Progress toward the total synthesis of ciguatoxins: A convergent synthesis of the FGHIJKLM ring fragment

Article abstract of DOI:10.1021/ol026306n

(Matrix presented) A highly convergent synthetic route to the FGHIJKLM ring fragment of ciguatoxins has been developed, which relied on extensive use of the B-alkyl Suzuki Miyaura coupling reaction.

Full text of DOI:10.1021/ol026306n

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2771-2774
Progress toward the Total Synthesis of
Ciguatoxins: A Convergent Synthesis of
the FGHIJKLM Ring Fragment
,‡
Hiroyuki Takakura,† Makoto Sasaki,* Shugo Honda,† 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 Laboratory of Biostructural Chemistry, Graduate School
of Life Science, Tohoku UniVersity, Tsutsumidori-Amamiya, Aoba-ku,
Sendai 981-8555, Japan
msasaki@bios.tohoku.ac.jp
Received June 5, 2002
ABSTRACT
A highly convergent synthetic route to the FGHIJKLM ring fragment of ciguatoxins has been developed, which relied on extensive use of the
B-alkyl Suzuki−Miyaura coupling reaction.
Ciguatera is a seafood poisoning prevalent in subtropical and
tropical areas with more than 20 000 victims annually and
continues to be a public health hazard.1,2 The causative toxins
originate in an epiphytic dinoflagellate Gambierdiscus toxi-
cus3 and are accumulated in fish through the food chain, thus
causing human intoxication. The principal toxins, ciguatoxin
(CTX, 1)4 and a number of congeners, including CTX3C
(2)5 and 51-hydroxyCTX3C (3),6 are extremely potent
neurotoxins that bind to voltage-sensitive Na+-channels
(VSSC) and inhibit depolarization to allow inward Na+ influx
to continue.7 The complex molecular architecture, remarkable
biological activity, and natural scarcity of these toxins make
them attractive and challenging targets for total synthesis,8-10
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.
(5) Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett. 1993, 34,
1975-1976.
(6) Satake, M.; Fukui, M.; Legrand, A.-M.; Cruchet, P.; Yasumoto, T.
Tetrahedron Lett. 1998, 39, 1197-1198.
† 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.
(7) (a) Bidard, J.-N.; Vijverberg, H. P. M.; Frelin, C.; Chungue, E.;
Legrand, A.-M.; Bagnis, R.; Lazdunski, M. J. Biol. Chem. 1984, 259, 8353-
8357. (b) Lambet, A.; Bidard, J. N.; Lazdunski, M. FEBS Lett. 1987, 219,
355-359.
(8) (a) Sasaki, M.; Inoue, M.; Noguchi, T.; Takeichi, A.; Tachibana, K.
Tetrahedron Lett. 1998, 39, 2783-2786. (b) Sasaki, M.; Noguchi, T.;
Tachibana, K. Tetrahedron Lett. 1999, 40, 1337-1340. (c) Inoue, M.;
Sasaki, M.; Tachibana, K. Tetrahedron 1999, 55, 10949-10970. (d) Sasaki,
M.; Inoue, M.; Takamatsu, K.; Tachibana, K. J. Org. Chem. 1999, 64,
9399-9415. (e) Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem. 1999,
64, 9416-9429. (f) Sasaki, M.; Honda, S.; Noguchi, T.; Takakura, H.;
Tachibana, K. Synlett 2000, 838-840. (g) Sasaki, M.; Noguchi, K.; Fuwa,
H.; Tachibana, K. Tetrahedron Lett. 2000, 41, 1425-1428. (h) Takakura,
(2) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T. Science 1967,
155, 1267-1268.
(3) Yasumoto, T.; Nakajima, R.; Bagnis, R.; Adachi, R. Bull. Jpn. Soc.
Sci. Fish. 1977, 43, 1021-1026.
(4) (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.;
10.1021/ol026306n CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/16/2002

culminating in the first total synthesis of 2 by Hirama, Oishi,
and co-workers.11 As part of our studies directed toward the
total synthesis of ciguatoxins and related compounds, we
have engaged in development of a general method for the
convergent assembly of a polycyclic ether structure based
on the B-alkyl Suzuki-Miyaura coupling.8h,12-14 Herein we
describe a highly convergent synthesis of the FGHIJKLM
ring fragment 4 of ciguatoxins by extensive use of the B-alkyl
Suzuki-Miyaura coupling reaction.
of the octacyclic polyether 4 with more convergency (Scheme
1). The target compound 4 was planned to be assembled by
Scheme 1. Retrosynthetic Analysis of Compound 4
2-fold B-alkyl Suzuki-Miyaura coupling from the FG, I,
and KLM ring fragments (7, 8, and 6, respectively).
Moreover, formation of a nine-membered ether ring within
Figure 1. Structures of ciguatoxin (CTX, 1) and its analogues
[CTX3C (2) and 51-hydroxyCTX3C (3)].
We previously reported approaches to the synthesis of the
G-M ring fragment of ciguatoxins.8h However, attempts to
construct the F ring from this advanced intermediate were
fruitless. These results prompted us to explore the synthesis
Scheme 2. Synthesis of the FG Ring Exocyclic Enol Ether 7a
H.; Noguchi, K.; Sasaki, M.; Tachibana, K. Angew. Chem., Int. Ed. 2001,
40, 1090-1093. (i) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana, K.
Tetrahedron 2002, 58, 1889-1911. (j) Sasaki, M.; Noguchi, T.; Tachibana,
K. J. Org. Chem. 2002, 67, 3301-3310 and references therein.
(9) For recent synthetic studies from other groups, see: (a) Liu, T.-Z.;
Isobe, M. Synlett 2000, 266-268. (b) Liu, T.-Z.; Kirschbaum, B.; Isobe,
M. Synlett 2000, 587-590. (c) Fujiwara, K.; Tanaka, H.; Murai, A. Chem.
Lett. 2000, 610-611. (d) Liu, T.-Z.; Isobe, M. Tetrahedron 2000, 56, 5391-
5404. (e) Kira, K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951-5955. (f)
Liu, T.-Z.; Li, J.-M.; Isobe, M. Tetrahedron 2000, 56, 10209-10219. (g)
Maruyama, M.; Maeda, K.; Oishi, T.; Oguri, H.; Hirama, M. Heterocycles
2001, 54, 93-99. (h) Oishi, T.; Nagumo, Y.; Shoji, M.; Le Brazidec, J.-
Y.; Kosaka, M.; Hirama, M. Chem. Commun. 2001, 381-382. (i) Saeeng,
R.; Isobe, M. Heterocycles 2001, 54, 789-798. (j) Kira, K.; Isobe, M.
Tetrahedron Lett. 2001, 42, 2821-2824. (k) Fujiwara, K.; Takaoka, D.;
Kusumi, K.; Kawai, K.; Murai, A. Synlett 2001, 691-693. (l) Nagumo,
Y.; Oguri, H.; Shindo, Y.; Sasaki, S.; Oishi, T.; Hirama, M.; Tomioka, Y.;
Mizugaki, M.; Tsumuraya, T. Bioorg. Med. Chem. Lett. 2001, 11, 2037-
2040. (m) Oishi, T.; Tanaka, S.; Ogasawara, Y.; Maeda, K.; Oguri, H.;
Hirama, M. Synlett 2001, 952-954. (n) Imai, H.; Uehara, H.; Inoue, M.;
Oguri, H.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2001, 42, 6219-6222.
(o) Candenas, M. L.; Pinto, F. M.; Cintado, C. G.; Morales, E. Q.; Brouard,
I.; D´ıaz, M. T.; Rico, M.; Rodr´ıguez, E.; Rodr´ıguez, R. M.; Pe´rez, R.; Mart´ın,
J. D. Tetrahedron 2002, 58, 1921-1942. (p) Kira, K.; Hamajima, A.; Isobe,
M. Tetrahedron 2002, 58, 1875-1888. (q) Maruyama, M.; Inoue, M.; Oishi,
T.; Oguri, H.; Ogasawara, Y.: Shindo, Y.; Hirama, M. Tetrahedron 2002,
58, 1835-1851. (r) Bond, S.; Perlmutter, P. Tetrahedron 2002, 58, 1779-
1787. (s) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183-1186. (t) Takai, S.;
Ploypradith, P.; Hamajima, A.; Kira, K.; Isobe, M. Synlett 2002, 588-592
and references therein.
a Reagents and conditions: (a) KHMDS, (PhO)2P(O)Cl, THF/
HMPA, -78 °C. (b) Pd(PPh3)4, CO, MeOH, Et3N, DMF, 50 °C,
76% (two steps). (c) AD mix-R, MeSO2NH2, t-BuOH/THF/H2O,
0 °C. (d) Me2C(OMe)2, CSA, CH2Cl2, rt, 79% (two steps) (+R-
diol acetonide, 18%). (e) DIBALH, CH2Cl2, -78 °C. (f) TIPSOTf,
2,6-lutidine, CH2Cl2, rt. (g) DMDO, CH2Cl2, -20 °C. (h) Et3SiH,
BH3‚THF, CH2Cl2, 0 °C, 75% (four steps). (i) TBAF, THF, rt, 97%.
(j) KOt-Bu, BnBr, THF, rt, 98%. (k) EtSH, Zn(OTf)2, CH2Cl2, rt,
then Me2C(OMe)2, rt, 78% (two steps). (l) EtSH, Zn(OTf)2, CH2Cl2,
rt, 86%. (m) TBSOTf, 2,6-lutidine, CH2Cl2, rt. (n) CSA, MeOH/
CH2Cl2, 0 °C, 96% (two steps). (o) I2, PPh3, imidazole, THF, rt.
(p) KOt-Bu, THF, 0 °C, 86% (two steps).
(10) 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.
(11) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri,
H.; Satake, M. Science 2001, 294, 1904-1907.
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Org. Lett., Vol. 4, No. 16, 2002

Scheme 3. Synthesis of the FGHI Ring Exocyclic Enol Ether
Scheme 4. Synthesis of the FGHIJKLM Ring System 4a
5a
a Reagents and conditions: (a) 7, 9-BBN-H, THF, rt, then 1 M
NaHCO3, 8, Pd(PPh3)4, DMF, rt, 85%. (b) DMDO, CH2Cl2, -20
°C, then Et3SiH, BH3‚THF, CH2Cl2, -20 °C, 82% (two steps). (c)
EVE, CSA, CH2Cl2, rt. (d) TBAF, THF, rt, 94% (two steps). (e)
TPAP, NMO, 4 Å MS, CH2Cl2, rt, 96%. (f) EtSH, Zn(OTf)2,
CH2Cl2, rt. (g) Me2C(OMe)2, CH2Cl2, rt, 68% from 18. (h) mCPBA,
NaHCO3, CH2Cl2, 0 °C. (i) Ac2O, pyridine, rt. (j) mCPBA,
NaHCO3, CH2Cl2, 0 °C, 84% from 18. (k) AlMe3, t-BuOMe, 0
°C. (l) K2CO3, MeOH, 60 °C. (m) Me2C(OMe)2, CSA, CH2Cl2, rt,
58% from 23 (+21, 38%). (n) EtSH, Zn(OTf)2, CH2Cl2, rt, 89%.
(o) TBSOTf, 2,6-lutidine, CH2Cl2, rt. (p) CSA, MeOH/CH2Cl2, 0
°C, 83% (two steps). (q) I2, PPh3, imidazole, THF, rt. (r) KOt-Bu,
THF, 0 °C, 94% (two steps).
a Reagents and conditions: (a) 5, 9-BBN-H, THF, rt, then 3 M
Cs2CO3, 6, Pd(PPh3)4, DMF, rt, 61%. (b) BH3‚THF, THF, rt, then
aq NaOH, H2O2, rt, 93%. (c) EVE, CSA, CH2Cl2, rt. (d) TBAF,
THF, rt, 73% (two steps). (e) TPAP, NMO, 4 Å MS, CH2Cl2, rt,
92%. (f) EtSH, Zn(OTf)2, CH2Cl2, rt, 73%. (g) Ph3SnH, AIBN,
toluene, 110 °C. (h) HC(OMe)3, PPTS, CH2Cl2, rt. (i) Ac2O, 160
°C, 87% (three steps).
steps. At this stage, the disubstituted olefin moiety was
masked as the protected diol. Dihydroxylation of 11 with
AD mix-R proceeded regio- and stereoselectively, and
subsequent acetonide formation gave â-diol acetonide 12 in
79% yield.17 DIBALH reduction was followed by protection
as its TIPS ether to give 13, which upon epoxidation with
dimethyldioxirane (DMDO) and immediate reduction with
Et3SiH and BH3‚THF8h produced 14 as the sole product (75%
yield over four steps). Alcohol 14 was then converted to diol
15 by a five-step sequence as shown. Subsequent silylation
followed by selective removal of the primary TBS group,
iodination of the derived alcohol, and subsequent treatment
with a base provided the requisite exocyclic enol ether 7 in
good overall yield.
7 was envisioned to be constructed from lactone 9 through
Pd(0)-mediated carbonylation of lactone-derived enol phos-
phate.8f
Synthesis of the FG ring exocyclic enol ether 7 began with
lactone 9,15 which was converted to the enol phosphate 10
(Scheme 2).16 Pd(0)-catalyzed carbonylation8f of 10 pro-
ceeded smoothly to give enoate 11 in 76% yield over two
(12) (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron
Lett. 1998, 39, 9027-9030. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.;
Tachibana, K. Org. Lett. 1999, 1, 1075-1077. (c) Fuwa, H.; Sasaki, M.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 8371-8375. (d) Fuwa, H.; Sasaki,
M.; Tachibana, K. Tetrahedron 2001, 57, 3019-3033. (e) Sasaki, M.;
Tsukano, C.; Tachibana, K. Org. Lett. 2002, 4, 1747-1750.
(13) For reviews on Suzuki-Miyaura reaction, see: (a) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki, A. In Metal-
Catalyzed Cross-Coupling Reactions; Diedlich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, Germany, 1998; Chapter 2. (c) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147-168.
Coupling of the FG and I rings followed by closure of
the H ring is summarized in Scheme 3. Hydroboration of 7
(15) Details of the synthesis of compound 9 are included in Supporting
Information.
(16) Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.; Ga¨rtner, P.; Yang, Z.
J. Am. Chem. Soc. 1997, 119, 5467-5768.
(17) The corresponding R-diol acetonide was formed in 18% yield, which
was potentially useful and could be converted to 4.
(14) For a recent comprehensive review on application of the B-alkyl
Suzuki-Miyaura reaction in natural product synthesis, see: Chemler, S.
R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-
4568.
Org. Lett., Vol. 4, No. 16, 2002
2773

with 9-BBN-H and subjection of the resultant alkylborane
to enol phosphate 88h [aqueous 1 M NaHCO3, Pd(PPh3)4,
DMF, room temperature]12 afforded cross-coupled product
16. Epoxidation of 16 with DMDO in CH2Cl2 and subsequent
reduction of unstable intermediary epoxide (Et3SiH, BH3‚
THF)8h were carried out in one pot to give alcohol 17 in
82% overall yield (three steps). Protection of the alcohol as
its ethoxy ethyl (EE) ether followed by desilylation and
oxidation of the resultant alcohol provided ketone 18.
Exposure of 18 with EtSH and Zn(OTf)2 effected mixed
thioketal formation with concomitant loss of the acetal groups
to afford tetraol 19. Reprotection of 19 as its bis-acetonide
and sulfide oxidation gave sulfone 20. However, treatment
of 20 with AlMe3 led to the undesired R-methylated product
21 in 84% yield along with a trace amount of the desired
â-methylated 22 (eq 1). After extensive experimentation, it
was eventually discovered that exposure of tetraacetate 23,
derived from 19, to AlMe3 in tert-butyl methyl ether led to
a mixture (ca. 1:1.5) of R- and â-methylated products with
the latter 24 predominating.18 The mixture, without separa-
tion, was deacetylated and reprotected as the bis-acetonide
to afford the desired 22 in 58% yield from 23 along with 21
(38% yield) (Scheme 3). Selective removal of the six-
membered acetonide group by using EtSH and Zn(OTf)2
afforded diol 25, which was readily converted to the FGHI
ring fragment 5 (71% overall yield from 25).
desilylation, and oxidation with TPAP/NMO19 gave ketone
27 exclusively (62% overall yield). Exposure of 27 to EtSH
and Zn(OTf)2 afforded mixed thioketal 28, which upon
radical reduction8h,12f,20 provided octacyclic ether 29. Intro-
duction of the cis double bond into the F ring was performed
by ortho ester formation of the Vis-diol followed by ther-
molysis in acetic anhydride21 to furnish the targeted
FGHIJKLM ring fragment 4 in 87% yield (three steps).
In conclusion, a highly convergent synthetic route to the
FGHIJKLM ring fragment 4 of ciguatoxins has been
achieved on the basis of extensive use of the B-alkyl Suzuki-
Miyaura reaction. Further studies directed toward the total
synthesis of ciguatoxins are in progress and will be reported
in due course.
The second Suzuki-Miyaura coupling of an alkylborane
derived from 5 with the KLM ring enol triflate 68h proceeded
smoothly to provide coupled product 26 in 61% yield
(Scheme 4). Hydroboration-oxidation, alcohol protection,
Acknowledgment. This work was financially supported
in part by a grant from Suntory Institute for Bioorganic
Research (SUNBOR).
(18) The effect of protective groups on the ability to generate 24 is not
easily understood, but the dioxolane ring attached to the F ring of 20 may
interefere with the approach of Me3Al to the oxocarbenium ion from the
â-face.
Supporting Information Available: Synthetic scheme
for compound 9 and experimental procedures and spectro-
scopic data for selected compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(20) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321-5330.
(21) Ando, M.; Ohhara, H.; Takase, K. Chem. Lett. 1986, 879-882.
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