring of STX could arise from the alkylation of
a pendant electrophile at C10, as in A. In turn, the N3ÀC4 or
N9ÀC4 bonds could be formed by the oxidative cyclization of a
neighboring guanidine on the eneÀguanidine B or C. These
intermediates were ultimately slated to arise from the competi-
tive 5-exo versus 6-exo hydroamination of the alkynyl bisguani-
dine D. From our previous studies, we were confident that
we could control the 5-exo versus 6-endo selectivity using Ag(I)
Received: October 18, 2011
Published: November 18, 2011
r
2011 American Chemical Society
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Scheme 1. Preparation of the Alkynyl bisguanidine
Scheme 3. One-Pot Synthesis of the Key Tricyclic
Carbamate
Scheme 4. Completing the Synthesis of (+)-Saxitoxin
Scheme 2. Stepwise Access to the Key Tricyclic Carbamate
Attempts to trigger 6 oxidatively to form the bicyclic guani-
dine via epoxidation with DMDO or mCPBA proved unsuccess-
ful. This led us to consider the possibility of using an electrophilic
halogen source to trigger the formation of the C4 aminal.
While this would place a halogen at C12 instead of an oxygen
atom, we were hopeful that the resulting halide might be
displaced by an adjacent Boc group, reminiscent of the Wood-
ward dihydroxylation.17 This strategic change would permit
differentiation of the two guanidines needed to successfully
execute the final annulation sequence. To our delight, treatment
of 6 with iodine promoted the cyclization, thus providing the
bicyclic aminal 8 as a single diastereomer. The stereochemistry of
the secondary iodide at C12 was not confirmed but is likely that
arising from iodonium ion formation on the β-face of the alkene.
Treatment of this secondary alkyl iodide with Ag(I) and AcOH
promoted the clean formation of oxazolidinone 9, in which only a
single Boc group had participated.17b,18
We recognized that the tricyclic carbamate 9 arose from
alternating Ag(I)-catalyzed processes (5 f 6 f 8 f 9).
This was conveniently streamlined to a one-pot operation
providing 9 in 57À67% isolated yield (Scheme 3). This success-
fully forged two CÀN bonds, one CÀO bond, and three rings
from an acyclic precursor in a single synthetic manipulation.
To ready this intermediate for the final annulation sequence,
the O- and N-benzyl groups were cleaved by hydrogenolysis, and
the resulting free alcohol was mesylated to give 10 (Scheme 4).
We anticipated that the oxazolidinone could be preferentially
3 as its bishydrochloride salt.13 Fearing yet another competitive
cyclization pathway from an unprotected primary alcohol in our
hydroamination strategy, at this point we installed the primary
carbamate. This was accomplished with potassium cyanate in
concentrated MsOH to give 4 as its free base after workup.14
Mercuric oxide-assisted guanylation with di-Boc-pseudothiourea
cleanly delivered alkynyl bisguanidine 5.
Exposure of 5 to our previously reported Ag(I)-catalyzed
cyclization conditions afforded a single regio- and stereoisomer
of a cyclic eneÀguanidine product (Scheme 2).10b,15 On the
basis of our experience with these compounds, chemical shift and
multiplicity analysis persuaded us to assign the structure of this
product as 6 arising from 5-exo-dig cyclization. More careful
analysis, however, revealed that the protons in the 6-exo-dig
product 7 would occupy identical spin systems and that this
connectivity would likely be indistinguishable through routine
1D or 2D NMR techniques. Particularly troubling was the
3
large J coupling between the methine protons H5 and H6
(3J = 15.6 Hz), which is more indicative of a trans-diaxial
orientation as expected in 7. However, a model compound
lacking the guanidine capable of forming the 6-exo-product
displayed analogous 3J couplings, 1H chemical shifts, and
multiplicities for H5, the vinylic proton (H12), and the two
allylic methylene protons (H11), suggesting that the 5-exo-dig
product 6 is indeed favored.16
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hydrolyzed because of both steric accessibility and its increased
electrophilicity. Treatment of this intermediate with Cs2CO3 in
EtOH cleanly and selectively cleaved the cyclic carbamate with-
out hydrolysis of the tert-butyl or primary carbamates.19 The
release of N1 resulted in the final five-membered-ring annulation
to give 11.
Deprotection of the remaining Boc groups in 11 with 1:1
TFA/CH2Cl2 cleanly gave β-saxitoxinol. Alternatively, oxidation
of the secondary alcohol could be accomplished with DessÀ
Martin periodinane to give the corresponding ketone. This
intermediate proved to be relatively unstable but could be im-
mediately deprotected to give (+)-saxitoxin in 81% yield over the
final two steps.20
This strategy delivered (+)-saxitoxin in 14 steps from com-
mercially available N-Boc-L-serine methyl ester, which is compar-
able to Du Bois’ second-generation synthesis.7b The approach
is highlighted by a regio- and stereoselective one-pot Ag(I)-
catalyzed cyclization cascade that generates two CÀN bonds,
one CÀO bond, and three rings in a single synthetic manipula-
tion. This work is poised to complement that of others in deliver-
ing new small-molecule modulators of ion channel function.
(5) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc.
1977, 99, 2818.
(6) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984,
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(8) Iwamoto, O.; Shinohara, R.; Nagasawa, K. Chem.—Asian. J. 2009,
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(9) Sawayama, Y.; Nishikawa, T. Synlett 2011, 651.
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Takahashi, Y.; Looper, R. E. Angew. Chem., Int. Ed. 2011, 50, 684.
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(a) Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1993, 58, 3235.
(b) Cohen, F.; Overman, L. E.; Sakata, S. K. L. Org. Lett. 1999, 1, 2169.
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(12) (a) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetra-
hedron: Asymmetry 1998, 9, 629. (b) Merino, P.; Franco, S.; Merchan,
F. L.; Tejero, T. J. Org. Chem. 1998, 63, 5627.
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Liebigs Ann. Chem. 1992, 1289.
’ ASSOCIATED CONTENT
(14) Choi, Y.-M.; Kim, M. W. U.S. Pat. Appl. 20050080268A1, 2005.
(15) Ermolatev, D.; Bariwal, J.; Steenackers, H.; De Keersmaecker,
S.; Van der Eycken, E. Angew. Chem., Int. Ed. 2010, 49, 9465.
(16) Model compound 13 was prepared by the AgOAc-catalyzed
cyclization of 12. See the Supporting Information for details and
comparisons of 1H NMR spectra.
S
Supporting Information. Experimental procedures and
b
analytical data for all new compounds, including H and 13C
1
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
r.looper@utah.edu
’ ACKNOWLEDGMENT
(17) (a) Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958,
80, 209–211. (b) Kang, S. H.; Ryu, D. H. Tetrahedron Lett. 1997, 38, 607.
(c) Kobayashi, S.; Isobe, T.; Ohno, M. Tetrahedron Lett. 1984, 25, 5079.
(18) The stereochemistry of the CÀO bond at C12 was not
unambiguously assigned but was inferred by the ultimate conversion
of this intermediate to β-saxitoxinol.
(19) Kunieda, T.; Ishizuka, T. Tetrahedron Lett. 1987, 28, 4185.
(20) Both synthetically prepared saxitoxin and β-saxitoxinol had
physical properties in agreement with those reported for the natural
products (see refs 4a and 7b).
This work is dedicated to the memory of Prof. David Y. Gin.
We are grateful to the National Institutes of Health, National
Institute of General Medical Sciences (R01 GM 090082) for
financial support of this research. We thank Dr. Jim Muller for
help with mass spectral analysis and Prof. Jon Rainier and Prof.
Matt Sigman for insightful discussions.
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