A synthesis of (+)-saxitoxin

Article abstract of DOI:10.1021/ja0608545

An asymmetric synthesis of the bis-guanidinium poison, (+)-saxitoxin (STX), is described. Commencing from an N,O-acetal starting material made readily available through sulfamate ester C-H amination, the completed route to STX showcases the utility of oxa

Full text of DOI:10.1021/ja0608545

Published on Web 03/03/2006
A Synthesis of (+)-Saxitoxin
James J. Fleming and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received February 5, 2006; E-mail: jdubois@stanford.edu
The unassuming molecular dimensions of the poison most
notably associated with oceanic red tides, (+)-saxitoxin (STX), belie
its complexity as a target for chemical synthesis and its acute
toxicity as a paralytic agent (Figure 1).1 The structure, a tricyclic
skeleton uniquely adorned with nitrogen and oxygen heteroatoms,
has contested those interested in its de novo assembly as well as
its isolation and characterization.2,3 Nevertheless, two formidable
efforts describe salient paths for preparing this compound.4,5 Our
own interest in STX followed for two reasons: (1) as a vehicle by
which to advance new strategies for crafting polar, nitrogen-rich
functional groups in the most demanding circumstances; (2) as a
blueprint for the design of pharmacological tools that could help
elucidate pathways for electrical conduction in excitable cells. The
lethality of STX derives from its ability to block selectively cation
influx through voltage-dependent Na+ ion channels.6 Although its
action has been known and exploited for some time, the molecular
details of STX lodged in the channel pore remain ambiguous and
subject to debate.7 Such knowledge, however, could empower the
development of new small molecules for the manipulation and study
of ion channel function. As such, a synthesis of STX was undertaken
with the goal of forwarding chemical methodologies in a preparative
route that offered sufficient flexibility for modifying the toxin’s
design.
An initial examination of STX reveals that both C4 and C12
centers reside formally at the ketone oxidation level (Figure 1). At
physiological pH, the equilibrium between the C12-ketone and its
hydrated form strongly favors the latter.8 Retrosynthetic discon-
nection of the adjacent spiro-aminal junction posits a cyclodehy-
dration reaction in which both guanidines are condensed onto a
ketone at C4.9 In principle, the stereochemical configuration of the
attendant C5 and C6 centers would predispose formation of the
requisite C4 epimer. To further enable this plan, one of the two
guanidines would be incorporated within a nine-membered ring 1.
Although almost no precedent for the assembly of medium-sized
guanidine rings is available, we anticipated that pseudothiourea 2
could be condensed with a 1° amine at C6, possibly through the
intermediacy of a reactive carbodiimide. The overarching strategy
to assemble STX thus reduces a complicated problem in cyclic
stereocontrolled synthesis to the seemingly more manageable task
of constructing an acyclic core 2.
Figure 1. Deconstructing (+)-saxitoxin to a problem of acyclic stereo-
controlled synthesis: the oxathiazinane strategy.
be activated for ring opening at an appropriate stage. Accordingly,
the N,O-acetal strategy offers a general approach to multiply
substituted amine derivatives that transcends its usefulness for the
construction of STX.
The preparation of the desired nine-membered ring guanidine 1
follows from oxathiazinane 4 through a series of straightforward
functional group transformations (Scheme 1). Notable steps in this
sequence include the assembly of pseudothiourea 6 using MeS-
(Cl)CdNMbs, a reagent specifically formulated for this work.12 In
addition, sequential reaction of oxathiazinane 6 with Cl2CdNMbs
and (Me3Si)2NH installs the first of two guanidines while serving
to activate the heterocyclic ring for subsequent hydrolytic open-
ing.13,14 Collectively, the conversion of 4 to 8 covers 11 steps and
provides a stereodefined acyclic intermediate bearing all of the
required components for assembling the tricyclic framework of
STX.
With very little precedent guiding our efforts to form the
medium-sized ring guanidine, a number of reaction conditions were
explored.15 The most successful of those tested afforded a 65%
yield (two steps) of the needed product 9. In the devised protocol,
reduction of azide 8 with Me3P was followed by immediate
exposure of this compound to AgNO3/Et3N.12 The latter conditions
presumably trigger formation of a reactive N-sulfonylcarbodiimide,
which in turn is intercepted by the pendant C6-amine. In the product
heterocycle 9, the highly polar nature of the two guanidine moieties
is nicely masked by Mbs protection; functionalization of the C13-
alcohol in 9 as the obligatory 1° carbamate is therefore easily
conducted (Cl3CC(O)NCO).16
The assembly of stereodefined, polyfunctionalized amines as
exemplified by 2 provides a unique opportunity to challenge our
current methods for catalytic C-H amination. In wanting to access
such complex intermediates, we have devised a strategy that
capitalizes on a novel class of N,O-acetal heterocycles made readily
available through Rh-catalyzed sulfamate ester C-H insertion.10
The particular N,O-acetal 3 needed for the STX synthesis is easily
prepared on multigram scale from commercial (R)-glycerol ac-
etonide.11 Lewis acid-promoted addition of a zinc-acetylide to 3
afforded oxathiazinane dioxide 4 (R ) CH2OTs) as a single
diastereomer. The advantage of this heterocycle is both as a masking
group of the basic amine and as a latent electrophile, which may
Difficulties encountered in the synthesis of 9 would prove, by
comparison, less perilous than those confronted in the oxidation of
10. The availability of select methods for effecting four-electron
alkene ketohydroxylation led us to consider such a transformation;17
tautomeric control of the R-ketol isomer, however, loomed as a
conspicuous uncertainty in this plan. In fact, reactions performed
t
with the known combination of OsO4 and BuOOH gave only the
undesired bicyclic structure 13 (Figure 2).17c Fortunately, continued
9
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J. AM. CHEM. SOC. 2006, 128, 3926-3927
10.1021/ja0608545 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 a
a Conditions: (a) H2, Pd/CaCO3/Pb, THF; (b) NaN3, nBu4NI, DMF, 90% (2 steps); (c) p-MeOC6H4CH2Cl, nBu4NI, K2CO3, CH3CN, 85%; (d) Me3P,
i
THF/H2O; (e) MeS(Cl)CdNMbs, Pr2NEt, CH3CN, 72% (2 steps); (f) Tf2O, C5H5N, DMAP, CH2Cl2; (g) NaN3, DMF, -15 °C, 70% (2 steps); (h)
t
(NH4)2Ce(NO3)6, BuOH/CH2Cl2, 74%; (i) KOtBu, Cl2CdNMbs; then (Me3Si)2NH, 70% (+20% of 6); (j) aq. CH3CN, 70 °C, 95%; (k) Me3P, THF/H2O;
(l) AgNO3, Et3N, CH3CN, 65% (2 steps); (m) Cl3CC(O)NCO, THF/CH3CN, -78 °C; then K2CO3, MeOH, 82%; (n) 10 mol % of OsCl3, Oxone, Na2CO3,
EtOAc/CH3CN/H2O, 57%; (o) B(O2CCF3)3, CF3CO2H, 82%; (p) DCC, C5H5N‚HO2CCF3, DMSO, 70%. Mbs ) p-MeOC6H4SO2.
Supporting Information Available: Analytical data for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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furnished an IC50 value of 5 nM, consistent with literature re-
ports.1b,7c,21 The completed work, while highlighting several method-
ological inventions, now serves as an entry point for the construction
of unique small molecules able to modify Na+ channel function.
Acknowledgment. The authors wish to thank Brian Andresen and
Justin Litchfield for their helpful contributions. J.J.F. is grateful to
Amgen for graduate fellowships (2002, 2004). This work has been
supported by a grant from the NIH.
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Note Added after ASAP Publication. After this paper published
ASAP, structure 1 in Figure 1 was corrected. The corrected version
was published ASAP on March 3, 2006.
(21) Moran, O.; Picollo, A.; Conti, F. Biophys. J. 2003, 84, 2999-3006.
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