Convergent total syntheses of gambierol and 16-epi-gambierol and their biological activities

Article abstract of DOI:10.1021/ja036984k

The convergent total syntheses of gambierol (1) and 16-epi-gambierol (2) have been achieved. The ABC and FGH ring segments 4 and 5 were prepared from known compounds 6 and 13, respectively, by linear manners. The fragments prepared were connected by our own synthetic strategy including the intramolecular allylation of α-acetoxy ether followed by ring-closing metathesis to furnish the octacyclic ether 3. The diiodoalkene 45, prepared from 3, was converted to the Z-iodoalkene 50 via a novel and stereoselective hydrogenolysis followed by deprotection. Construction of the triene side chain was performed by the modified Stille coupling of 50 with the Z-vinylic stannane 41 to afford 1. The similar transformations were carried out on the epimeric octacycle 34 to give 2, which showed no toxicity against mice at the concentration of 14 mg/kg.

Full text of DOI:10.1021/ja036984k

Published on Web 09/09/2003
Convergent Total Syntheses of Gambierol and
16-epi-Gambierol and Their Biological Activities
Isao Kadota,*,† Hiroyoshi Takamura,‡ Kumi Sato,‡ Akio Ohno,‡ Kumiko Matsuda,‡
Masayuki Satake,§ and Yoshinori Yamamoto*,‡
Contribution from the Research Center for Sustainable Materials Engineering,
Institute of Multidisciplinary Research for AdVanced Materials, and Department of Chemistry,
Graduate School of Science, and Graduate School of Life Science, Tohoku UniVersity,
Sendai 980-8578, Japan
Received June 30, 2003; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp; ikadota@mail.cc.tohoku.ac.jp
Abstract: The convergent total syntheses of gambierol (1) and 16-epi-gambierol (2) have been achieved.
The ABC and FGH ring segments 4 and 5 were prepared from known compounds 6 and 13, respectively,
by linear manners. The fragments prepared were connected by our own synthetic strategy including the
intramolecular allylation of R-acetoxy ether followed by ring-closing metathesis to furnish the octacyclic
ether 3. The diiodoalkene 45, prepared from 3, was converted to the Z-iodoalkene 50 via a novel and
stereoselective hydrogenolysis followed by deprotection. Construction of the triene side chain was performed
by the modified Stille coupling of 50 with the Z-vinylic stannane 41 to afford 1. The similar transformations
were carried out on the epimeric octacycle 34 to give 2, which showed no toxicity against mice at the
concentration of 14 mg/kg.
Introduction
In recent years there has been an explosion of interest in
biologically active natural products of marine origin.1 Due to
their structural novelty and toxicity, polycyclic ethers are
particularly attractive targets for synthetic chemists.2 Gambierol
(1), a potent neurotoxin isolated from the cultured cells of
Gambierdiscus toxicus, has 8 ether rings and 18 stereogenic
centers (Figure 1).3 The compound shows toxicity against mice
(LD50 50 µg/kg), and the symptoms resemble those caused by
ciguatoxins, inferring the possibility that it is also implicated
in ciguatera poisoning. The unique structural features have
attracted the attention of synthetic chemists, and a number of
strategies have been investigated.4 Soon after the first total
synthesis of 1 was accomplished by Sasaki, Tachibana, and co-
workers,5 we also communicated the total synthesis of 1.6 In
this contribution, we report full details of the convergent total
synthesis of gambierol (1) together with the synthesis of 16-
epi-gambierol (2), based on our own synthetic methodology,
and the biological activities of 1 and 2.
Figure 1. Structures of gambierol (1) and 16-epi-gambierol (2).
Results and Discussion
Retrosynthetic Analysis. A brief retrosynthetic analysis of
1 is illustrated in Scheme 1. According to our preliminary study
for the synthesis of the H ring moiety, the triene side chain
† Institute of Multidisciplinary Research for Advanced Materials.
‡ Graduate School of Science.
(4) (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) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett.
2000, 41, 8371-8375. (e) Sakamoto, Y.; Matsuo, G.; Matukura, H.; Nakata,
T. Org. Lett. 2001, 3, 2749-2752. (f) Cox, J. M.; Rainier, J. D. Org. Lett.
2001, 3, 2919-2922. (g) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron
2001, 57, 3019-3033. (h) Fuwa, H.; Sasaki, M.; Tachibana, K. Org. Lett.
2001, 3, 3549-3552. (i) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto,
Y. J. Am. Chem. Soc. 2001, 123, 6702-6703. (j) Kadota, I.; Kadowaki,
C.; Park, C.-H.; Takamura, H.; Sato, K.; Chan, P. W. H.; Thorand, S.;
Yamamoto, Y. Tetrahedron 2002, 58, 1799-1816. (k) Kadota, I.; Taka-
mura, H.; Sato, K.; Yamamoto, Y. J. Org. Chem. 2002, 67, 3494-3498.
(l) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 3562-3566. (m) Majumder, U.; Cox, J. M.; Rainier, J. D. Org.
Lett. 2003, 5, 913-916.
§ Graduate School of Life Sciences.
(1) For reviews on marine polycyclic ethers, see: (a) Shimizu, Y. Chem. ReV.
1993, 93, 1685-1698. (b) Yasumoto, T.; Murata, M. Chem. ReV. 1993,
93, 1897-1909. (c) Scheuer, P. J. Tetrahedron 1994, 50, 3-18. (d) Murata,
M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293-314. (e) Yasumoto, T.
Chem. Rec. 2001, 1, 228-242.
(2) For reviews on synthesis of polycyclic ethers, see: (a) Alvarez, E.;
Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J. D. Chem. ReV. 1995,
95, 1953-1980. (b) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 589-607. (c) Mori, Y. Chem. Eur. J. 1997, 3, 849-852. (d) Marmsa¨ter,
F. P.; West, F. G. Chem. Eur. J. 2002, 8, 4347-4353. Also see: (e) Hoberg,
J. O. Tetrahedron 1998, 54, 12630-12670.
(3) (a) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115,
361-362. (b) Morohashi, A.; Satake, M.; Yasumoto, T. Tetrahedron Lett.
1998, 39, 97-100.
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J. AM. CHEM. SOC. 2003, 125, 11893-11899
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A R T I C L E S
Kadota et al.
Scheme 1. Retrosynthetic Analysis of Gambierol (1)
Scheme 2. Synthesis of the ABC Ring Segment 4a
would be constructed by a modified Stille coupling at a late
stage. Recently, we developed a convergent method for the
synthesis of polycyclic ether frameworks via the intramolecular
allylation of R-acetoxy ethers and subsequent ring-closing
metathesis.4i,l Upon the basis of this methodology, the key
intermediate, octacyclic ether 3, can be retrosynthetically broken
down into the ABC and FGH segments, 4 and 5.
a (a) (c-Hex)2BH, THF, 0 °C, then H2O2, NaOH, 95%; (b) (i) TEMPO,
NaClO, KBr, NaHCO3, CH2Cl2-H2O, 0 °C; (ii) 1,3-propanedithiol,
BF3.OEt2, CH2Cl2, -78 to 0 °C; (iii) TBAF, THF, rt, 86% (3 steps); (c)
ethyl propiolate, NMM, CH2Cl2, rt, 94%; (d) MeI, NaHCO3, CH3CN-
H2O, 50 °C, 94%; (e) SmI2, MeOH, THF, 0 °C, 98%; (f) (i) TBSOTf,
2,6-lutidine, CH2Cl2, 0 °C (ii) LiAlH4, ether, 0 °C, 92% (2 steps); (g) (i)
TEMPO, NaClO, KBr, NaHCO3, CH2Cl2-H2O, 0 °C; (ii) NaClO2, 2-methyl-
2-butene, NaH2PO4, t-BuOH-THF-H2O, rt, quant (2 steps).
Synthesis of the ABC Ring Segment 4. Synthesis of the
ABC ring segment 4 was started from the known bicycle 6,4h
corresponding to the AB ring system (Scheme 2). Hydroboration
of 6 gave the alcohol 7 in 95% yield. TEMPO oxidation of 7,7
protection of the resulting aldehyde as a dithio acetal, and
desilylation with TBAF afforded 8 in 86% yield. Reaction with
ethyl propiolate and N-methylmorpholine gave the acrylate 9
in 94% yield. The dithio acetal protection of 9 was removed
by MeI in wet acetonitrile to give the aldehyde 10 in 94% yield.
Construction of the C ring moiety was performed by using
Nakata protocol. Thus, treatment of 10 with SmI2 in the presence
of MeOH provided the tricyclic compound 11 as a single
stereoisomer in 98% yield.8 TBS protection followed by LiAlH4
reduction of the ester group gave the alcohol 12, which was
oxidized to the carboxylic acid 4 in quantitative yield.
primary alcohol with PivCl/pyridine gave 18 in 98% yield. Acid-
catalyzed acetal formation with the γ-methoxyallylstannane 19
followed by acetal cleavage with TMSI/HMDS furnished the
allylic stannane 20 in 81% yield.9 Reductive removal of the
Piv protection with DIBALH gave the alcohol 21, which was
oxidized with SO3‚py/DMSO/Et3N to afford the aldehyde 22
in 97% yield. Cyclization of 22 mediated by BF3‚OEt2 gave
the 6,6,7-tricyclic compound 23 in 99% yield as a single
stereoisomer.10 Ozonolysis of the olefin followed by reductive
workup, protection of the resulting 1,3-diol as a benzylidene
acetal, and selective desilylation of the primary alcohol furnished
24 in 86% yield. Treatment of 24 with 2-nitrophenyl seleno-
cyanate/Bu3P followed by oxidative work up gave the alkene
25 in 97% yield.11 Treatment of 25 with TBAF afforded the
FGH ring segment 5 in quantitative yield.
Construction of the Octacyclic Ether Framework. The next
task of the total synthesis was the construction of the octacyclic
framework. The carboxylic acid 4 and the alcohol 5 were
connected by Yamaguchi conditions to give the ester 26 in 94%
yield (Scheme 4).12 A series of reactions including desilylation
with TBAF, acid-catalyzed acetal formation with 19, and acetal
cleavage with TMSI/HMDS furnished the allylic stannane 28
in 77% yield. The ester 28 was converted to the R-acetoxy ether
29 via the Rychnovsky protocol. Thus, partial reduction of 28
with DIBALH, followed by treatment of the resulting aluminum
Synthesis of the FGH Ring Segment 5. Synthesis of the
FGH ring segment 5 is shown in Scheme 3. Reduction of the
known ester 134e having 1,3-diaxial methyl groups with LiAlH4
followed by protection with TBSOTf/2,6-lutidine gave the bis-
silyl ether 14 in quantitative yield. Hydrolysis of the benzylidene
acetal followed by selective tosylation of the primary alcohol
afforded 16 in 84% yield. Treatment of 16 with an excess
amount of allylmagnesium bromide in the presence of CuBr
gave the alkylated product 17 in 95% yield. Ozonolysis of the
olefin, reduction with NaBH4, and selective protection of the
(5) Fuwa, H.; Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002, 4, 2981-
2984. (b) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem.
Soc. 2002, 124, 14983-14992.
(6) For a preliminary communication, see: Kadota, I.; Takamura, H.; Sato,
K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125,
46-47.
(9) Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron Lett. 1996, 37, 3195-
3198.
(10) (a) Yamamoto, Y.; Yamada, J.; Kadota, I. Tetrahedron Lett. 1991, 32,
7069-7072. (b) Kadota, I.; Kawada. M.; Gevorgyan, V.; Yamamoto, Y.
J. Org. Chem. 1997, 62, 7439-7446.
(7) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52,
2559-2562.
(8) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999,
40, 2811-2814. (b) Hori, N.; Matsukura, H.; Nakata, T. Org. Lett. 1999,
1, 1099-1101. (c) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron Lett. 1999,
40, 8859-8862.
(11) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485-
1486.
(12) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
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Total Syntheses of Gambierol and 16-epi-Gambierol
A R T I C L E S
Scheme 3. Synthesis of the FGH Ring Segment 5a
Scheme 4. Coupling of the Segments 4 and 5a
a (a) (i) LiAlH4, ether, 0 °C; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to
rt, 100% (2 steps); (b) H2, Pd(OH)2-C, EtOAc, rt, 100%; (c) TsCl, Et3N,
CH2Cl2, reflux, 84%; (d) allylmagnesium bromide, CuBr, THF, -20 °C to
rt, 95%; (e) (i) O3, MeOH, -78 °C, then Me2S, NaBH4; (ii) PivCl, pyridine,
CH2Cl2, 0 °C to rt, 98% (2 steps); (f) (i) 19, CSA, CH2Cl2, rt, 99%; (ii)
HMDS, TMSl, CH2Cl2, 0 °C, 82%; (g) DIBALH, CH2Cl2, -78 °C, 100%;
(h) SO3‚py, DMSO, Et3N, CH2Cl2, 0 °C to rt, 97%; (i) BF3‚OEt2, CH2Cl2,
-78 °C, 99%; (j) (i) O3, CH2Cl2-MeOH, -78 °C, then NaBH4; (ii)
PhCH(OMe)2, CSA, CH2Cl2, 0 °C; (iii) AcOH, THF-H2O, 30 °C, 86% (3
steps); (k) 2-nitrophenyl selenocyanate, PBu3, THF, rt, then H2O2, NaHCO3,
40 °C, 97%; (l) TBAF, THF, reflux, 100%.
a (a) 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, 40 °C, then 5, DMAP,
toluene, 40 °C, 90%; (b) TBAF, THF, rt 99%; (c) (i) 19, CSA, CH2Cl2, rt;
(ii) HMDS, TMSI, CH2Cl2, 0 °C, 78% (2 steps); (d) DIBALH, CH2Cl2,
-78 °C, then R2O, DMAP, pyridne, -78 °C to rt, 78% for 29, 88% for 32;
(e) MgBr2‚OEt2, MS4A, CH2Cl2, rt, or BF3‚OEt2, MS4A, CH3CN-CH2Cl2
(20:1), -40 to 0 °C.
hemiacetal with Ac2O/pyridine/DMAP gave 29 as a 3:2
inseparable mixture of diastereoisomers in 78% yield.13 The
cyclization precursor 29 was then treated with MgBr2‚OEt2 in
CH2Cl2 to afford a mixture of the desired product 30 and its
epimer 31 in 61% yield. Unfortunately, the undesired stereo-
isomer 31 was the major component. The ratio of 30 and 31
was 36:64. After several unfruitful attempts, we found the
conditions giving the desired product predominantly. Treatment
of the R-chloroacetoxy ether 32, prepared from 28 via DIBALH
reduction followed by trapping with (CH2ClCO)2O/pyridine/
DMAP, with BF3‚OEt2 in CH3CN-CH2Cl2 (20:1) furnished 30
and 31 in the ratio of 64:36 in 87% yield. Although the reason
is not clear, probably, the greater leaving ability of chloroacetoxy
group, in comparison with that of the acetoxy group, would
drive the reaction to proceed through SN1 pathway giving the
desired isomer 30 predominantly. It should be noted that the
use of chloroacetyl group improved not only the cyclization
step but also preparation of the substrate. The reaction time
required for the chloroacetylation was decreased to 1 h in
comparison to 12 h for the acetylation, and the yield was
improved to 88% from 78%.
Scheme 5. Ring-closing Metathesis of 30 and 31
The diene 30 obtained was subjected to ring-closing metath-
esis using the second-generation Grubbs catalyst 33,14 leading
to the octacyclic ether 3 in 88% yield (Scheme 5). Similarly,
the stereoisomer 31 was converted to 34 in 94% yield. The
stereochemistries of 3 and 34 were determined on the basis of
(13) (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317-
8320. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191-
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
198.
956.
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A R T I C L E S
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Scheme 7
Figure 2. Structure determination of 3 and 34.
Scheme 8
Scheme 6 a
alcohol as a single stereoisomer.16 TBS protection and subse-
quent selective deprotection of the primary silyloxy group
afforded 39 in 82% yield.
Model Studies for the Synthesis of the Triene Side Chain.
As well as the synthesis of the octacyclic ether framework, the
stereoselective construction of the triene side chain was one of
the challenging problems inherent in the total synthesis of
gambierol. We chose the Stille coupling reaction17 as a possible
route to the triene side chain, since we had established a rather
easy synthetic method for the Z-vinylstannane 41.4c,18 For a
preliminary study, the Z-bromoalkene 40, prepared from the
corresponding dibromoalkene by the Uenishi procedure,19 was
subjected to the coupling with the Z-vinyl stannane 41 under
the modified Stille conditions20 to afford the triene 42 as a single
stereoisomer in 63% yield (Scheme 7).4c Although 42 was
obtained selectively in an allowable yield, the reaction was very
slow. A significant amount of the starting material 40 remained
even after 4 days. It was easily expected that the reaction of
the bulky substrate having an octacyclic ether skeleton would
be much slower. This problem prompted us to develop an
efficient method for the construction of the triene side chain.21
After several unfruitful attempts, we found that the reduction
of the diiodoalkene 43 with Zn-Cu couple and acetic acid gave
the Z-iodoalkene 44 as the sole product in 80% yield (Scheme
8).22,23 As expected, the iodoalkene 44 showed higher reactivity,
and the coupling reaction with 41 was finished within 1.5 h to
afford 42 in 95% yield. None of the other olefinic isomers was
detected in this reaction.
a (a) (i) CSA, CH2Cl2-MeOH, 30 °C; (ii) TBSCl, imidazole, CH2Cl2, 0
°C, 80% (2 steps); (b) TPAP, NMO, MS4A, CH2Cl2, rt, 96%; (c) (i) H2,
Pd-C, EtOAc, rt; (ii) H2, Pd(OH)2-C, EtOAc, rt; (iii) PivCl, DMAP,
CH2Cl2, rt; (iv) TIPSOTf, 2,6-lutidine, DMF, 65 °C, 80% (4 steps); (d) (i)
LiHMDS, TMSCl, Et3N, THF, -78 °C; (ii) Pd(OAc)2, CH3CN, rt, 92% (2
steps); (e) (i) MeMgI, toluene, -78 °C; (ii) TBSOTf, 2,6-lutidine, CH2Cl2,
°
rt; (iii) CSA, CH2Cl2-MeOH, 0 C, 82% (3 steps).
Completion of the Total Synthesis of Gambierol. Encour-
aged by the results obtained above, we faced up to the final
1H NMR coupling constant and NOE experiments as shown in
Figure 2.
(15) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-1013.
(16) Feng, F.; Murai, A. Chem. Lett. 1992, 1587-1590.
Modification of the H Ring Moiety. Hydrolysis of the
benzylidene acetal of 3 followed by selective protection of the
primary alcohol gave 35 in 80% yield (Scheme 6). TPAP
oxidation of the secondary alcohol 35 gave the ketone 36 in
96% yield. Hydrogenation of 36 followed by debenzylation gave
the saturated diol. The primary and secondary alcohols were
protected by Piv and TIPS groups, respectively, to afford 37 in
80% yield. Treatment of 37 with LiHMDS/TMSCl/Et3N gave
the corresponding enol silyl ether,5 which was subjected to
dehydrosilylation with Pd(OAc)2 to afford the enone 38 in 92%
overall yield.15 Stereoselective introduction of a methyl group
was carried out using MeMgI in toluene to give the tertiary
(17) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(18) (a) Matsukawa, Y.; Asao, N.; Kitahara, H.; Yamamoto, Y. Tetrahedron
1999, 55, 3779-3790. Also see: (b) Shirakawa, E.; Yamasaki, K.; Yoshida,
H.; Hiyama, T. J. Am. Chem. Soc. 1999, 121, 10221-10222.
(19) (a) Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem. 1996, 61,
5716-5717. (b) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.
Tetrahedron Lett. 1996, 37, 6759-6762. (c) Uenishi, J.; Kawahama, R.;
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965-8975.
(20) (a) Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364.
(b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J.
Org. Chem. 1994, 59, 5905-5911.
(21) Sasaki found an effective catalyst system for the coupling of Z-bromo-
alkenes, see ref 5.
(22) The palladium-catalyzed hydrogenolysis of diiodoalkenes with Bu3SnH was
not selective, see ref 19c.
(23) The iodoolefination of the corresponding aldehyde using Wittig reagent
gave a mixture of stereoisomers.
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Total Syntheses of Gambierol and 16-epi-Gambierol
A R T I C L E S
Scheme 9 a
Scheme 10. Completion of the Total Synthesis of Gambierol (1)a
a (a) DIBALH, CH2Cl, -78 °C, 100% form 45 (2 steps); (b) SiF4,
CH2Cl2-CH3CN, 0 °C; (c) 41, Pd2(dba)3‚CHCl3, P(furyl)3, CuI, DMSO, 40
°C, 72% (2 steps).
Scheme 11 a
a (a) (i) PCC, MS4A, CH2Cl2, rt; (ii) Cl4, PPh3, CH2Cl2, 0 °C, 92% (2
steps); (b) Zn-Cu, AcOH, THF-MeOH, 0 °C; (c) 41, Pd2(dha)3‚CHCl3,
P(furyl)3, CuI, DMSO, 40 °C, quant (2 steps); (d) DIBALH, CH2Cl2, -78
°C.
stage of the total synthesis. Thus, PCC oxidation of 39 followed
by treatment of the resulting aldehyde with CI4 and PPh3 gave
the diiodoalkene 45 in 92% yield (Scheme 9).24 Stereoselective
hydrogenolysis of 45 using Zn-Cu couple and AcOH afforded
the Z-iodoalkene 46 (88%), which was then subjected to the
modified Stille coupling with 41, leading to the fully protected
gambierol 47 as a single stereoisomer in quantitative yield. The
remaining sequence was that of deprotection. Although removal
of the Piv group with DIBALH proceeded cleanly, all attempts
to remove the silyl groups under various conditions including
the use of TBAF, HF‚py, TASF, and SiF4 were unsuccessful.
The triene moiety seemed to be unstable under the desilylation
conditions employed.
The same problem was reported by Sasaki and was solved
by deprotection before synthesizing the triene side chain.5 Thus,
removal of the Piv group of 46 with DIBALH afforded 49 in
quantitative yield (Scheme 10). Deprotection of the bis-silyl
ether 49 with SiF4 proceeded smoothly, leading to the corre-
sponding triol 50.25 Finally, the iodoalkene 50 was subjected
to the modified Stille coupling with 41 to give gambierol (1) in
72% yield. The synthetic gambierol exhibited physical and
spectroscopic data identical with those reported previously (see
Supporting Information).3,5
Total Synthesis of 16-epi-Gambierol. We next examined
the synthesis of 16-epi-gambierol (2) starting from the octacycle
34 obtained. It was thought that since most of the polycyclic
ethers isolated from nature have trans-fused systems, biological
investigation of 2, having a cis-fused DE ring system, would
provide valuable information regarding the structure-activity
relationship of the polyether ladder marine toxins.26 Thus,
hydrolysis of the benzylidene acetal of 34, selective TBS
a (a) (i) CSA, CH2Cl2-MeOH, 35 °C; (ii) TBSCl, imidazole, CH2Cl2, 0
°C, 96% (2 steps); (b) TPAP, NMO, MS4A, CH2Cl2, rt, 95%.
protection of the primary alcohol, and oxidation of the remaining
secondary hydroxy group afforded the ketone 52 (Scheme 11).
Surprisingly, debenzylation of 52 with H2/Pd(OH)2-C resulted
in the formation of a complex mixture of the products. The
allylic ether moiety of the E ring seemed to be cleaved under
the hydrogenation conditions.
An alternative approach is illustrated in Scheme 12. Selective
hydrogenation of the double bond of 52 with H2/Pd-C in the
presence of Et3N as a poison,27 conversion of the resulting
ketone to the corresponding enol silyl ether, and dehydrosilyl-
ation with Pd(OAc)2 gave the enone 54 in 89% yield. Grignard
reaction followed by TBS protection gave the bis-silyl ether 55
(26) Very recently, Sasaki reported the biological evaluation of synthetic
gambierol analogues varied with the H ring functionalities, see: Fuwa,
H.; Kainuma, N.; Satake, M.; Sasaki, M. Bioorg. Med. Chem. Lett. 2003,
13, 2519-2522.
(27) For a example of the use of amines as a catalyst poison, see: Czech, B. P.;
Bartsch, R. A. J. Org. Chem. 1984, 49, 4076-4078.
(24) Gavin˜a, F.; Luis, S. V.; Ferrer, P.; Costero, A. M.; Marco, J. A. J. Chem.
Res. 1986, 330-331.
(25) Corey, E. J.; Yi, K. Y. Tetrahedron Lett. 1992, 33, 2289-2290.
9
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A R T I C L E S
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Scheme 12 a
Scheme 13 a
a (a) DIBALH, CH2Cl2, -78 °C, 95% from 57 (2 steps); (b) SiF4,
CH2Cl2-CH3CN, 0 °C; (c) 41, Pd2(dba)3‚CHCl3, P(furyl)3, CuI, DMSO,
40 °C, ca. 60% (2 steps).
Scheme 14 a
a (a) (i) H2, Pd-C, Et3N, EtOAc, rt; (ii) LiHMDS, TMSCl, Et3N, THF,
-78 °C; (iii) Pd(OAc)2, CH3CN, rt, 89% (3 steps); (b) (i) MeMgI, toluene,
-78 °C; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 92% (2 steps); (c) (i) LiDBB,
THF, -78 to -40 °C; (ii) PivCl, DMAP, CH2Cl2, rt; (iii) TIPSOTf, 2,6-
lutidine, DMF, 60 °C; (iv) CSA, CH2Cl2-MeOH, 0 °C, 75% (4 steps); (d)
(i) PCC, MS4A, CH2Cl2, rt; (ii) Cl4, PPh3, CH2Cl2, 0 °C, 83% (2 steps);
(e) Zn-Cu, AcOH, THF-MeOH, 0 °C; (f) 41, Pd2(dba)3‚CHCl3, P(furyl)3,
CuI, DMSO, 40 °C; (g) (i) DIBALH, CH2Cl2, -78 °C; (ii) TBAF, THF,
50 °C, 30% (4 steps).
a (a) SiF4, CH2Cl2-CH3CN, 0 °C; (b) 41, Pd2(dba)3‚CHCl3, P(furyl)3,
CuI, DMSO, 40 °C; (c) DIBALH, CH2Cl2, -78 °C, 64% from 57 (4 steps).
in 92% yield. The stereochemistry of the methyl group
introduced was confirmed at later stage. The benzyl groups of
55 were removed by LiDBB to give the corresponding diol,28
which was converted to the alcohol 56 in 75% yield by Piv
and TIPS protection followed by selective cleavage of the
primary TBS ether. The triene side chain was constructed by
PCC oxidation of 56, diiodoolefination of the resulting aldehyde,
stereoselective hydrogenolysis of the diiodoalkene 57, and the
modified Stille coupling of the resulting iodoalkene 58 with
41. This sequential process gave the fully protected 16-epi-
Figure 3. NOE experiment on 2.
gambierol 59 in 83% yield. Removal of the Piv group with
DIBALH followed by desilylation with TBAF gave 16-epi-
gambierol (2) in 30% yield. In contrast to the case of 1, the
desilylation using TBAF did not decompose completely the
product 2 although the yield was not satisfactory. It is interesting
that the stereochemistry at C16 position exerts strong influence
upon the stability of the triene moiety, and thereby the stability
of the compounds themselves, located at the end of the molecule.
(28) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854-860.
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11898 J. AM. CHEM. SOC. VOL. 125, NO. 39, 2003

Total Syntheses of Gambierol and 16-epi-Gambierol
A R T I C L E S
Figure 4. Energy-minimized structures (Macromodel 6.5, MM2* force field) of gambierol (upper) and 16-epi-gambierol (lower).
Conclusions
To solve this problem, we examined the deprotection of the
iodoalkene 58 (Scheme 13). Treatment of 58 with DIBALH,
followed by desilylation of the resulting 60 with SiF4, gave the
triol 61, which was subjected to the modified Stille coupling to
afford 2 smoothly. However, purification of 2 was problematic.
Due to the high polarity of 2,29 isolation of the product from
the reaction mixture was very difficult.
Scheme 14 shows the final and successful approach to the
total synthesis of 2. Desilylation of 58 with SiF4 gave the diol
62, which was coupled with 41 leading to the monoprotected
stereoisomeric gambierol 63. Finally, the Piv ester 63 was treated
with DIBALH to furnish pure 16-epi-gambierol (2) in 64%
yield. The stereochemistry of the methyl group on the H ring
was confirmed by the NOE experiment at this stage as shown
in Figure 3.
Efficient total syntheses of gambierol and 16-epi-gambierol
have been executed on the basis of a convergent strategy.
Demonstrated in this study is the power of the methodology,
involving the intramolecular allylation of R-chloroacetoxy ether
and subsequent ring-closing metathesis, as a practical tool for
constructing polycyclic ether frameworks. The longest linear
sequence leading to 1 is 66 steps with 1.2% overall yield, and
the total number of the steps is 102. The synthesis and biological
investigation of 2 demonstrates clearly the importance of the
trans-fused framework for the toxicity of polycyclic ethers. The
novel method for the synthesis of Z-iodoalkenes is also deserving
of attention (see Scheme 8). Application of the present strategy
to the synthesis of other marine polycyclic ethers is in progress.
Biological Studies. The mouse lethality of synthetic gambi-
erol (150 µg/kg) was equal to that of the natural product. In
contrast, 16-epi-gambierol exhibited no toxicity at the concen-
tration of 14 mg/kg which is 300 times as much as the LD50
value reported for natural gambierol. As shown in Figure 4,
gambierol has a flat “ladder-shaped” skeleton as do the other
natural polycyclic ethers. On the other hand, 16-epi-gambierol
is bent into a “stepladder-like” structure. These results indicate
that the trans-fused polycyclic ether framework is essential to
the toxicity. Probably, the bend of the molecule would inhibit
the ligand-receptor interaction although the detail is not clear
yet.30
Acknowledgment. We thank Professor T. Yasumoto (Tohoku
University) for providing the 1H NMR spectrum of 1, Professor
M. Hirama (Tohoku University) for supporting the measurement
of MALDI TOF mass spectra, Professor T. Oishi (Osaka
University) and Professor M. Inoue (Tohoku University) for
valuable dicussion on the intramolecular allylation of R-acetoxy
ethers. This work was financially supported by the Naito
Foundation and the Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan.
Supporting Information Available: Experimental procedures
and characterization data for all new compounds; copies of 1H
NMR spectra for selected compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(29) TLC analyses of 1 (Rf ) 0.22, CH2Cl2/MeOH ) 20:1) and 2 (Rf ) 0.12,
CH2Cl2/MeOH ) 20:1) indicated the significant difference of their polarity.
See Supporting Information.
(30) Recently, inhibition of brevetoxin binding to the voltage-gated sodium
channel by natural gambierol was reported, see: Inoue, M.; Hirama, M.;
Satake, M.; Suguyama, K.; Yasumoto, T. Toxicon 2003, 41, 469-474.
JA036984K
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