Synthesis of the BCDE rings of ciguatoxin 1B via an acetylene biscobalthexacarbonyl-vinylsilane strategy

Article abstract of DOI:10.1016/S0040-4039(01)00286-6

A synthetic route to the BCDE rings of ciguatoxin 1B has been explored through acetylene biscobalthexacarbonyl complex and vinylsilane strategy. The key issues in the current synthesis are (i) ether ring cyclization by means of the acetylene cobalt complex and (ii) reductive decomplexation of the product endo-complexes into the corresponding vinylsilanes. A sequential cyclization route is also described along this line.

Full text of DOI:10.1016/S0040-4039(01)00286-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2821–2824
Synthesis of the BCDE rings of ciguatoxin 1B via an acetylene
biscobalthexacarbonyl–vinylsilane strategy
Kazunobu Kira and Minoru Isobe*
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa,
Nagoya 464-8601, Japan
Received 29 January 2001; accepted 16 February 2001
Abstract—A synthetic route to the BCDE rings of ciguatoxin 1B has been explored through acetylene biscobalthexacarbonyl
complex and vinylsilane strategy. The key issues in the current synthesis are (i) ether ring cyclization by means of the acetylene
cobalt complex and (ii) reductive decomplexation of the product endo-complexes into the corresponding vinylsilanes. A sequential
cyclization route is also described along this line. © 2001 Elsevier Science Ltd. All rights reserved.
Ciguatoxin 1B (CTX 1B, 1) is a major component in
the creation of ciguatera poisoning. This structure was
elucidated by Yasumoto et al.1 Due to the limitation of
the availability from nature, much effort has been paid
to the synthetic studies.2 We have recently explored
various methodologies toward the total synthesis of 1,
which include C-alkynylation to sugar acetylenes,3 acety-
lene biscobalthexacarbonyl complexes for medium size
ether ring formation,4 and reductive decomplexation to
cis-olefins or vinylsilanes.5 In this communication, we
report the synthesis of a tetracyclic BCDE ring portion
as the left part of 1 with special references to the
employment of the above methodologies. The key issue
is cationic cyclization with highly stereoselective syn–
trans manner for the ladder shape target molecule. Our
previous studies have culminated in the synthesis of
ABC rings with the side chain,6 D%EF rings7 and H%IJK
rings.8 We planned the total synthesis of 1 as in
Schemes 1 and 3, where the A-ring cyclization will be
achieved at the latest stage from 2. The coupling step
between an anion of 3 and an aldehyde 4 would be
followed by the cyclization of F- and G-rings. In this
report we focus on the synthesis of the left half of 1 in
the form of compound 3.
Scheme 1.
* Corresponding author. Fax: +81-52-789-4111; e-mail: isobem@agr.nagoya-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00286-6

2822
K. Kira, M. Isobe / Tetrahedron Letters 42 (2001) 2821–2824
We have recently reported the synthesis of a D%EF
analog7 10 of CTX 1B as shown in Scheme 2. The key
issues are the sequential route of the endo cobalt com-
plex 6 to another complex 10 via steps including
cyclization, hydrosilylation (to vinyl silane), transfor-
mation of the epoxysilane 7 to allylic alcohol 8 and
then cyclization of the precursor 9 to the new complex
10. We employed this methodology in the synthesis of 3
as summarized in the retrosynthetic analysis in Scheme
3. The E-ring allylic alcohol in 3 would be cyclized
from the precursor cation9 11 and the D-ring having a
similar allylic alcohol in 13 would be derived from the
cation 14. The starting material was selected to be 15.10
stereochemistry was established from the NMR data.
The primary alcohol and the terminal olefin in 22 were
oxidized to give the methyl ketone–carboxylic acid 23
in two steps. Conversion of the terminal olefin was due
to its reactive nature during the following iodo-lac-
tonization step to provide a tetrahydrofuran by-
product; thus Wacker oxidation was employed to
protect this olefin. Iodo-lactonization of 23 was fol-
lowed by protection of the methyl ketone to afford the
dithioketal 24. DIBAL-H reduction of this lactone and
subsequent DBU treatment in THF solvent yielded the
epoxysilane 25. After converting the aldehyde 25 into
the acetylene13 27, the crucial acidic transformation14
was achieved to provide the allylic alcohol 28 by treat-
ment with BF3·OEt2, and its configuration was cor-
rected by a modified Mitsunobu inversion15 and
protected to afford 29. Its syn–trans stereochemistry
was also confirmed from the coupling constant 9.0 Hz
between C19 and C20.
The synthetic route leading to 3 of CTX-1B (1) is
illustrated in Scheme 4 commencing from 16. Prepara-
tion of this material having a different protective group
was previously reported6c and it was converted into the
dibromoolefin 18 as an equivalent precursor of acetyl-
ene 15.10 Treatment of the dibromoolefin 18 with n-
BuLi generated the corresponding acetylide, which was
mixed with the aldehyde 19 to give the propargyl
alcohol 20. After deprotection of the hydroxyl groups,
it was successively treated with Co2(CO)8 and then
BF3·OEt2 in one-pot to afford the cyclization product
21 as a single stereoisomer having a syn–trans relation-
ship.11 Hydrosilylation5 of 21 was conducted with 20
equiv. of Et3SiH by heating at 60°C in dichloroethane
solvent in the presence of propargyl alcohol.12 The
product, vinyl silane 22 was isolated in 90% yield as the
only isolable product with high regioselectivity. The
The method for the D-ring formation was employed for
the E-ring formation by repeating the following steps;
carbon chain elongation through the acetylide of 29
and cobalt complexation (30), cyclization (31), hydrosi-
lylation (32),16 epoxysilane (33), Peterson type carbon
chain elongation to the cis ene-yne 35,17 transformation
into the allylic alcohol 36 and finally the correction of
the stereochemistry to provide 3 of CTX-1B.18
Further studies on 1 are now in progress and will be
published elsewhere.
Scheme 2.
Scheme 3.

K. Kira, M. Isobe / Tetrahedron Letters 42 (2001) 2821–2824
2823
Scheme 4. Reagents, conditions and yields: (a) 18, n-BuLi–THF then 19; (b) Amberlyst-15E–MeOH, 80% in two steps; (c)
Co2(CO)8–CH2Cl2 then BF3·OEt2, 83%; (d) Et3SiH, propargyl alcohol–C2H4Cl2, 60°C, 90%; (e) Jones’ reagent–acetone; (f) PdCl2,
CuCl–DMF–H2O, 88% in two steps; (g) I(collidine)2PF6–CH2Cl2, 86%; (h) propanedithiol, BF3·OEt2–CH2Cl2, 90%; (i) DIBAL-
H–CH2Cl2; (j) DBU–THF, 88% in two steps; (k) dimethyl-1-diazo-2-oxopropylphosphonate 26, K2CO3–MeOH, 81%; (l)
BF3·OEt2–CH2Cl2, 90%; (m) p-nitro benzoic acid, DEAD, PPh3–toluene; (n) K2CO3–MeOH, 94% in two steps; (o) EVE, PPTS,
CH2Cl2, quant.; (p) 29, n-BuLi–THF then 19; (q) Amberlyst-15E–MeOH, 88% in two steps; (r) (CF3CO2)2PhI–CH3CN–H2O; (s)
Co2(CO)8–CH2Cl2, 83% in two steps; (t) BF3·OEt2–CH2Cl2, 86%; (u) Et3SiH–C2H4Cl2–EtOH, 60°C, quant.; (v) Jones’ reagent–
acetone; (w) I(collidine)2PF6–CH2Cl2; (x) propanedithiol, BF3·OEt2–CH2Cl2, 63% in three steps; (y) DIBAL-H–CH2Cl2; (z)
DBU–THF, 83% in two steps; (a%) n-BuLi, 34, then 33, 69%; (b%) BF3·OEt2–CH2Cl2, 65%; (c%) TBAF, THF, 83%; (d%) p-nitro
benzoic acid, DEAD, PPh3–toluene; (e%) K2CO3–MeOH quant. in two steps.

2824
K. Kira, M. Isobe / Tetrahedron Letters 42 (2001) 2821–2824
11. The stereochemistry of the cyclic products is governed by
Acknowledgements
the reaction condition, the anti isomer being the kinetic
product and the syn isomer being the thermodynamic
product.
This work was supported by JSPS-RFTF, Grant-In-
Aid for Scientific Research, and JSPS-DC fellowship.
12. Propargyl alcohol was added to prevent isomerization of
the terminal olefin to the inner olefin and silylation of the
hydroxyl group at C22. The details will be reported
separately.
References
13. (a) Callant, P.; D’HAenens, L.; Vandewalle, M. Synth.
Commun. 1984, 14, 155–161; (b) Ohira, S. Synth. Com-
mun. 1989, 19, 561–564; (c) Mueller, S.; Lieplld, B.; Roth,
G. J.; Bestmann, H. J. Synlett 1996, 521–522.
14. This transformation was reported under different condi-
tion, see: (a) Hudrik, P. F.; Wan, C.-N.; Withers, G. P.
Tetrahedron Lett. 1976, 1449–1452.; (b) Hudrlik, P. F.;
Tafesse, L.; Hudrlik, A. M. J. Am. Chem. Soc. 1997, 119,
11689–11690.
15. Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 26,
3017–3020.
16. EtOH was added to prevent the silylation of the hydroxyl
group at C26.
1. Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama,
M.; Harada, N.; Yasumoto, T. J. Am. Chem. Soc. 1997,
119, 11325–11326 and references cited therein.
2. (a) Oguri, H.; Tanaka, S.; Oishi, T.; Hirama, M. Tetra-
hedron Lett. 2000, 41, 975–978 and references cited
therein; (b) Sasaki, M.; Noguchi, K.; Fuwa, H.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 1425–1428 and
references cited therein; (c) Fujiwara, K.; Tanaka, H.;
Murai, A. Chem. Lett. 2000, 610–611 and references cited
therein; (d) Leeuwenburgh, M. A.; Kulker, C.;
Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H.
Synlett 1999, 12, 1945–1947.
3. Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa, T.
J. Chem. Soc., Chem. Commun. 1998, 2665–2676.
4. (a) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron
Lett. 1993, 34, 5757–5760; (b) Tanaka, S.; Isobe, M.
Tetrahedron 1994, 50, 5633–5644; (c) Tanaka, S.; Isobe,
M. Tetrahedron Lett. 1994, 35, 7801–7804; (d) Tanaka,
S.; Tatsuta, T.; Yamashita, O.; Isobe, M. Tetrahedron
1994, 50, 12883–12894; (e) Isobe, M.; Yenjai, C.; Tanaka,
S. Synlett 1994, 916–918; (f) Isobe, M.; Hosokawa, S.;
Kira, K. Chem. Lett. 1996, 473–474.
17. Corey, E. J.; Ruker, C. Tetrahedron Lett. 1982, 23,
719–722.
18. 1H NMR (CDCl3, 400 MHz): l 1.51 (3H, s, H-6), 1.55
(1H, q, J=11.0 Hz, H-14a), 1.73–1.90 (2H, m,
-SCH2CH2CH2S-), 1.80 (1H, dd, J=15.0, 8.5 Hz, H-8a),
2.34 (1H, dt, J=11.0, 4.0 Hz, H-14b), 2.48 (1H, ddd,
J=14.0, 5.5, 2.5 Hz, -SCH2CH2CH2S-), 2.56 (1H, d,
J=15.0 Hz, H-8b), 2.56–2.63 (1H, m, -SCH2CH2CH2S-),
2.66 (1H, dddd, J=14.5, 8.0, 6.5, 1.5 Hz, H-25a), 2.68
(1H, ddd, J=14.5, 11.0, 3.0 Hz, -SCH2CH2CH2S-), 2.78
(1H, dddd, J=14.5, 7.0, 3.5, 1.5 Hz, H-25b), 2.79 (1H,
ddd, J=14.5, 11.0, 3.0 Hz, -SCH2CH2CH2S-), 3.09-3.14
(2H, m, H-12, 13), 3.13 (1H, dd, J=2.5, 0.7 Hz, H-29),
3.24 (1H, dd, J=9.5, 8.5 Hz, H-10), 3.33 (1H, ddd,
J=11.5, 9.0, 4.5 Hz, H-15), 3.50 (1H, ddd, J=9.0, 6.5,
3.5 Hz, H-24), 3.56 (1H, dd, J=9.5, 8.5 Hz, H-9), 3.64
(1H, t, J=8.5 Hz, H-11), 3.83 (1H, dq, J=9.0, 2.0 Hz,
H-16), 4.01 (1H, dq, J=9.0, 2.0 Hz, H-20), 4.08 (1H, dq,
J=9.0, 2.0 Hz, H-19), 4.11 (1H, m, H-23), 4.62 (1H, d,
J=11.2 Hz, -OCH2Ph), 4.77 (1H, d, J=11.2 Hz,
-OCH2Ph*), 4.98 (1H, d, J=11.2 Hz, -OCH2Ph*), 5.01
(1H, d, J=11.2 Hz, -OCH2Ph), 5.54 (1H, dt, J=13.0, 2.0
Hz, H-21), 5.61 (1H, ddm, J=11.0, 2.5 Hz, H-27), 5.63-
5.70 (3H, m, H-17, 18, 22), 6.18 (1H, dddd, J=11.0, 8.0,
7.0, 0.7 Hz, H-26), 7.26–7.38 (10H, m, aromatic). TOF
MS calcd for C41H49O7S2 717.284 [M+H]+. Found
717.285.
5. Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39,
2609–2612.
6. (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, 789–798.
7. Kira, K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951–
5955.
8. (a) Liu, T.-Z.; Isobe, M. Synlett 2000, 587–589; (b) Liu,
T.-Z.; Li, J.-M.; Isobe, M. Tetrahedron 2000, 56, 5391–
5404.
9. Connor, R. E.; Nicholas, K. M. J. Organomet. Chem.
1977, 125, C45–C48.
10. Compound 18 was prepared in 15 steps from B-ring
aldehyde 16. The analog of B-ring aldehyde 16 was
already reported in Ref. 6c.
.