Convergent Synthesis of the E′FGH′ Ring Fragment of Ciguatoxin 1B via an Acetylene Cobalt Complex Strategy

Article abstract of DOI:10.1021/ol0256264

matrix presented A convergent synthesis of the E′FGH′ ring fragment of ciguatoxin has been accomplished through (i) coupling between the E′ ring-acetylide and the H′ ring-aldehyde, (ii) stereoselective F ring cyclization via an acetylene cobalt complex, (

Full text of DOI:10.1021/ol0256264

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1183-1186
Convergent Synthesis of the E′FGH′
Ring Fragment of Ciguatoxin 1B via an
Acetylene Cobalt Complex Strategy
Shigeyuki Takai and Minoru Isobe*
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences,
Nagoya UniVersity, Chikusa, Nagoya 464-8601, Japan
isobem@agr.nagoya-u.ac.jp
Received January 26, 2002
ABSTRACT
A convergent synthesis of the E′FGH′ ring fragment of ciguatoxin has been accomplished through (i) coupling between the E′ ring-acetylide
and the H′ ring-aldehyde, (ii) stereoselective F ring cyclization via an acetylene cobalt complex, (iii) conversion to a carbonyl function, and (iv)
reductive hydroxy-ketone cyclization to construct the G ring.
Ciguatoxin 1B (CTX 1B, 1)1 is one of the most toxic marine
natural products causing seafood poisoning “ciguatera”.
Several synthetic groups2 have been involved in the total
synthesis of CTX due to its remarkable structural complexity,
biological activity, and limited availability from nature.
Recently, Hirama’s group reported the first total synthesis
of CTX-3C,2a a member of the CTX family.1d
During the course of our synthetic studies toward 1,
various methodologies have been developed on the basis of
(i) construction of medium-size (7-10) ether rings via
acetylene cobalt complexes in a highly stereoselective syn-
trans mode,3 (ii) reductive decomplexation reaction into cis-
olefins or vinylsilanes,4 (iii) ring-opening reactions of cyclic
R,â-epoxysilanes into allyl alcohols,5 and (iv) stereoselective
heteroconjugate additions.6 We have already reported the
model syntheses of the ABC,7 BCDE,8 D′EF,9 and HIJK
rings.10
(1) (a) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T. Science
1967, 155, 1267-1268. (b) Murata, M.; Legurand, A. M.; Ishibashi, Y.;
Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-4386. (c)
Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.;
Yasumoto, T. J. Am. Chem. Soc. 1997, 119, 11325-11326. (d) Yasumoto,
T. Chem. Rec. 2001, 1, 228-242.
(2) (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.;
Oguri, H.; Satake, M. Science 2001, 294, 1904-1907. (b) Takakura, H.;
Noguchi, K.; Sasaki, M.; Tachibana, K. Angew. Chem., Int. Ed. 2001, 40,
1090-1093. (c) Fujiwara, K.; Takaoka, D.; Kusumi, K.; Kawai, K.; Murai,
A. Synlett 2001, 691-693. (d) Eriksson, L.; Guy, S.; Perlmutter, P. J. Org.
Chem. 1999, 64, 8396-8398. (e) Leeuwenburgh, M. A.; Kulker, C.;
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J. D. Tetrahedron Lett. 1996, 37, 2869-2872. (g) Soler, M. A.; Palazon, J.
M.; Martin, V. S. Tetrahedron Lett. 1993, 34, 5471-5474 and references
therein.
Scheme 1 exhibits retrosynthetic analysis toward 1, where
the A, F, and G ring cyclization would be achieved at the
last stage from 2 that would be synthesized through a
(3) (a) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett 1994, 11, 916-918. (b)
Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 2509-2520. (c) Isobe, M.;
Hosokawa, S.; Kira, K. Chem. Lett. 1996, 473-474. (d) For a review, see;
Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa, T. Chem. Commun.
1998, 2665-2676.
(4) (a) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609-2612.
(b) Shibuya, S.; Isobe, M. Tetrahedron 1998, 54, 6677-6698.
(5) (a) Kira, K.; Isobe, M. Chem. Lett. 2001, 432-433. (b) Kira, K.;
Hamajima, A.; Isobe, M. Tetrahedron 2002, 58, 1875-1888.
10.1021/ol0256264 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/05/2002

Scheme 1
coupling between acetylide 3 (Segment L) and aldehyde 4
further converted into 11 by Peterson-type olefination13 in
73% yield (Z:E ) 4.9:1). Finally, protective group manipula-
tions afforded E′ ring-enyne 12.
The counter H′ ring-aldehyde as a model of Segment R 4
was synthesized as shown in Scheme 3. 2-Acetoxy-D-glucal
13 was consecutively subjected to C-glycosidation,14 Luche
reduction,15 and protection to give R-acetylene 14, which
was epimerized into more stable â-acetylene 15 via an
acetylene cobalt complex exclusively.16 Elongation of the
C-1 unit by acetylide coupling with formaldehyde gave
propargyl alcohol 16 followed by hydroaluminative trans
(Segment R). On the basis of this analysis, we planned the
synthesis of 5 as a model of the E′FGH′ ring.11 In this paper,
we describe the convergent synthesis of 5, which means not
only a partial synthesis but also a virtual synthesis in the
last stage toward CTX 1.
An E′ ring-enyne as a model of Segment L 3 was
synthesized as shown in Scheme 2. A nitrile group was
Scheme 2a
(6) (a) Isobe, M.; Kitamura, M.; Goto, T. Tetrahedron Lett. 1979, 3465-
3468. (b) Isobe, M.; Funabashi, Y.; Ichikawa, Y.; Mio, S.; Goto, T.
Tetrahedron Lett. 1984, 25, 2021-2024. (c) Isobe, M. New Synthetic
Methods Using Vinyl Sulfones-Developments in Heteroconjugate Addition.
In PerspectiVes in the Organic Chemistry of Sulfur; Zwanenburg, B.,
Klunder, A. J. H., Eds.; Studies in Organic Chemistry; 1987; Vol. 28, pp
209-229.
(7) (a) Hosokawa, S.; Isobe, M. Synlett 1995, 1179-1180. (b) Hosokawa,
S.; Isobe, M. Synlett 1996, 351-352. (c) Hosokawa, S.; Isobe, M. J. Org.
Chem. 1999, 64, 37-48. (d) Saeeng, R.; Isobe, M. Tetrahedron Lett. 1999,
40, 1911-1914. (e) Saeeng, R.; Isobe, M. Heterocycles 2001, 54, 789.
(8) Kira, K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821-2824.
(9) Kira, K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951-5955.
(10) (a) Liu, T.-Z.; Isobe, M. Synlett 2000, 587-589. (b) Liu, T.-Z.;
Isobe, M. Tetrahedron 2000, 56, 5391-5404. (c) Liu, T.-Z.; Li, J.-M.; Isobe,
M. Tetrahedron 2000, 56, 10209-10219. (d) Liu, T.-Z.; Isobe, M. Synlett
2000, 266-268.
(11) Synthesis of another model system of the EFGH ring: (a) Sasaki,
M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett. 1999, 40, 1337-1340.
(b) Imai, H.; Uehara, H.; Inoue, M.; Oguri, H.; Oishi, T.; Hirama, M.
Tetrahedron Lett. 2001, 42, 6219-6222.
(12) (1) Et3SiH, BF3‚OEt2, CH2Cl2; (2) Et3N, MeOH, H2O; (3) H2, Pd/
C, MeOH; (4) I2, PPh3, imidazole, Et2O, CH3CN; (5) TBSCl, imidazole,
DMF.
a Synthesis of E′ ring-enyne. (a) NaCN, DMSO, 80 °C, 85%;
(b) DIBAL, toluene, -78 °C, 58%; (c) 10, n-BuLi, THF, from -78
to 0 °C, and then 9, -78 °C, 73%; (d) TBAF, THF, 94%; (e) EVE,
PPTS, CH2Cl2, 97%.
(13) Corey, E. J.; Ruker, C. Tetrahedron Lett. 1982, 23, 719-722.
(14) Isobe, M.; Tsukiyama, T. Tetrahedron Lett. 1992, 33, 7911-7914.
(15) Gemal, A.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454-5459.
(16) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993, 34,
5757-5760.
introduced to the primary iodide 7, prepared from tri-O-
acetyl-D-glucal in five steps in a known procedure12 to give
8. After DIBAL reduction of 8, the product aldehyde 9 was
1184
Org. Lett., Vol. 4, No. 7, 2002

Scheme 3a
Scheme 4a
a Coupling and F ring cyclization. (a) 12 (1.5 equiv), n-BuLi,
THF, -78 °C, and then 22, 86%; (b) TBAF, THF; (c) Ac2O, Py,
DMAP, CH2Cl2, 96% in two steps; (d) PPTS, MeOH; (e) Co2(CO)8,
CH2Cl2, 96% in two steps; (f) BF3‚OEt2, CH2Cl2, from 0 °C to rt
over 30 min, 77%.
a Synthesis of H′ ring-aldehyde 22. (a) Bistrimethylsilyl-
acetylene, SnCl4, CH2Cl2, -20 °C; (b) NaBH4, CeCl3, MeOH, 0
°C, 86% in two steps; (c) TBDPSCl, imidazole, DMF, 100%; (d)
Co2(CO)8, CH2Cl2, rt; (e) BF3‚OEt2, CH2Cl2, from 0 °C to rt; (f)
I2, THF, 92% in three steps; (g) K2CO3, MeOH, 99%; (h) BnCl,
KOH, 90 °C, 87%; (i) n-BuLi, THF, (HCHO)n, from -78 to 0 °C,
85%; (j) Red-Al, 0 °C, THF, 95%; (k) mCPBA, Na2HPO4, CH2Cl2,
0 °C; (l) Red-Al, toluene, 0 °C, 86% (1:1) in two steps; (m) H2,
10% Pd/C, NaHCO3, EtOH, 100%; (n) separation; (o) TBSCl,
imidazole, DMF, 92%; (p) IBX, DMSO, 82%; (q) DIBAL, CH2Cl2,
-78 °C, 83% (95:5); (r) CSA, MeOH, 0 °C, 100%; (s) Ph-
CH(OMe)2, CSA, CH2Cl2, 99%; (t) BH3‚THF, reflux, 89%; (u) IBX,
DMSO, 92%.
With the coupling precursors, i.e., E′ ring-enyne 12 and
H′ ring-aldehyde 22, in hand, we tried the coupling reaction
to provide propargyl alcohol in 86% yield as shown in
Scheme 4. In addition, protecting group manipulation and
installation of a cobalt complex gave 24 as a precursor of
cyclization. Treatment of acetylene cobalt complex 24 with
BF3‚OEt2 at room-temperature effected the F ring cyclization
in 77% yield to afford a single diastereomer 25 (on the other
hand, the (E)-isomer of 24 could not be cyclized). The
syn stereochemistry of 25 was determined by a NOE
experiment.
Scheme 5 illustrates the final stage of the current strategy
toward the E′FGH′ ring synthesis. In the course of substantial
trials and errors in regard to the conversion of the acetylene
cobalt complex moiety into ketone, we found a novel reaction
under high-pressure hydrogenation,20 where acetylene cobalt
complex 25 gave rise to the desired ketone 26 in 37% yield
as a major compound along with conjugated enone 27 (4%)
and diene 28 (15%). This reaction mechanism, however, has
not been proven in detail yet. With the precursor 26 of the
G ring cyclization in hand, we treated 26 with K2CO3 in
MeOH and BF3‚OEt2 in the presence of Et3SiH in CH3CN21
to accomplish the stereoselective construction of the E′FGH′
ring 5 as a white solid in 57% yield. In the 1H NMR analysis
reduction to give allyl 17. In the next step, Sharpless
asymmetric epoxidation17 was very sluggish (TBHP, Ti-
(OPri)4, (+)-DET, CH2Cl2, -23 °C, 12 h) in 30% yield as a
single diastereomer. Therefore, mCPBA oxidation was fol-
lowed by Red-Al reduction and hydrogenation to furnish the
desired 19 and undesired 20 in 86% overall yield as a 1:1
mixture of two diastereomers. The undesired diastereomer
20, however, was reusable in the following procedure; thus,
temporary protection of the primary alcohol by the TBS
group, IBX oxidation,18 DIBAL reduction, and deprotection
of the TBS group occurred. IBX oxidation of primary alcohol
21 resulting from a protection of secondary alcohol 19 by
way of BH3 reduction19 of benzylidene acetal afforded H′
ring-aldehyde 22.
(17) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974-5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(18) (a) Hartman, C.; Meyer, V. Chem. Ber. 1893, 26, 1727. (b) Frigerio,
M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.
(19) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647-7648.
(20) Kira, K.; Isobe, M. J. Synth. Org. Chem., Jpn. 2000, 58, 23-30.
(21) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978.
Org. Lett., Vol. 4, No. 7, 2002
1185

Scheme 5a
a G ring cyclization. (a) H2, 100 kg/cm2, benzene, 65 °C, 6 h,
26 (37%), 27 (4%), 28 (15%); (b) K2CO3, MeOH, 100%; (c)
BF3‚OEt2, Et3SiH, CH3CN, from -15 °C to rt over 30 min, 57%.
at room temperature, a considerable broadening phenomenon
was observed due to the slow conformational changes of the
F ring, as reported for natural product CTX1b and other model
systems.10c,11,22 When the NMR measurement of 5 was
carried out in CDCl3 at -20 °C, the spectrum exhibited a
2:1 mixture of two conformational isomers (DOWN and UP
conformers, whose olefinic bonds are located below the down
side or above the up side of the ring plane, respectively) as
sharp signals. Comparison of the observed coupling constants
of 3J5,6 and 3J9,10 with those of energy-minimized conformers
by Macromodel (MM2* force field) should predict the
majority to be the DOWN conformer as shown in Figure 1.
Although the syn stereochemistry between H-10 and H-15
could not be determined directly by NOE experiments, the
fact that the coupling constants between H-10 and H-11
showed 9.5 Hz for the DOWN conformer and 11.0 Hz for
the UP conformer undoubtedly demonstrated the trans
stereochemistry of 5.
Figure 1. DOWN and UP conformers of the E′FGH′ ring 5 and
their coupling constants at -20 °C in CDCl3.
through the coupling between E′ ring-enyne and H′ ring-
aldehyde, highly stereoselective cyclization of the F ring
using an acetylene cobalt complex, and a novel conversion
of the acetylene cobalt complex into the ketone followed by
reductive cyclization of the G ring. Further studies toward
the total synthesis of CTX are now in progress and will be
published elsewhere.
Acknowledgment. The authors thank JSPS for a DC
scholarship to S.T.
In conclusion, we have accomplished the synthesis of an
E′FGH′ ring model fragment of CTX in a convergent manner
Supporting Information Available: Full experimental
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(22) (a) Inoue, M.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 1997,
38, 1611-1614. (b) Inoue, M.; Sasaki, M.; Tachibana, K. Terahedron 1999,
55, 10949-10970.
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