Synthesis of the fully functionalized ABCDE ring moiety of ciguatoxin

Article abstract of DOI:10.1021/ol0364475

A fully functionalized ABCDE ring moiety of ciguatoxin (CTX), the major causative agent of ciguatera poisoning, was synthesized for the first time. The present strategy involves the efficient installation of the C5-dihydroxybutenyl substituent and constru

Full text of DOI:10.1021/ol0364475

ORGANIC
LETTERS
2004
Vol. 6, No. 5
751-754
Synthesis of the Fully Functionalized
ABCDE Ring Moiety of Ciguatoxin
Shoji Kobayashi, Babak H. Alizadeh, Shin-ya Sasaki, Hiroki Oguri, and
Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan
hirama@ykbsc.chem.tohoku.ac.jp
Received December 17, 2003
ABSTRACT
A fully functionalized ABCDE ring moiety of ciguatoxin (CTX), the major causative agent of ciguatera poisoning, was synthesized for the first
time. The present strategy involves the efficient installation of the C5-dihydroxybutenyl substituent and construction of the tetrahydrooxepin
E ring using a novel r-chlorosulfide synthon.
Ciguatoxins (CTXs), the causative agents from epiphytic
dinoflagellate (Gambierdiscus toxicus),1 are transferred into
more than 100 species of fish through the food chain, causing
ciguatera poisoning primarily in tropical and subtropical
regions.2 The extremely low content of toxins in fish has
limited the isolation from natural sources and detailed
biological studies on the voltage-sensitive sodium channels
(VSSC),3 as well as the preparation of anti-CTX antibodies
for detecting CTXs.4 Chemical synthesis is therefore the only
plausible solution. In 2001, our synthetic efforts culminated
in the first total synthesis of CTX3C 1.5,6 The final stage of
the synthesis of 1 involved the coupling of the left and right
wings with the concomitant construction of the central FG
ring system. This strategy is expected to be applicable to all
CTXs due to the common FG ring. In this context, the left
wing 3 serves as a key intermediate for synthesizing a
biologically more potent and structurally more complex
ciguatoxin (CTX, 2).7,8 The dihydroxybutenyl substituent
embedded in the A ring of 2 poses a greater synthetic
challenge. A fully functionalized ABCDE ring moiety such
as 3, therefore, has yet to be achieved, while several methods
to construct the AB(C) ring system with the dihydroxybute-
nyl substituent have been reported.9,10 Herein, an efficient
synthesis of 3 is reported for the first time.
(1) Yasumoto, T.; Nakajima, I.; Bagnis, R.; Adachi, R. Bull. Jpn. Soc.
Sci. Fish. 1977, 43, 1021-1026.
(2) (a) Scheuer, P. J. Tetrahedron 1994, 50, 3-18. (b) Lewis, R. J.
Toxicon 2001, 39, 97-106. (c) Yasumoto, T.; Murata, M. Chem. ReV. 1993,
93, 1897-1909.
(3) Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand, A.-M. Toxicon
1999, 37, 125-143.
(4) Oguri, H.; Hirama, M.; Tsumuraya, T.; Fujii, I.; Maruyama, M.;
Uehara, H.; Nagumo, Y. J. Am. Chem. Soc. 2003, 125, 7608-7612 and
references therein.
(5) (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.;
Oguri, H.; Satake, M. Science 2001, 294, 1904-1907. (b) Inoue, M.; Uehara,
H.; Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551-4554.
The NAP-protected ABCD ring fragment 4 was selected
as a versatile starting material, because a practical, asym-
10.1021/ol0364475 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/12/2004

Scheme 1. Ni-Catalyzed Coupling of Alkenyl Borates 6 with the AB Ring Model 5
metric route to such an ABCD ring system was recently
double bond in the D ring. The resulting enol ether 9 was
oxidized with Pb(OAc)4 at -5 °C in the presence of
14
established11 and this unit is expected to be a common
precursor for the divergent synthesis of the left wings of both
1 and 2. The required steps for synthesizing 3 include the
assembly of the A ring substituent as well as the tetra-
hydrooxepin E ring. On the other hand, alternative construc-
tion of the tetrahydrooxocin E ring system will produce the
corresponding left wing of CTX3C 1 as well.
pyridine, as an acid scavenger yielding a single stereoisomer
of unstable 10. Addition of pyridine to this oxidation reaction
was essential to effectively attain 10. The Ni-catalyzed
coupling of 10 with the alkenylborate 6b9d,12 proceeded with
high stereoselectivity yielding the R-adduct 11 and the
γ-adduct 12 with a 42% yield (three steps from 4) in a 1:1
ratio. The stereochemistry of 11 was established using NOE
experiments. Thus, efficient installation of the dihydroxy-
butenyl substituent into the ABCD ring fragment was
achieved with complete stereocontrol.
In an effort to adopt the recently developed Ni-catalyzed
coupling technology,9d,12 the effect of dihydroxybutenyl
borate protective groups on the regioselectivity was inves-
tigated. Since the NAP group proved to be optimal for the
total synthesis of 1,5b bis NAP ether 6a was examined as a
coupling agent with the model AB ring fragment 5 (Scheme
1). The R/γ selectivity, however, resulted in a less satisfactory
ratio (7a:8a ) 1:3), while the TBS ether 6b afforded a more
acceptable ratio (7b:8b ) 1:1.1).
Scheme 2. Assembly of the Dihydroxybutenyl Substituent in
the ABCD Ring Systema
The allylic acetate 10 of the ABCD ring was stereoselec-
tively synthesized from 411 via enol ether 9 (Scheme 2).
Isomerization of the C6,7-double bond of 4 was achieved
using Wilkinson catalyst and DBU13 without affecting the
(6) Recent synthetic studies from other groups, see: (a) Takai, S.;
Sawada, N.; Isobe, M. J. Org. Chem. 2003, 68, 3225-3231. (b) Takakura,
H.; Sasaki, M.; Honda, S.; Tachibana, K. Org. Lett. 2002, 4, 2771-2774.
(c) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.; Murai, A. Synlett
2002, 1835-1838. (d) Bond, S.; Perlmutter, P. Tetrahedron 2002, 58, 1779-
1787. (e) 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.; Pe´rez, R. L.; Mart´ın, J. D. Tetrahedron 2002, 58, 1921-1942.
(7) (a) Isolation: Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Yasumoto,
T. J. Am. Chem. Soc. 1989, 111, 8929-8931. Murata, M.; Legrand, A. M.;
Ishibashi, Y.; Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-
4386. (b) Absolute configuration: Satake, M.; Morohashi, A.; Oguri, H.;
Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T. J. Am. Chem. Soc. 1997,
119, 11325-11326.
a Reagents and conditions: (a) (Ph3P)3RhCl (0.1 equiv), DBU
(1 equiv), MeOH-ClCH2CH2Cl (1:1), 65 °C, 15 min. (e) Pb(OAc)4
(3 equiv), pyridine (3 equiv), CH2Cl2, -18 to -5 °C, 42 h. (f) 6b
(3.3 equiv), NiCl2(PPh3)2 (0.3 equiv), tBuCN (2.0 equiv), NaI (1.0
equiv), THF, 0 °C to room temperature, 1.7 h, 11 (20%), 12 (22%)
(three steps from 4).
(8) Tatami, A.; Inoue, M.; Uehara, H.; Hirama, M. Tetrahedron Lett.
2003, 44, 5229-5233.
(9) Previous our approaches, see: (a) Sato, O.; Hirama, M. Synlett 1992,
705-707. (b) Oguri, H.; Tanaka, S.; Hishiyama, S.; Oishi, T.; Hirama, M.;
Tsumuraya, T.; Tomioka, Y.; Mizugaki, M. Synthesis 1999, 1431-1436.
(c) Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999,
40, 5405-5408. (d) Oguri, H.; Tanaka, S.; Oishi, T.; Hirama, M.
Tetrahedron Lett. 2000, 41, 975-978.
(10) Approaches of other groups, see: (a) Oka, T.; Fujiwara, K.; Murai,
A. Tetrahedron 1998, 54, 21-44. (b) Hosokawa, S.; Isobe, M. J. Org. Chem.
1999, 64, 37-48. (c) Saeeng, R.; Isobe, M. Heterocycles 2001, 54, 789-
798.
The tetrahydrooxepin E ring was subsequently assembled
using a novel synthon, R-chlorosulfide 1515 (Scheme 3). After
sequential manipulation of the protective groups of 11 and
(13) (a) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973, 38, 3224. (b)
Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van Boom,
J. H. Synlett 1997, 1263-1264.
(14) (a) Dunkerton, L. V.; Euske, J. M.; Serino, A. J. Carbohydr. Res.
1987, 171, 89-107. (b) Hurd, C. D.; Edward, O. E. J. Org. Chem. 1954,
19, 1319-1324.
(15) R-Chlorosulfide 15 was synthesized from 2,3-O-isopropylidene-
glyceraldehyde in six steps: (i) Ph3PCH3Br, KOtBu, THF, 0 °C; (ii) pTsOH‚
H2O, THF-MeOH (8:1); (iii) TBSCl, imidazole, DMF; (iv) PPTS, EtOH,
20% in four steps; (v) Bu3P, (PhS)2, pyridine, 89%; (vi) NCS, CCl4, 100%.
(11) Oishi, T.; Tanaka, S.; Ogasawara, Y.; Maeda, K.; Oguri, H.; Hirama,
M. Synlett 2001, 952-954.
(12) (a) Kobayashi, Y.; Mizojiri, R.; Ikeda, E. J. Org. Chem. 1996, 61,
5391-5399. (b) Kobayashi, Y.; Takahisa, E.; Usmani, S. B. Tetrahedron
Lett. 1998, 39, 597-600. (c) Usmani, S. B.; Takahisa, E.; Kobayashi, Y.
Tetrahedron Lett. 1998, 39, 601-604. (d) Kobayashi, Y.; Murugesh, M.
G.; Nakano, M. Takahisa, E.; Usmani, S. B.; Ainai, T. J. Org. Chem. 2002,
67, 7110-7123.
752
Org. Lett., Vol. 6, No. 5, 2004

Scheme 3. Synthesis of the ABCDE Ring Moiety 3 of CTX (2)a
a Reagents and conditions: (a) TBAF, THF, rt, 1 h, 93%. (b) NaH, NAPBr, TBAI, THF-DMF (3:1), 40 °C, 5 h, 89%. (c) 1 N HCl-
MeOH-THF (1:5:10), rt, 25 h. (d) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 10 min, 72% (two steps). (e) CSA, MeOH-THF (1:1), -5 °C, 69
h, 91%. (f) (COCl)2, DMSO, Et3N, CH2Cl2, -60 °C, 1 h. (g) Ph3PCH3Br, KOtBu, THF, 0 °C to rt, 1 h. (h) TBAF, THF, rt, 1 h, 83% (three
steps). (i) 15 (3.0 equiv), AgOTf, 2,6-di-tert-butyl-4-methylpyridine, MS4A, CH2Cl2, -50 to -30 °C, 1 h. (j) TBAF, THF, rt, 30 min, 83%
(two steps). (k) 18 (0.05 equiv), CH2Cl2 (3 mM), rt, 2 h, 92%. (l) TBSCl, imidazole, DMF, rt, 12 h. (m) mCPBA, CH2Cl2, -10 °C, 18 h,
71% (two steps). (n) Allyltrimethylsilane, EtAlCl2, CH2Cl2, -70 °C, 30 min, 63%, 21 (24R:24S ) 1:3). (o) TBAF, THF, rt, 1 h, 93%. (p)
C6H4CO2I(OAc)3, CH2Cl2, rt, 1.2 h, 87%. (q) DBU, CH2Cl2, rt, 8 h, 23 (24R:24S ) 2.6:1). (r) NaBH4, CeCl3‚7H2O, CH2Cl2-MeOH (1:1),
0 °C, 10 min, 3 (64%), diastereomers of 3 (24%) (two steps).
Swern oxidation of the primary alcohol 13 followed by
Wittig olefination, the resulting alcohol 14 was coupled with
15 using an AgOTf-mediated method16,17 in the presence of
2,6-di-tert-butyl-4-methylpyridine, affording a single stereo-
isomer of the thioacetal 16. Whereas ring-closing metathesis
(RCM) of the TBS ether 16 using 1818 was sluggish, the
corresponding alcohol 17 smoothly underwent RCM, yield-
ing 19 in a 92% yield without reacting with other double
bonds.
The next step requires the insertion of an allyl group at
C24, necessary for the construction of the nine-membered
F ring via RCM in the total synthesis of 2.5,8,16 Ley’s
method19 was examined for the model DE ring system, 24a
and 24b, under a variety of conditions using allyltrimethyl-
silane and Lewis acids to elucidate the stereoselectivity.
Some of the results are summarized in Table 1. The highest
syn/anti ratio was realized when the alcohol 24a was treated
with TiCl4 at -78 °C (entry 3). However, these conditions
were not applicable to the ABCDE ring intermediate because
they were accompanied by the cleavage of NAP ethers.
Careful monitoring of the reaction indicated that deprotection
of the NAP groups was slow and could be suppressed if
allylation proceeded rapidly. Since the neighboring hydroxyl
group was suspected to affect the reaction rate, the alcohol
was protected as TBS ether 24b. In contrast to that observed
for 24a, allylation of 24b was completed within 1 h, even at
low temperatures, with a high yield of the allylated products,
25b and 26b, but with a reversed syn/anti ratio (entries 6, 7,
and 9). Since the stereochemistry of the allyl group can be
readily corrected at the later stage, the protected TBS ether
20 was used (Scheme 3). The sulfide of 20 was carefully
oxidized using mCPBA (at -10 °C to avoid olefin epoxi-
dation) to give the sulfone. This sulfone was then reacted
under the modified allylation conditions. A higher yield was
obtained using the less acidic EtAlCl2 (63% yield) than when
using AlCl3 (42% yield), leaving the NAP groups untouched.
The TBS group was then removed and oxidized to the ketone
as a 1:3 mixture of the C24 epimers, which enabled
epimerization and provided the more stable isomer 23 in a
2.6:1 ratio. Finally, stereoselective reduction20 of 23 yielded
the ABCDE ring fragment 3 from 22 with an overall yield
of 56%. The stereochemistry of 3 was fully assigned from
the results of NOE and NOESY experiments.21
(16) (a) Inoue, M.; Wang, G.-X.; Wang, J.; Hirama, M. Org. Lett. 2002,
4, 3439-3442. (b) Inoue, M.; Wang, J.; Wang, G.-X. Ogasawara, Y.;
Hirama, M. Tetrahedron 2003, 59, 5645-5659.
(17) (a) Mukaiyama, T.; Sugaya, T.; Marui, S.; Nakatsuka, T. Chem.
Lett. 1982, 1555-1558. (b) McAuliffe, J. C.; Hindsgaul, O. J. Org. Chem.
1997, 62, 1234-1239. (c) McAuliffe, J. C.; Hindsgaul, O. Synlett 1998,
307-308.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(19) (a) Brown, D. S.; Ley, S. V.; Bruno, M. Heterocycles 1989, 28,
773-777. (b) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V.
Tetrahedron 1989, 45, 4293-4308. (c) Simpkins, N. S. Tetrahedron 1991,
47, 323-332.
(20) Fujiwara, K.; Takaoka, D.; Kusumi, K.; Kawai, K.; Murai, A. Synlett
2001, 691-693.
Org. Lett., Vol. 6, No. 5, 2004
753

Table 1. Allylation with the DE Ring Model 24
entry
sulfone
Lewis acida
temperature
time (h)
yield (%)b
ratio (25:26)c
1
2
3
4
5
6
7
8
9
24a
24a
24a
24a
24a
24b
24b
24b
24b
AlCl3
EtAlCl2
TiCl4
TiCl4
TiCl2(OiPr)2
AlCl3
EtAlCl2
Et2AlCl
TiCl4
-78 to 0 °C
-78 °C to rt
-78 °C
-78 to -45 °C
-78 to -20 °C
-78 to -45 °C
-78 to -60 °C
-78 °C to rt
-78 °C
17
10
11
10
81
0
62 (78)d
56
0
89
73
0
60:40
no reaction
84:16
71:29
no reaction
17:83
20:80
no reaction
31.69
e
10
0.8
0.8
9.5
0.3
74
a Performed with 3-6 equiv of Lewis acid. b Isolated yield. c Determined by 1H NMR analysis (500 MHz, CDCl3). d Based on recovery of 24a. e Prepared
from TiCl4 and Ti(OiPr)4.
In summary, the fully functionalized ABCDE ring frag-
ment 3 of CTX 2 was synthesized from the readily accessible
ABCD ring moiety 4 for the first time. The present synthesis
features a short-step installation of the dihydroxybutenyl
substituent and efficient construction of the tetrahydrooxepin
E ring using the novel synthon 15. Further investigations
directed toward the total synthesis of 2 are currently under
way in our laboratory.
Acknowledgment. This work was supported by the
CREST and SORST programs from the Japan Science and
Technology Corporation (JST) and by a Grant-in-Aid for
Scientific Research (S) from the Japanese Society for the
Promotion of Science (JSPS). A fellowship to S.K. and S.S.
from the JSPS is also acknowledged.
(21) NOE and NOESY experiments of 3 were performed after converting
to diol 27: (i) Ac2O, pyridine, DMAP, CH2Cl2, rt, 5 h, 100%; (ii) DDQ,
CH2Cl2-H2O (20:1), rt, 35 min; (iii) CSA, MeOH-THF (1:1), rt, 45 min,
67% (two steps); (iv) TBSCl, Et3N, DMAP, CH2Cl2, 62 h, 100%.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all new synthetic products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0364475
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Org. Lett., Vol. 6, No. 5, 2004