Novel assembly of cyclic ethers by coupling alpha-chlorosulfides and alcohols.

Article abstract of DOI:10.1021/ol026529d

A novel protocol for assembling polycyclic ethers was developed and successfully applied to the synthesis of the EFGH ring system of ciguatoxin CTX3C. A key transformation involves construction of an O,S-acetal through coupling of alpha-chlorosulfide and

Full text of DOI:10.1021/ol026529d

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3439-3442
Novel Assembly of Cyclic Ethers by
Coupling r-Chlorosulfides and Alcohols
Masayuki Inoue, Guang Xing Wang, Jin Wang, and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, and
CREST, Japan Science and Technology Corporation (JST), Sendai 980-8578, Japan
hirama@ykbsc.chem.tohoku.ac.jp
Received July 16, 2002
ABSTRACT
A novel protocol for assembling polycyclic ethers was developed and successfully applied to the synthesis of the EFGH ring system of
ciguatoxin CTX3C. A key transformation involves construction of an O,S-acetal through coupling of r-chlorosulfide and a secondary alcohol
under mild conditions. The method is highly applicable to use with sensitive substrates and will enable the synthesis of various natural and
artificial polycyclic ethers.
Recently, many ladder-shaped polyethers have been isolated
from marine sources and their structures determined by
extensive modern spectroscopic techniques using minute
amounts of the materials.1 Their most notable structural
feature lies in their long semirigid architectures comprising
trans/syn-fused ether rings of various sizes. Ciguatoxins
(CTXs),2 a representative collection of ladder-shaped poly-
ethers, have received much attention among chemists and
biologists, as such polyethers have been found to cause
widespread seafood poisoning known as ciguatera3 and bind
to the voltage-gated sodium channel at picomolar concentra-
tions.4 To supply ciguatoxins for further studies, we launched
a project into their total synthesis over 10 years ago5,6 and
very recently achieved the synthesis of ciguatoxin CTX3C
(1, Figure 1).7
(4) (a) Lombet, A.; Bidard, J.-N.; Lazdunski, M. FEBS Lett. 1987, 219,
355. (b) Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand, A.-M. Toxicon
1999, 37, 125.
(5) For recent synthetic studies from our laboratory, see: (a) Oguri, H.;
Sasaki, S.-y.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405. (b)
Oguri, H.; Tanaka, S.-i.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2000, 41,
975. (c) Oishi, T.; Tanaka, S.-i.; Ogasawara, Y.; Maeda, K.; Oguri, H.;
Hirama, M. Synlett 2001, 952. (d) Imai, H.; Uehara, H.; Inoue, M.; Oguri,
H.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2001, 42, 6219. (e) Maruyama,
M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara, Y.; Shindo, Y.; Hirama,
M. Tetrahedron 2002, 58, 1835. (f) Uehara, H.; Oishi, T.; Inoue, M.; Shoji,
M.; Nagumo, Y.; Kosaka, M.; Le Brazidec, J.-Y.; Hirama, M. Tetrahedron
2002, 58, 6493.
(1) For recent reviews, see: (a) Yasumoto, T.; Murata, M. Chem. ReV.
1993, 93, 1897. (b) Shimizu, Y. Chem. ReV. 1993, 93, 1685. (c) Murata,
M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293. (d) Yasumoto, T. Chem.
Rec. 2001, 1, 228.
(2) (a) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T.J. Am.
Chem. Soc. 1989, 111, 8929. (b) Murata, M.; Legrand, A.-M.; Ishibashi,
Y.; Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380. (c) Satake,
M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto,
T. J. Am. Chem. Soc. 1997, 119, 11325. (d) Satake, M.; Murata, M.;
Yasumoto, T. Tetrahedron Lett. 1993, 34, 1975. (e) Lewis, R. J.; Vernoux,
J.-P.; Brereton, I. M. J. Am. Chem. Soc. 1998, 120, 5914. (f) Yasumoto,
T.; Igarashi, T.; Legrand, A.-M.; Cruchet, P.; Chinain, M.; Fujita, T.; Naoki,
H. J. Am. Chem. Soc. 2000, 122, 4988.
(6) For recent synthetic studies of ciguatoxins from other groups, see:
(a) Takakura, H.; Noguchi, K.; Sasaki, M.; Tachibana, K. Angew. Chem.,
Int. Ed. 2001, 40, 1090. (b) Sasaki, M.; Ishikawa, M.; Fuwa, H.; Tachibana,
K. Tetrahedron 2002, 58, 1889. (c) Takakura, H.; Sasaki, M.; Honda, S.;
Tachibana, K. Org. Lett. 2002, 4, 2771. (d) Fujiwara, K.; Tanaka, H.; Murai,
A. Chem. Lett. 2000, 610. (e) Fujiwara, K.; Takaoka, D.; Kusumi, K.; Kawai,
K.; Murai, A. Synlett 2001, 691. (f) Kira, K.; Isobe, M. Tetrahedron Lett.
2000, 41, 5951. (g) Kira, K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821.
(h) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183. (i) Eriksson, L.; Guy, S.;
Perlmutter, P. J. Org. Chem. 1999, 64, 8396. (j) Leeuwenburgh, M. A.;
Kulker, C.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H. Synlett
1999, 1945. (k) Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39,
372 and references therein.
(3) For reviews, see: (a) Scheuer, P. J. Tetrahedron 1994, 50, 3. (b)
Lewis, R. J. Toxicon 2001, 39, 97.
(7) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri,
H.; Satake, M. Science 2001, 294, 1904.
10.1021/ol026529d CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/06/2002

Table 1. Construction of O,S-Acetal from R-Chlorosulfide
Our synthesis relied on the highly convergent strategy of
assembling simple cyclic ethers. The final stage involved
coupling between the A-E ring5e and the H-M ring
systems5f with subsequent construction of the central FG ring
system (Figure 1).5d,7,8 This strategy is applicable to all
mediated O,S-acetal formation (4 f 5); (iii) radical cycliza-
tion to the seven-membered ring (5 f 6);10-12 and (iv) ring-
Scheme 1. Schematic Presentation of Previous and New
Coupling Methods
Figure 1. Structure of ciguatoxin CTX3C (1).
ciguatoxins, because they all have the FG ring structure in
common.2 To combine the fragments,5d,7,8 four key trans-
formations were used, which are shown schematically in
Scheme 1: (i) coupling of the right and left fragments by
acetalization using Sc(OTf)3 (2 + 3 f 4);9 (ii) Lewis acid-
(8) (a) Sasaki, M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett. 1999,
40, 1337; (b) J. Org. Chem. 2002, 67, 3301.
(9) (a) Fukuzawa, S.-i.; Tsuchimoto, T.; Hotaka, T.; Hiyama, T. Synlett
1995, 1077. (b) Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett
1996, 839. (c) Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem. 1999,
64, 9416.
3440
Org. Lett., Vol. 4, No. 20, 2002

Scheme 2a
Scheme 3a
a Reaction conditions: (a) TBAF, THF, rt; (b) methyl propiolate,
4-methylmorpholine, CH2Cl2, 82% (two steps); (c) n-Bu3SnH,
AIBN, toluene, 80 °C, 92%.
closing olefin metathesis reaction (RCM)13 to build the nine-
membered ring (6 f 7). Although this sequence was
successfully applied to the total synthesis of CTX3C, the
Lewis acid nature of the first two reactions (i and ii) restricts
the protective group strategy, and potentially causes problems
in synthesizing CTX congeners as well as other natural and
artificial polyethers. We therefore decided to develop a new
route to O,S-acetal, without the need for strongly acidic
conditions, which would further expand the applicability of
the strategy to multisensitive functionalities. Here we report
a mild method of constructing O,S-acetals, the syntheses of
model compounds, and the EFGH ring system of CTX3C
itself.
Our alternative synthetic strategy relied on the direct
construction of the O,S-acetal 5 by coupling secondary
alcohol 8 and R-halosulfide 9 (Scheme 1). This type of
reaction was developed by Mukaiyama et al.14 and recently
further explored by the Hindsgaul group15 in the context of
their syntheses of oligosaccharides. The obtained 5 would
be readily subjected to the radical cyclization to form the
seven-membered ring (5 f 6). One important aspect of the
strategy is that the stereoselective synthesis of the O,S-acetal
a Reaction conditions: (a) DIBAL, CH2Cl2, -78 °C, 100%; (b)
CH3PPh3Br, NaN(SiMe3)2, THF, from 0 °C to rt, 95%; (c) (PhS)2,
n-Bu3P, pyridine, rt, 100%; (d) NCS, CCl4, rt; (e) 18 (2.5 equiv),
AgOTf (1.5 equiv), 2,6-di-tert-butyl-4-methylpyridine (2.0 equiv),
CH2Cl2, from -50 °C to -30 °C, 70% from 20, 96% recovery of
18; (f) TBAF, THF, rt, 87%; (g) methyl propiolate, 4-methylmor-
pholine, CH2Cl2, 100%; (h) n-Bu3SnH, AIBN, toluene, 80 °C, 82%
(25:26 ) 2.1:1); (i) DIBAL, CH2Cl2, -90 °C; (j) CH3PPh3Br,
NaN(SiMe3)2, THF, from 0 °C to rt, 54% from a mixture of 25
and 26 (two steps); (k) (PCy3)2Cl2RudCHPh (30 mol %), CH2Cl2
(0.01 M), reflux, 3 h, 100%.
(10) Sasaki, M.; Inoue, M.; Noguchi, T.; Takeichi, A.; Tachibana, K.
Tetrahedron Lett. 1998, 39, 2783.
(11) Radical reaction using â-alkoxyacrylate to build oxacycle was
developed by Lee et al. (a) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M.
Tetrahedron Lett. 1993, 34, 4831. For recent applications to total syntheses
from his laboratory, see: (b) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-
S.; Jung, C.-K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124, 384. (c) Lee, E.;
Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min, S. J.; Son, S. H.; Lim,
S. M.; Jang, W. S. Angew. Chem., Int. Ed. 2002, 41, 176. (d) Lee, E.; Jeong,
E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K. J. Am. Chem. Soc. 2001, 123,
10131.
(12) For earlier examples of radical cyclization using O,S-acetal, see:
(a) Burke, S. D.; Rancourt, J. J. Am. Chem. Soc. 1991, 113, 2335. (b)
Lolkema, L. D. M.; Hiemstra, H.; Ghouch, A. A. Al.; Speckamp, W. N.
Tetrahedron Lett. 1991, 32, 1491.
(13) For recent reviews of RCM, see: (a) Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013.
(14) Mukaiyama, T.; Sugaya, T.; Marui, S.; Nakatsuka, T. Chem. Lett.
1982, 1555.
of 5 is not necessary, because the stereochemical information
of the radical precursor is usually lost upon formation of
the radical. Halophilic activators such as the silver cation
for the coupling are highly chemoselective and nonacidic,
allowing the use of a wide variety of protective groups in a
multifunctional system. There are also fewer synthetic steps
from the coupling reaction than in the previous method
because it is not necessary to proceed via O,O-acetal 4.
First, we applied the coupling sequence to model com-
pounds with hydroxyl groups masked by various protective
groups (Table 1). The substrates used here (10, 11) were
prepared from 2-deoxy-D-ribose via standard synthetic
manipulations.16 The sulfide 11 was treated with N-chloro-
succinimide in CCl4 to install chloride under neutral condi-
(15) (a) McAuliffe, J. C.; Hindsgaul, O. J. Org. Chem. 1997, 62, 1234.
(b) McAuliffe, J. C.; Hindsgaul, O. Synlett 1998, 307.
Org. Lett., Vol. 4, No. 20, 2002
3441

tions,14,17 and the obtained R-chlorosulfide 12 was activated
by silver triflate, in the presence of 2,6-di-tert-butyl-4-
methylpyridine as a buffer, to give the desired O,S-acetal
13 in good yield.15b The thioalkyl group of 13, which could
be potentially activated by silver salt, was stable under the
coupling conditions. While acid-sensitive acetal-type protec-
tive groups were not usable with the previous strategy,
ethoxyethyl (EE), p-methoxyphenyl (MP) acetal (13a), and
acetonide (13b) are compatible with the present reaction
conditions, clearly demonstrating the advantage of this
method.
To test seven-membered ring formation, compound 13a
was chosen for further synthetic transformations (Scheme
2). First, the TBS ether 13a was converted to â-alkoxyacry-
late 15 via a two step sequence: (i) TBAF, THF; (ii) methyl
propiolate, 4-methylmorpholine, CH2Cl2.11a Treatment of 15
(a 2:1 mixture of diastereomers) with n-Bu3SnH in the
presence of AIBN at 80 °C gave the seven-membered ring
as a single diastereomer in 92% yield.10 Thus, as expected,
the chirality of the acetal carbon is indifferent to the
stereoselectivity of the radical cyclization. Since construction
of a medium-sized ring by RCM of an O-linked oxacycle
such as 16 is well established,5,7,8,18,19 this synthesis is readily
applicable to the synthesis of 6-x-7-6 ring systems.
Having successfully developed a novel strategy for form-
ing O,S-acetals, we turned our attention to the synthesis of
the EFGH ring system as a model study of the total syntheses
of ciguatoxins (Scheme 3). The E-ring 175d and the H-ring
195d,8 were prepared using the previously published proce-
dures. Nitrile 17 was converted to the E-ring olefin 18 via
DIBAL reduction and subsequent Wittig olefination (95%
yield). The phenylthio group was introduced to 19 using
(PhS)2 and Bu3P in pyridine to afford 20 in quantitative
yield.20 Treatment of 20 with NCS in CCl4 led to the
R-chlorosulfide 21, and then the crude 21 was immediately
coupled with 2.5 equiv of 18 by silver triflate to give the
O,S-acetal 22 in 70% yield as a single diastereomer. The
TIPS group of 22 was removed with TBAF to give the
secondary alcohol 23, which was converted to the â-alkoxy-
acrylate 24 using methyl propiolate and 4-methylmorpholine
in 87% yield.11a Subjecting 24 to the radical cyclization
allowed the G ring to be constructed stereoselectively to
afford 25 as an inseparable mixture with 26 arising from
the 6-exo cyclization to the terminal olefin (25:26 ) 2.1:1,
82% yield). DIBAL reduction of the mixture, followed by
methylenation, gave pure diene 28 in 54% yield for the two
steps. Finally, RCM of 28 using Grubbs catalyst21 formed
the nine-membered F ring to afford quantitatively the EFGH
ring system 29. Although the regioselectivity of the radical
cyclization (24 f 25) should be optimized, the transforma-
tions from the coupling reaction require only 8 steps
(previously 12 steps were required).5d
A novel coupling protocol for rapidly constructing poly-
cyclic ethers was developed, and we have demonstrated the
application of this method to the EFGH structural fragment
of CTX3C. The neutral nature and high chemoselectivity of
the coupling protocol will enable the synthesis of a wide
variety of substrates having acid-sensitive functionality.
Further studies toward the synthesis of ciguatoxins and
artificial polyether compounds with biological importance
are currently underway in our laboratory.
Acknowledgment. This work was financially supported
in part by a grant from Takeda Science Foundation to M.I.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Preparation of 11a-c will be described in a full account. A similar
compound has previously been prepared from 2-deoxy-D-ribose; see: Fuwa,
H.; Sasaki, M.; Tachibana, K. Tetrahedron 2001, 57, 3019.
(17) For a review on R-chlorosulfides, see: Dilworth, B. M.; McKervey,
M. A. Tetrahedron 1986, 42, 3731.
OL026529D
(18) Oishi, T.; Nagumo, Y.; Hirama, M. Chem. Commun. 1998, 1041.
(19) Very recently, Kadota and Yamamoto et al. have reported the
convergent synthesis of polycyclic ethers via the intramolecular allylation
of R-acetoxy ethers and subsequent RCM. (a) Kadota, I.; Ohno, A.; Matsuda,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 6702. (b) Kadota, I.; Ohno,
A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 3562.
(20) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 17, 1409.
(21) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856. (b) Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9858. (c) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
3442
Org. Lett., Vol. 4, No. 20, 2002