Total synthesis of gambierol

Article abstract of DOI:10.1021/ol026394b

(Formula Represented) The first total synthesis of gambierol, a marine polycyclic ether toxin, has been achieved. The synthesis features the Pd(PPh₃)₄/CuCl/LiCl-promoted Stille coupling for the stereoselective construction of the sen

Full text of DOI:10.1021/ol026394b

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2981-2984
Total Synthesis of Gambierol
,‡
Haruhiko Fuwa,† Makoto Sasaki,* Masayuki Satake,‡ and Kazuo Tachibana†
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo, and
CREST, Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku, Tokyo
113-0033, Japan, and Graduate School of Life Science, Tohoku UniVersity,
Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
msasaki@bios.tohoku.ac.jp
Received June 20, 2002
ABSTRACT
The first total synthesis of gambierol, a marine polycyclic ether toxin, has been achieved. The synthesis features the Pd(PPh3)4/CuCl/LiCl-
promoted Stille coupling for the stereoselective construction of the sensitive triene side chain that includes a conjugated (Z,Z)-diene moiety.
The fused polcyclic ether class of marine natural products,
exemplified by brevetoxins, ciguatoxins, and maitotoxin, has
received much attention due to the structural complexity and
biological potency of these molecules.1,2 Gambierol (1) is a
marine polycyclic ether isolated as a toxic constituent from
cultured cells of the ciguatera causative dinoflagellate,
Gambierdiscus toxicus. The gross structure and relative
stereochemistry have been established by Yasumoto and co-
workers on the basis of extensive NMR studies,3 and
subsequently, the absolute configuration was determined by
an application of a chiral anisotropic reagent.4 Gambierol
exhibits potent toxicity against mice at 50 µg/kg (ip), and
the symptoms caused in mice resemble those shown for
ciguatoxins,5 the principal toxins responsible for ciguatera,
which is a very widespread seafood poisoning. This finding
implies that gambierol is also implicated in ciguatera fish
poisoning. However, the biological basis of the potent
toxicity remains unknown mainly due to its limited avail-
ability from natural sources. Its polycyclic ether structure
including a characteristic triene side chain, as well as its
biological profile, has inspired a number of efforts toward
its synthesis.6,7 We have previously reported a highly
convergent synthesis of the octacyclic polyether core 2 of
gambierol by extensive use of the B-alkyl Suzuki-Miyaura
coupling reaction.6c Herein we describe the first total
synthesis of gambierol, featuring the stereoselective con-
struction of a highly sensitive triene side chain via the Pd-
(PPh3)4/CuCl/LiCl-promoted Stille coupling.
† The University of Tokyo and CREST, JST.
‡ Tohoku University.
(1) For reviews on ciguatoxins and related marine polycyclic ethers,
see: (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909. (b)
Scheuer, P. J. Tetrahedron 1994, 50, 3-18. (c) Murata, M.; Yasumoto, T.
Nat. Prod. Rep. 2000, 293-314. (d) Yasumoto, T. Chem. Rec. 2001, 3,
228-242.
(2) For reviews, see: (a) Alvarez, E.; Candenas, M.-L.; Pe´rez, R.; Ravelo,
J. L.; Mart´ın, J. D. Chem. ReV. 1995, 95, 1953-1980. (b) Mori, Y. Chem.
Eur. J. 1997, 3, 849-852.
The presence of a partially skipped triene side chain that
includes a conjugated (Z,Z)-diene system represents a
formidable synthetic challenge for the completion of the total
synthesis of gambierol. A modified Stille coupling protocol
for the C33-C34 bond formation reported as a model study
(3) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115,
361-362.
(4) Morohashi, A.; Satake, M.; Yasumoto, T. Tetrahedron Lett. 1998,
39, 97-100.
10.1021/ol026394b CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/19/2002

and improved the yield of 5 (entries 3 and 4). Furthermore,
the Pd(PPh3)4/CuCl/LiCl-promoted Stille conditions devel-
oped by Corey and co-workers13 worked well in this reaction.
Thus, the reaction of 3 and 4 with Pd(PPh3)4 (20 mol %),
10 equiv of CuCl, and 12 equiv of LiCl in 1:1 THF/DMSO
at 60 °C afforded 5 in a gratifying 81% yield (entry 6).
Notably, under these conditions, the cross-coupling reaction
proceeded with complete retention of olefin stereochemistry.
Having established reliable conditions for the construction
of the sensitive triene side chain, we proceeded forward to
complete the total synthesis. Removal of the acetyl groups
of 2 followed by selective silylation of the primary alcohol
and oxidation of the residual secondary alcohol with TPAP/
NMO14 led to ketone 6 in 69% overall yield (Scheme 1).
Table 1. Stille Coupling of (Z)-Vinyl Bromide 3 and (Z)-Vinyl
Stannane 4a
cocatalystc additive
entry
Pd(0)
ligandb
(equiv)
(equiv) temp yield
1
2
3
4
5
6
Pd2(dba)3‚CHCl3 TFP
Pd2(dba)3‚CHCl3 TFP
Pd2(dba)3‚CHCl3 TFP
Pd2(dba)3‚CHCl3 TFP
Pd(PPh3)4
CuI (1.6)
CuI (10)
CuTC (10)
CuTC (10)
CuCl (10) LiCl (12) rt
CuCl (10) LiCl (12) 60 °C 81
rt
49d
60 °C 50
60 °C 69
rt
75
49d
Pd(PPh3)4
a All reactions were carried out using 3 (1 equiv) and 4 (2 equiv) in the
presence of Pd(0) catalyst (20 mol %) and ligand (80 mol %) in 1:1 v/v
THF/DMSO for 2 days. b TFP ) (2-furyl)3P. c TC ) thiophene-2-carboxy-
late. d Vinyl bromide 3 was not consumed completely, and the yield was
Scheme 1. Synthesis of Alcohol 9a
1
estimated by H NMR analysis of an inseparable mixture of 3 and 5.
by Kadota, Yamamoto, and co-workers7c is a promising
candidate for the construction of the triene side chain.
However, an initial attempt to bring about the coupling of
model substrate (Z)-vinyl bromide 38 with (Z)-vinyl stannane
49 in the presence of Pd2(dba)3‚CHCl3, (2-furyl)3P, and CuI
in THF/DMSO10 afforded the desired cross-coupled product
5 in only a modest yield (Table 1, entries 1 and 2). Therefore,
we reinvestigated the conditions to establish the optimal
conditions for the cross-coupling reaction.11 Use of copper-
(I) thiophene-2-carboxylate (CuTC)12 accelerated the reaction
(5) (a) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Yasumoto, T. J. Am.
Chem. Soc. 1989, 112, 8929-8931. (b) Murata, M.; Legrand, 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.; Igarashi, T.; Legrand, A.-M.; Cruchet, P.; Chinain, M.;
Fujita, T.; Naoki, H. J. Am. Chem. Soc. 2000, 122, 4988-4989 and
references therein.
(6) (a) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 2000, 41,
8371-8375. (b) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron 2001,
57, 3019-3033. (c) Fuwa, H.; Sasaki, M.; Tachibana, K. Org. Lett. 2001,
3, 3549-3552.
a Reagents and conditions: (a) NaOMe, 1:1 MeOH/CH2Cl2, rt.
(b) TBSCl, imidazole, DMF, 0 °C. (c) TPAP, NMO, 4 Å MS,
CH2Cl2, rt, 69% (three steps). (d) LiHMDS, TMSCl, Et3N, CH2Cl2,
THF, -78 °C. (e) Pd(OAc)2, acetonitrile, rt. (f) MeMgBr, toluene,
-78 °C, 94% (three steps). (g) TBSOTf, Et3N, CH2Cl2, rt. (h)
LiDBB, THF, -78 f -45 °C. (i) TBDPSCl, Et3N, DMAP, CH2Cl2,
rt, 99% (three steps). (j) TBSOTf, Et3N, CH2Cl2, rt. (k) CSA, 1:1
MeOH/CH2Cl2, 0 °C, 93% (two steps).
(7) (a) Kadota, I.; Park, C.-H.; Ohtaka, M.; Oguro, N.; Yamamoto, Y.
Tetrahedron Lett. 1998, 39, 6365-6368. (b) Kadota, I.; Kadowaki, C.;
Yoshida, N.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 6369-6372. (c)
Kadota, I.; Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 6373-6376. (d) Kadowaki, C.; Chan, P. W. H.; Kadota, I.;
Yamamoto, Y. Tetrahedron Lett. 2000, 41, 5769-5772. (e) Kadota, I.;
Takamura, H.; Sato, K.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 4729-
4731. (f) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem.
Soc. 2001, 123, 6702-6703. (g) Sakamoto, Y.; Matsuo, G.; Matsukura,
H.; Nakata, T. Org. Lett. 2001, 3, 2749-2752. (h) Kadota, I.; Park, C.-H.;
Sato, K.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6195-6198. (i) Kadota,
I.; Kadowaki, C.; Takamura, H.; Yamamoto, Y. Tetrahedron Lett. 2001,
42, 6199-6202. (j) Cox, J. M.; Rainier, J. D. Org. Lett. 2001, 3, 2919-
2922. (k) Kadota, I.; Kadowaki, C.; Park, C.-H.; Yakamura, H.; Sato, K.;
Chan, P. W. H.; Thorand, S.; Yamamoto, Y. Tetrahedron 2002, 58, 1799-
1816. (l) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 3562-3566. (m) Kadota, I.; Takamura, H.; Sato, K.;
Yamamoto, Y. J. Org. Chem. 2002, 67, 3494-3498.
(8) The corresponding vinyl iodide was too unstable to be used.
(9) (a) Shirakawa, E.; Yamasaki, K.; Yoshida, H.; Hiyama, T. J. Am.
Chem. Soc. 1999, 121, 10221-10222. (b) Matsukawa, Y.; Asao, N.;
Kitahara, H.; Yamamoto, Y. Tetrahedron 1999, 55, 3779-3790.
(10) A mixed solvent system of 1:1 THF/DMSO was used in the present
study due to the low solubility of vinyl stannane 4 in DMSO.
(11) In the absence of copper(I) salt, the yield of Stille product 5 was
very low.
Treatment of 6 with LiHMDS in the presence of TMSCl
and Et3N gave the corresponding enol silyl ether, which upon
exposure to Pd(OAc)2 in CH3CN delivered enone.15 Subse-
quent Grignard reaction (MeMgBr, toluene, -78 °C)16
(12) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-
2749.
(13) Han, X.; Stolz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600-7605.
(14) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(15) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-1013.
(16) Feng, F.; Murai, A. Chem. Lett. 1992, 1587-1590.
2982
Org. Lett., Vol. 4, No. 17, 2002

afforded tertiary alcohol 7 in 94% overall yield as a single
diastereomer. After protection as its TBS ether, the benzyl
groups were reductively removed with LiDBB (THF, -78
f -45 °C),17 and the resulting diol was selectively protected
as the tert-butyldiphenylsilyl (TBDPS) ether 8 in high overall
yield. Further silylation of the C6 alcohol and selective
removal of the primary TBS group led to alcohol 9 in 93%
yield over two steps.
Scheme 3. Total Synthesis of Gambierol (1)a
Oxidation of 9 with TPAP/NMO followed by Corey-
Fuchs reaction18 provided dibromoolefin, which was stereo-
selectively reduced with n-Bu3SnH and Pd(PPh3)419 to deliver
(Z)-vinyl bromide 10 in 82% overall yield, setting the stage
for the crucial Stille coupling (Scheme 2). As expected, cross-
Scheme 2. Synthesis of Fully Protected Gambierol 11a
a Reagents and conditions: (a) HF‚pyridine, THF, rt, quant. (b)
4, Pd(PPh3)4, CuCl, LiCl, 1:1 DMSO/THF, 60 °C, 2 days, 43%.
TBS ether could not be removed under a variety of
conditions, using TBAF, tris(dimethylamino)sulfonium di-
fluorotrimethylsilicate (TASF),21 or HF‚pyridine. Further-
more, undesired side reactions that resulted in isomerization
or loss of the highly labile triene moiety could not be
suppressed. After extensive investigations, it was found that
treatment of vinyl bromide 10 with excess HF‚pyridine (THF,
room temperature, 6 days) cleanly afforded triol 12 in
quantitative yield. Finally, cross-coupling of 12 with 4 under
the described Pd(PPh3)4/CuCl/LiCl-promoted Stille condi-
tions proceeded stereoselectively to furnish gambierol 1 in
43% isolated yield. The synthetic gambierol was completely
identical to the natural sample by 1H and 13C NMR spectra;
thus, the structure of gambierol was unambiguously con-
firmed. Moreover, mouse lethality of synthetic gambierol (ip,
50-75 µg/kg) was comparable to that of the natural sample.
In summary, the first total synthesis of gambierol (1) has
been achieved. The Pd(PPh3)4/CuCl/LiCl-promoted Stille
coupling process has been successfully applied to the
stereoselective synthesis of the sensitive triene side chain
that includes a conjugated (Z,Z)-diene. Careful choice of the
global deprotection stage was found to be crucial for the
success of the present total synthesis. The described chem-
istry provides easy access to structural analogues of gam-
bierol for further study, including biological evaluation.
Further investigation along these lines is currently under way
and will be reported in due course.
a Reagents and conditions: (a) TPAP, NMO, 4 Å MS, CH2Cl2,
rt. (b) CBr4, PPh3, Et3N, CH2Cl2, 0 °C. (c) n-Bu3SnH, Pd(PPh3)4,
benzene, rt, 82% (three steps). (d) 4, Pd(PPh3)4, CuCl, LiCl, 1:1
DMSO/THF, 60 °C, 43 h, 66%.
coupling of the sterically congested vinyl bromide 10 with
4 was effected under the optimal conditions described above,
giving rise to fully protected gambierol 11 with complete
retention of olefin stereochemistry.20
For completion of the total synthesis of 1, there remained
only removal of the silyl protective groups. However, global
silyl ether deprotection proved to be problematic. The C30
(17) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924-1930. (b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110,
854-860.
(18) Corey, E. J.; Fuchs, P. J. Tetrahedron Lett. 1972, 36, 3769-3772.
(19) (a) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.; Tsuji, J.
Tetrahedron Lett. 1996, 37, 6759-6752. (b) Uenishi, J.; Kawahama, R.;
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1996, 61, 5716-5717. (c) Uenishi,
J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965-
8975.
Acknowledgment. This work was financially supported
in part by a grant from Suntory Institute for Bioorganic
Research (SUNBOR). A fellowship (to H.F.) from the Japan
Society for the Promotion of Science is also gratefully
acknowledged.
(20) In this reaction, vinyl bromide 10 was not consumed completely
and an inseparable 4:1 mixture of 11 and 10 was obtained in 82% yield.
The yield of 11 was estimated to be 66% by the H NMR analysis of the
(21) (a) Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem.
Soc. 1980, 102, 1223-1225. (b) Scheidt, K. A.; Chen, H.; Follows, B. C.;
Chemler, A. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-
6437.
1
purified mixture.
Org. Lett., Vol. 4, No. 17, 2002
2983

Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 5 and 1 and
1H and 13C NMR spectra for synthetic gambierol. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026394B
2984
Org. Lett., Vol. 4, No. 17, 2002