Total synthesis of gambierol

Article abstract of DOI:10.1021/ol9017408

The total synthesis of gambierol has been achieved utilizing an oxiranyl anion strategy in an iterative manner. Synthetic highlights of this route include direct carbon-carbon formation on epoxides, sulfonyl-assisted 6-endo cyclization, and expansion reac

Full text of DOI:10.1021/ol9017408

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4382-4385
Total Synthesis of Gambierol
Hiroki Furuta, Yuki Hasegawa, and Yuji Mori*
Faculty of Pharmacy, Meijo UniVersity, 150 Yagotoyama,
Tempaku, Nagoya 468-8503, Japan
mori@ccmfs.meijo-u.ac.jp
Received July 29, 2009
ABSTRACT
The total synthesis of gambierol has been achieved utilizing an oxiranyl anion strategy in an iterative manner. Synthetic highlights of this
route include direct carbon-carbon formation on epoxides, sulfonyl-assisted 6-endo cyclization, and expansion reaction of tetrahydropyranyl
rings to oxepanes to forge the polycyclic architecture of the target molecule.
Gambierol (1) was isolated as a neurotoxin from the cultured
cells of the ciguatera causative dinoflagellate Gambierdiscus
toxicus in 19931 and classified as a member of the polycyclic
ether family of marine toxins.2 The toxin exhibits potent
toxicity against mice at LD50 50 µg/kg (ip), and its symptoms
occurring in mice resemble those shown for ciguatoxins,
indicating that gambierol is also responsible for ciguatera
seafood poisoning. The ability of gambierol to inhibit the
binding of dihydrobrevetoxin B to voltage-gated sodium
channels3 has also attracted attention, leading to structure-
activity relationship (SAR) studies4 and evaluation of its
molecular target on the voltage-gated potassium channels.5
The structure consists of a ladder-shaped trans-fused octacyclic
ring system that includes 18 stereogenic centers and a partially
conjugated triene side chain, including a conjugated (Z,Z)-diene
system. The complex architecture and the need for biological active
analogues for SAR study continue to interest organic chemists,
and three total syntheses have been reported,6 as well as related
methodology studies.7 We were motivated to construct gambierol
by a different strategy through the implementation of our own
methods. We describe herein a new approach to the total synthesis
of gambierol (1).
(1) (a) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993,
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Our approach includes the reaction of sulfonyl-stabilized oxiranyl
anions,8 which enables direct and efficient carbon-carbon bond
formation on an oxirane ring,9 sulfonyl-assisted 6-endo cycliza-
tion,10 and a ring-expansion reaction with trimethylsilyldiazo-
methane.11 We envisioned that two seven-membered rings in 2
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E.; Yanagihara, A.; Rainier, J. D.; Tytgat, J. Biochem. Biophys. Res.
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2005, 127, 848–849. (f) Majumder, U.; Cox, J. M.; Johnson, H. W. B.;
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10.1021/ol9017408 CCC: $40.75
Published on Web 09/04/2009
 2009 American Chemical Society

would be constructed by an expansion reaction of tetrahydropyranyl
rings at suitable stages of synthesis (Scheme 1), so we tentatively
Scheme 2. Preparation of Hexacyclic Triflate 15
Scheme 1. Retrosynthetic Analysis of Gambierol (1)
regarded 3 as an imaginary precursor and dissected it at the
indicated bonds, furnishing the ABCD ring diol 4 and epoxy
sulfones 6 and 7 as potential building blocks.
Synthesis of the E ring started from the coupling reaction of the
oxiranyllithium generated from epoxy sulfone 612 with the ABCD
ring triflate 5 prepared from diol 413 in a one-pot procedure
(Scheme 2). Treatment of a mixture of 5 and 6 with n-BuLi in
THF-HMPA at -100 °C afforded 8 in 83% yield after desily-
lation. A sulfonyl-assisted 6-endo cyclization10b was effected by
BF3·OEt2 to quantitatively provide ketone 9. The ketone was then
subjected to a ring-expansion reaction with trimethylsilyldiazo-
methane in the presence of BF3·OEt2 to furnish the desired oxepane
10 in 51% overall yield after desilylation of the resulting R-trim-
ethylsilyl ketone with TBAF. Reduction of ketone 10 with NaBH4
and dehydrobromination with TBAF in DMF14 gave a terminal
acetylene. Hydration of the acetylene with a catalytic amount of
Hg(OTf)215 followed by a hetero-Michael reaction with methyl
propiolate provided keto acrylate 11. Treatment of 11 with SmI2
in the presence of methanol effected ketyl radical cyclization16 to
afford, after silylation, hexacyclic ester 12 in 92% yield as a single
diastereoisomer with sterically congested 1,3-diaxial dimethyl
groups. The ester was then reduced with DIBALH to furnish an
alcohol, which was converted to olefin 13 via o-nitrophenyl
selenide17 in 82% overall yield. Subsequent oxidative cleavage of
the double bond followed by reduction of the resulting aldehyde
provided the ABCDEF ring diol 14, which was transformed into
triflate 15 in 93% overall yield for the five steps.
Installation of the G and H rings was based on the use of
an oxiranyl anion strategy carried out in an iterative manner,
which involved the reactions of epoxy sulfone 711 and
triflates 15 and 19 (Scheme 3). Thus, lithiation of 7 with
n-BuLi at -100 °C in the presence of triflate 15 furnished
epoxy sulfone 16 in 93% yield. Exposure of 16 to BF3·OEt2
caused 6-endo cyclization, which formed the G ring ketone
17 in 91% yield. Stereoselective reduction of the ketone and
removal of the TBDPS group afforded diol 18, which was
then subjected to one-pot triflation and silylation to furnish
(8) For reviews on oxiranyl anions, see: (a) Satoh, T. Chem. ReV. 1996,
96, 3303–3325. (b) Mori, Y. In ReViews on Heteroatom Chemistry; Oae,
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Gras, E. Synthesis 2002, 1625–1642.
(9) (a) Ashwell, M.; Clegg, W.; Jackson, R. F. W. J. Chem. Soc. Perkin
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118, 8158–8159. (b) Furuta, H.; Takase, T.; Hayashi, H.; Noyori, R.; Mori,
Y. Tetrahedron 2003, 59, 9767–9777.
(11) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron 1997, 53,
12917–12932.
(12) Prepared from 4-bromopent-4-en-2-one and (R)-(-)-chloromethyl
p-tolyl sulfoxide according to the following: Satoh, T.; Oohara, T.; Ueda,
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4064.
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Scheme 3. Synthesis of Octacyclic Ketone 22
triflate 19 in 91% for the three steps. The second coupling
reaction of 19 with the oxiranyllithium of 7 provided, after
desilylation, epoxy sulfone 20 in 94% yield. The BF3-
promoted cyclization of 20 resulted in the formation of
octacyclic ketone 21 in 83% yield. Conversion of the ketone
to the 7-membered H ring ketone 22 occurred smoothly with
trimethylsilyldiazomethane in the presence of BF3·OEt2. This
ring enlargement was achieved in an excellent 81% yield
(two steps) compared with the case of the E ring formation.
Octacyclic ketone 22 was then elaborated to the desired
unsaturated aldehyde 25 by the sequence depicted in Scheme 4.
Thus, treatment of ketone 22 with LiHMDS in the presence of
TMSCl and Et3N followed by dehydrosilylation of the corre-
sponding enol silyl ether with Pd(OAc)218 provided an enone,
which was subjected to methylation with MeMgBr in toluene6b,d
to afford tertiary alcohol 23 in 91% overall yield as a single
diastereoisomer. The alcohol 23 was converted into the
primary alcohol 24 by a three-step procedure in 93% overall
yield. Oxidation of the alcohol with TPAP provided aldehyde
25 in 93% yield.
Finally, our attention turned to incorporation of the skipped
triene side chain to complete the total synthesis (Scheme 5).
In this context, the Stille coupling reaction utilizing vinyl
iodide 2 and vinyl stannane 27 is a powerful and reliable
Scheme 5. Synthesis of Gambierol
Scheme 4. Synthesis of Aldehyde 25
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Org. Lett., Vol. 11, No. 19, 2009

method, as demonstrated in the previous studies.6 In these
studies, the robust C(1) and C(6) benzyl groups of the TBS
ether analogues of 22 or 23 were replaced by silyl groups
prior to installation of a (Z)-vinyl iodide moiety. However,
if debenzylation in the presence of the vinyl iodide func-
tionality were feasible, a shorter route to reaching 2 would
be made possible. To this end, aldehyde 25 was subjected
to iodomethylenation with Ph3P+CH2I·I- and NaHMDS19 to
afford (Z)-vinyl iodide 26 in 68% yield.20 Debenzylation of
26 was now critical for successful evolution of our route, as
it needed to be executed in the presence of labile (Z)-vinyl
iodide, cyclic allylic ether, and TES ether functionalities.
Upon considerable experimentation, it was found that gentle
heating of 26 with DDQ in the presence of water and diallyl
ether in 1,2-dichloroethane at 50 °C induced debenzylation,21
leading to a 78% yield of the desired triol 2 after removal
of TES ether. Finally, Stille coupling of triol 2 with dienyl
stannane 2722 was carried out by using Kadota and Rainier’s
protocols6c,e to provide gambierol (1) in 68% yield. The
spectroscopic and physical data for synthetic gambierol were
identical to those reported previously.1,6
oxiranyl anion coupling strategy to other marine polycyclic
ethers is in progress.
Acknowledgment. This research was supported by Grant-
in-Aids for Scientific Research on Priority Areas (18032079)
and for Scientific Research (C) (21590029) from The
Ministry of Education, Culture, Sports, Science, and Tech-
nology. We thank Professors M. Sasaki (Tohoku University)
and I. Kadota (Okayama University) for providing the NMR
spectra of gambierol.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL9017408
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1485–1486.
In conclusion, total synthesis of gambierol has been
achieved utilizing an oxiranyl anion strategy in an iterative
manner. The salient features of the route include: (1) direct
carbon-carbon bond formation on an oxirane ring and the
subsequent sulfonyl-assisted 6-endo cyclization; (2) a ring-
expansion approach to seven-membered ether rings; (3) a
successful implementation of debenzylation in the presence
of labile functional groups. Further application of this
(18) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
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J. E.; Lee, V. Tetrahedron 2003, 59, 1719–1729.
(20) Although the (E)-isomer was not obtained in this reaction, the
C(31)-C(32) unsaturated iodide was isolated in 27% yield.
(21) Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941–
2945.
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