Convergent synthesis of the E′FGH ring fragment of ciguatoxin 1B via an acetylene cobalt complex strategy

Article abstract of DOI:10.1021/jo034021y

A convergent synthesis of the E'FGH ring fragment 28 of ciguatoxin 1B, a principal toxin causing widespread seafood poisonings "ciguatera", has been accomplished through (i) coupling between the E' ring-acetylide 9 and the H ring-aldehyde 20, (ii) stereoselective F ring cyclization via an acetylene cobalt complex, (iii) conversion to a carbonyl function under high-pressure hydrogenation, and (iv) reductive hydroxyketone cyclization to construct the G ring. In the ¹H NMR analysis of 28 at room temperature, a considerable broadening phenomenon was observed due to the slow conformational changes of the FG ring, as reported for natural ciguatoxin 1B. When measured in pyridine at -20 °C, the spectra of 28 exhibited a 3.5:1 mixture of two conformational isomers (UP and DOWN conformers).

Full text of DOI:10.1021/jo034021y

Con ver gen t Syn th esis of th e E′F GH Rin g F r a gm en t of Cigu a toxin
1B via a n Acetylen e Coba lt Com p lex Str a tegy
Shigeyuki Takai, Naotaka Sawada, and Minoru Isobe*
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University,
Chikusa, Nagoya 464-8601, J apan
isobem@agr.nagoya-u.ac.jp
Received J anuary 8, 2003
A convergent synthesis of the E′FGH ring fragment 28 of ciguatoxin 1B, a principal toxin causing
widespread seafood poisonings “ciguatera”, has been accomplished through (i) coupling between
the E′ ring-acetylide 9 and the H ring-aldehyde 20, (ii) stereoselective F ring cyclization via an
acetylene cobalt complex, (iii) conversion to a carbonyl function under high-pressure hydrogenation,
1
and (iv) reductive hydroxyketone cyclization to construct the G ring. In the H NMR analysis of 28
at room temperature, a considerable broadening phenomenon was observed due to the slow
conformational changes of the FG ring, as reported for natural ciguatoxin 1B. When measured in
pyridine at -20 °C, the spectra of 28 exhibited a 3.5:1 mixture of two conformational isomers (UP
and DOWN conformers).
In tr od u ction
polyether compound in 1980.5 The gross structure, except
the absolute configuration and the relative one at C2
position, was elucidated by Yasumoto and co-workers in
1989 using a purified sample of only 0.35 mg.6 The
absolute configuration was determined by Yasumoto and
co-workers in 1997 as shown in Scheme 1.7 Despite
structural similarity to brevetoxins, the binding affinity
of 1 was shown to be some 10 times more potent than
that of brevetoxins. The activity of 1 remains one of the
most potent neurotoxins known with mice lethality LD50
of 0.35 µg/kg (i.p.).3
The striking constitution of 1 presents a formidable
challenge to organic synthesis. The unique and fascinat-
ing molecular architecture of 1, its association with fish
poisoning, its potent biological activity, the limited avail-
ability of the compound from nature, and the prospects
for expanding the arsenal of synthetic methods all
contributed to our decision to pursue a total synthesis of
1.8 Recently, Hirama’s group reported the first total
synthesis of CTX3C, a member of the CTX family.9
Ciguatoxin (recently called CTX1B, 1) is a principal
toxin causing ciguatera, which is one of the most wide-
spread seafood poisonings (Scheme 1).1 Ciguatoxin 1 and
its congeners are produced by the epiphytic dinoflagellate
Gambierdiscus toxicus2 and transferred through the food
chain among coral biota and accumulated in carnivorous
fish, thus causing human intoxication. It is a major
problem in the Pacific and Indian Oceans and the
Caribbean Sea, where roughly 20 000 people are affected
annually.1 Ciguatoxins are potent neurotoxins that bind
quasi-irreversibly to site 5 on the voltage-sensitive
sodium channels (VSSC).3 However, the mechanism for
the binding mode of ciguatoxins to the channel protein
has not been elucidated. The binding site on VSSC was
reported to be shared by brevetoxins or another class of
structurally related marine toxins.4
Ciguatoxin 1 was first isolated from moray eel, Gym-
nothorax javanicus, by Scheuer and co-workers at the
University of Hawaii in 1967 and characterized as a
During the course of our synthetic studies toward 1,
various methodologies have been developed on the basis
of (i) construction of medium-size (7-10) ether rings via
acetylene cobalt complexes in a highly stereoselective syn-
trans orientation,10 (ii) reductive decomplexation reaction
into cis-olefins or vinylsilanes,11 (iii) ring-opening reac-
* To whom correspondence should be addressed. Fax: +81-52-789-
4111.
(1) For reviews, see: (a) Gillespie, N. C.; Lewis, R. J .; Pearn, J .;
Bourke, A. T. C.; Helms, M. J .; Bourke, J . B.; Shields, W. J . Ned. J .
Aust. 1986, 145, 584-590. (b) Yasumoto, T.; Murata, M. Chem. Rev.
1993, 93, 1897-1909. (c) Scheuer, P. J . Tetrahedron 1994, 50, 3-18.
(d) Yasumoto, T. Chem. Rec. 2001, 1, 228-242.
(2) Yasumoto, T.; Nakajima, R.; Bagnis, R.; Adachi, R. Nippon
Suisan Gakkaishi 1977, 43, 1021-1023.
(3) (a) Lombert, A.; Bidard, J .-N.; Lazdunski, M. FEBS Lett. 1987,
219, 355-359. (b) Lewis, R. J .; Sellin, M.; Poli, M. A.; Norton, R. S.;
Macleod, J . K.; Sheil, M. M. Toxicon 1991, 29, 1115-1127. (c)
Dechraoui, M.-Y.; Naar, J .; Pauillac, S.; Legrand, A.-M. Toxicon 1999,
37, 125-143. (d) Anger, T.; Madge, D.-J .; Mulla, M.; Riddall, D. J . Med.
Chem. 2001, 44, 115-137.
(4) (a) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Engen, D. V.; Clardy, J .; Golik,
J .; J ames, J . C.; Nakanishi, K. J . Am. Chem. Soc. 1981, 103, 6773-
6776. (b) Shimizu, Y.; Chou, H.-N.; Bando, H.; Duyne, G. V.; Clardy,
J . C. J . Am. Chem. Soc. 1986, 108, 514-518.
(5) (a) Scheuer, P. J .; Takahashi, W.; Tsutsumi, J .; Yoshida, T.
Science 1967, 155, 1267-1268. (b) Tachibana, K. Ph.D. Thesis,
University of Hawaii, 1980.
(6) (a) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T.J .
Am. Chem. Soc. 1989, 111, 8929-8931. (b) Murata, M.; Legrand, A.
M.; Yasumoto, T. Tetrahedron Lett. 1989, 30, 3793-3794. (c) Murata,
M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J . Am.
Chem. Soc. 1990, 112, 4380-4386. (d) Murata, M.; Legrand, A. M.;
Scheuer, P. J .; Yasumoto, T. Tetrahedron Lett. 1992, 33, 525-526.
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Harada, N.; Yasumoto, T. J . Am. Chem. Soc. 1997, 119, 11325-11326.
10.1021/jo034021y CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/18/2003
J . Org. Chem. 2003, 68, 3225-3231
3225

Takai et al.
SCHEME 1. Retr osyn th etic An a lysis tow a r d CTX1B
tions of cyclic R,â-epoxysilanes into allyl alcohols,12 and
(iv) stereoselective heteroconjugate additions.13 We have
already reported the model syntheses of the ABC,14
BCDE,15 D′EF,16 H′IJ K,17 and E′FGH′ ring fragments.18
In this paper, we describe the convergent synthesis of
E′FGH′ ring 5 (without an angular methyl group corre-
sponding to the C56 position) and E′FGH ring 28 (with
an angular methyl group) using these methodologies,
which means not only a partial synthesis but also a
virtual synthesis in the last stage toward 1.
Resu lts a n d Discu ssion
(8) For recent synthetic studies from other groups, see: (a) Uehara,
H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.; Le
Brazidec, J .-Y.; Hirama, M. Tetrahedron 2002, 58, 6493-6512. (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) Leeuwenburgh, M. A.; Kulker,
C.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J . H. Synlett
1999, 1945-1947. (f) 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. (g) Soler, M.-A.; Palazo´n, J .-M.; Mart´ın, V. S.
Tetrahedron Lett. 1993, 34, 5471-5474. (h) Clark, J . S.; Hamelin, O.
Angew. Chem., Int. Ed. 2000, 39, 372-374 and references therein.
(9) (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.
Scheme 1 exhibits retrosynthetic analysis toward 1,
where the A, F, and G ring would be cyclized at the latest
stage from 2 after the coupling between acetylide of 3
(segment L) and aldehyde 4 (segment R). On the basis
of this analysis, we planned the synthesis of model
compound 5 for the E′FGH′ ring first without the angular
methyl group corresponding to the C56 position.19
Scheme 2 shows retrosynthetic analysis of 5. The G
ring cyclization would be achieved from hydroxyvinylsi-
lane 6, where the hydroxyl group would attack at the â
carbon to the silyl atom due to its electrophilicity under
either acidic or basic condition. Hydroxyvinylsilane 6
should be derived from acetylene cobalt complex 7.
Retrosynthetic disconnection of F ring of 7 gives 8, which
should be prepared by the coupling reaction between
acetylide of 9 and aldehyde 10.20
(10) (a) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett 1994, 11, 916-
918. (b) Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 2509-2520. (c)
Isobe, M.; Hosokawa, S.; Kira, K. Chem. Lett. 1996, 473-474. (d) For
a review, see; Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa, T.
Chem. Commun. 1998, 2665-2676.
(11) (a) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609-
2612. (b) Shibuya, S.; Isobe, M. Tetrahedron 1998, 54, 6677-6698. (c)
Takai, S.; Ploypradith, P.; Hamajima, A.; Kira, K.; Isobe, M. Synlett
2002, 588-592.
(15) (a) Kira, K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821-2824.
(b) Kira, K.; Hamajima, A.; Isobe, M. Tetrahedron 2002, 58, 1875-
1888.
(16) Kira, K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951-5955.
(17) (a) Liu, T.-Z.; Isobe, M. Synlett 2000, 587-589. (b) Liu, T.-Z.;
Isobe, M. Tetrahedron 2000, 56, 5391-5404. (c) Liu, T.-Z.; Li, J .-M.;
Isobe, M. Tetrahedron 2000, 56, 10209-10219. (d) Liu, T.-Z.; Isobe,
M. Synlett 2000, 266-268.
(18) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183-1186.
(19) Synthesis of another model system of the EFGH ring: (a)
Sasaki, M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett. 1999, 40,
1337-1340. (b) Imai, H.; Uehara, H.; Inoue, M.; Oguri, H.; Oishi, T.;
Hirama, M. Tetrahedron Lett. 2001, 42, 6219-6222. (c) Sasaki, M.;
Noguchi, T.; Tachibana, K. J . Org. Chem. 2002, 67, 3301-3310. (d)
Inoue, M.; Wang, G. X.; Wang, J .; Hirama, M. Org. Lett. 2002, 4, 3439-
3442.
(12) Kira, K.; Isobe, M. Chem. Lett. 2001, 432-433.
(13) (a) Isobe, M.; Kitamura, M.; Goto, T. Tetrahedron Lett. 1979,
20, 3465-3468. (b) Isobe, M.; Funabashi, Y.; Ichikawa, Y.; Mio, S.; Goto,
T. Tetrahedron Lett. 1984, 25, 2021-2024. (c) Perspectives in the
Organic Chemistry of Sulfur. Zwanenburg, B., Klunder, A. J . H., Eds.
New Synthetic Methods Using Vinyl SulfonessDevelopments in Het-
eroconjugate Addition. Isobe, M. Studies Org. Chem. 1987, 28, 209-
229.
(14) (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. Tetrahe-
dron Lett. 1999, 40, 1911-1914. (e) Saeeng, R.; Isobe, M. Heterocycles
2001, 54, 789.
3226 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of the E′FGH Ring Fragment of Ciguatoxin 1B
SCHEME 2. Retr osyn th etic An a lysis of E′F GH′ Rin g 5
SCHEME 3a
to afford tetracyclic compound 13. Extensive NMR analy-
ses (NOESY, HMBC, etc.) of the product, however,
indicated a much different compound 15 via transannular
reaction, where the lone pair of ether oxygen in F ring of
12 would attack at the â′ carbon to give intermediate 14
followed by 6-exo recyclization (Scheme 5).
Due to the difficulty in preventing from the transan-
nular reaction, we revised retrosynthetic analysis for
E′FGH′ ring 5 as shown in Scheme 6. Retrosynthetic
disconnection of G ring in 5 could provide hydroxyketone
16 as a reliable precursor, which could be converted from
acetylene cobalt complex 7 in one step, though it was
known that high-pressure hydrogenation of an acetylene
cobalt complex in F ring gave the corresponding ketone
in moderate yield.23
a
Segment coupling and F ring cyclization: (a) 9 (1.5 equiv),
n-BuLi, THF, -78 °C then 10, 86% (recovered 10: 14%); (b) TBAF,
THF; (c) Ac2O, Py, DMAP, CH2Cl2, 99% in two steps; (d) PPTS,
MeOH, 100%; (e) Co2(CO)8, CH2Cl2, 99%; (f) BF3‚OEt2, CH2Cl2, 0
°C to rt, 30 min, 77%.
Scheme 7 illustrates the final stage of the current
strategy toward the E′FGH′ ring synthesis. High-pres-
sure hydrogenation of 7 without any catalyst gave rise
to the desired ketone 17 in 37% yield as a major
compound along with conjugate enone 18 (4%) and diene
19 (15%).24 After deacetylation of 17, hydroxyketone 16
was treated with BF3‚OEt2 in the presence of Et3SiH in
CH3CN25 to accomplish the stereoselective construction
of the E′FGH′ ring 5 in 57% yield.18 In the 1H NMR
analysis of 5 at room temperature, a considerable broad-
ening phenomenon was observed due to the slow confor-
mational changes of the FG ring, as reported for natural
product CTX1B6,26 and other model systems.19,27 When
measured in CDCl3 at -20 °C, the spectra of 5 exhibited
a 2:1 mixture of two conformational isomers (DOWN and
UP conformers, whose olefinic bonds are located below
the down side or above the up side of the ring plane,
respectively) as sharp signals (Figure 1 and Figure 2).28
As shown in Scheme 3, the coupling reaction between
9 and 10, in fact, provided a propargyl alcohol in 86%
yield and protecting group manipulation followed by
conversion to a cobalt complex gave 11 as a precursor of
cyclization in four steps. Treatment of acetylene cobalt
complex 11 with BF3‚OEt2 at room temperature effected
the F ring cyclization in 77% yield to afford a single
diastereomer 7 under a thermodynamic condition with
the acid at 10 mM for half an hour. The stereochemistry
of 7 was determined to be syn by an NOE experiment.
Acetylene cobalt complex 7 was subjected to hydrosi-
lylation by heating in the presence of trapping agent, bis-
(trimethylsilyl)acetylene,21 for the active cobalt residues
and deprotection of acetate to give 6 as a precursor of G
ring cyclization (Scheme 4). J udging from conformational
analysis based on 1H NMR data of a product from 6
exposed to condition (c), it seemed likely that TBCO
(2,4,4,6-tetrabromo-2,5-cyclohexadienone)22 would attack
from â side of the disubstituted olefin of 6 followed by
intramolecular SN2′ reaction at the â carbon to silyl atom
(23) Kira, K.; Isobe, M. J . Synth. Org. Chem., J pn. 2000, 58, 23-
30.
(24) This reaction mechanism, however, has not been proven in
detail yet.
(25) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,
104, 4976-4978.
(26) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto,
T. J . Am. Chem. Soc. 1990, 112, 4380-4386.
(27) Conformational change of another model system: (a) Inoue, M.;
Sasaki, M.; Tachibana, K. Tetrahedron Lett. 1997, 38, 1611-1614. (b)
Inoue, M.; Sasaki, M.; Tachibana, K. Tetrahedron 1999, 55, 10949-
10970.
(20) Synthetic route and data of 9 and 10 were reported in ref 18.
(21) Kira, K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai, S.; Isobe,
M. Tetrahedron 2002, 58, 6485-6492.
(22) Kato, T.; Ichinose, I.; Hosogai, T.; Kitahara, Y. Chem. Lett. 1976,
1187.
J . Org. Chem, Vol. 68, No. 8, 2003 3227

Takai et al.
SCHEME 4a
a
Attempt to cyclize G ring: (a) Et3SiH, bis(trimethylsilyl)acetylene, 1,2-dichloroethane, 60 °C, 81%; (b) K2CO3, MeOH, 95%; (c) TBCO,
CH2Cl2, 0 °C, 100%.
SCHEME 5. Tr a n sa n n u la r Rea ction
SCHEME 6. Revised Retr osyn th etic An a lysis for E′F GH′ Rin g 5
SCHEME 7 a
Figure 2 illustrates possible conformational isomers
A-D,29,30 which were energy-minimized by Macromodel
(MM2* force field).31 Comparison of the coupling con-
stants observed by HOM2DJ (homo J -resolved 1H-1H
spectroscopy)32 of 5 with these of conformers A-D by
Macromodel should predict the majority to exist in
similar conformation to DOWN conformer A and the
minority to exist in similar conformation to UP conformer
B (Table 1).33 The orientation of methylene proton at C31
(28) When measured in Py-d5 at -20 °C, 1H NMR spectra of 28
exhibited a 1:1 mixture of two conformational isomers (UP and DOWN
conformers).
(29) Three conformers A, B, and C were extracted from results of
global search. Conformer
D was extracted from results of local
minimum after flipping the C31 of B and corrected for the angle of
H29-C29-C30-H30 of B as 180°.
(30) The parameters of conformer A, B, C, and D are shown in the
Supporting Information.
(31) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caulfield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1900, 11, 440.
(32) (a) Aue, W. P.; Karhan, J .; Ernst, R. R. J . Chem. Phys. 1976,
64, 4226-4227. (b) Derome, A. E. Modern NMR Techniques for
Chemistry Research; Pergamon: Oxford, 1991; pp 270-275. (c) Free-
man, R. A Handbook of NMR; Longman: Harlow, 1987; pp 106-110.
(33) Although reported in ref 18 (our previous paper) that the
majority should exist in similar conformation to DOWN conformer C,
we revise it to DOWN conformer A in this paper.
a
G ring cyclization: (a) H2, 100 kg/cm2, benzene, 65 °C, 6 h,
17: 37%, 18: 4%, 19: 15%; (b) K2CO3, MeOH, 100%; (c) BF3‚OEt2,
Et3SiH, CH3CN, -15 °C to rt, 30 min, 57%.
3228 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of the E′FGH Ring Fragment of Ciguatoxin 1B
F IGURE 1. 1H NMR spectra (600 MHz) of 5.
F IGURE 2. Conformational isomers of 5.
position in conformer C (D) is just different from that of
conformer A (B).
the synthesis of 11 as shown in Scheme 3, acetylene
cobalt complex 21, precursor for cyclization, was synthe-
sized from coupling between acetylide of E′ ring-enyne 9
and H ring-aldehyde having an angular methyl group 20
(Scheme 8).34 In contrast to the synthesis of demethyl
analogue 7, treatment of 21 with BF3‚OEt2 gave cycliza-
tion product 22 and reduction product 24. Presumably
acetylene cobalt complex 22 takes more strained struc-
ture than 7 due to the angular methyl group, which
triggered ring-opening followed by hydride-transfer from
benzyl ether to propargyl cation 23 to afford 24.35
Although the syn stereochemistry between H29 and
H34 could not be determined directly by NOE experi-
ments, the fact that the coupling constants between H29
and H30 showed 8.8 Hz for the major conformer and 10.1
Hz for the minor conformer undoubtedly demonstrated
the trans stereochemistry of 5.
Having accomplished the convergent synthesis of the
E′FGH′ ring fragment 5, our attention turned to the
synthesis of the E′FGH ring fragment 28 having an
angular methyl group which exists in natural CTX1B at
the G/H ring junction (Schemes 8 and 9). According to
(34) Synthetic scheme and data of 20 are reported in the Supporting
Information.
J . Org. Chem, Vol. 68, No. 8, 2003 3229

Takai et al.
SCHEME 8 a
a
Segment coupling and side reaction in the F ring cyclization: (a) 9 (1.5 equiv), n-BuLi, THF, -78 °C then 20, 73% (recovered 20:
16%); (b) K2CO3, MeOH, 95%; (c) Ac2O, Py, DMAP, CH2Cl2, 100%; (d) PPTS, MeOH, 96%; (e) Co2(CO)8, CH2Cl2, 95%; (f) BF3‚OEt2, CH2Cl2,
0 °C, 5 min then rt, 8 min.
F IGURE 3. Conformational Isomers of 28.
SCHEME 9 a
TABLE 1. Com p a r ison of Obser ved Cou p lin g Con sta n ts
of 5 w ith Th ose of Con for m er A-D (in Hz)a
obsd
obsd
3J
(major)b
A
C
(minor)b
B
D
24, 25R
24, 25â
28R, 29
28â, 29
29, 30
30, 31R
30, 31â
31R, 32
31â, 32
32, 33
ca. 0
9.9
1.3
10.0
8.8
8.6
3.3
2.2
6.5
4.0
2.5
11.6
1.9
11.4
8.6
10.8
1.3
3.0
1.4
10.9
1.8
11.3
7.8
1.9
5.2
1.4
11.1
9.6
5.6
ca. 0
5.9
ca. 0
10.1
13.3
4.8
5.0
2.5
2.9
5.4
1.7
4.3
2.4
8.5
10.5
1.2
3.0
3.5
3.5
5.4
1.7
7.1
1.2
8.8
1.3
6.8
1.6
11.4
9.6
3.5
4.9
a
The observed coupling constants were obtained from HOM2DJ
in CDCl3. On the other hand, the coupling constants of conformers
b
A-D were obtained by Macromodel. The experimental error was
( 0.2 Hz.
On the other hand, 21 was treated with TsOH‚H2O to
give 22 in 86% yield without byproduct 24 (Scheme 9).
High-pressure hydrogenation of 22 in hexane gave rise
to desired ketone 25 in 46% yield as a major product
along with conjugate enone 26 (7%) and diene 27 (12%).
Finally, hydroxyketone 25 was successfully transformed
into 28 under conditions similar to those of Scheme 7.
a
FG ring cyclization: (a) TsOH‚H2O, CH2Cl2, 0 °C to room
temperature, 1 h, 86%; (b) H2, 100 kg/cm2, hexane, 65 °C, 25: 46%,
26: 7%, 27: 12%; (c) K2CO3, MeOH, 97%; (d) BF3‚OEt2, Et3SiH,
CH3CN, 72%.
(35) (a) D´ıaz, D.; Mart´ın, V. S. Org. Lett. 2000, 2, 335-337. (b) D´ıaz,
D.; Mart´ın, V. S. Tetrahedron Lett. 2000, 41, 743-746. (c) D´ıaz, D.;
Mat´ın, V. S. J . Org. Chem. 2000, 65, 7896-7901.
1
In the H NMR analysis of 28 at room temperature, a
considerable broadening phenomenon was observed as
3230 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of the E′FGH Ring Fragment of Ciguatoxin 1B
TABLE 2. Com p a r ison of Obser ved Cou p lin g Con sta n ts
of 28 w ith Th ese of Con for m er X a n d Y (in Hz)a
Con clu sion
We have accomplished the convergent synthesis of the
central part (E′FGH ring 28 having an angular methyl
group) of CTX1B through the coupling reaction between
E′ ring-acetylide 9 and H ring-aldehyde 20, highly
stereoselective cyclization of the F ring using an acetylene
cobalt complex, and a novel conversion of the complex
22 into ketone 25 followed by reductive hydroxyketone
cyclization of the G ring.
3J
obsd (major)b
X
Y
24, 25R
24, 25â
28R, 29
28â, 29
29, 30
30, 31R
30, 31â
31R, 32
31â, 32
5.3
2.4
5.1
ca. 0
12.5
10.1
1.0
5.5
1.7
4.4
2.4
8.6
10.9
1.3
4.6
2.3
2.5
11.6
1.9
11.4
8.6
11.1
1.4
4.7
8.2
5.0
1
In the H NMR analysis of 28 at room temperature, a
2.2
considerable broadening phenomenon was observed due
to the slow conformational changes of the FG ring, as
reported for natural CTX1B. When measured in pyridine-
d5 at -20 °C, the spectra exhibited a 3.5:1 mixture of
two conformational isomers (UP and DOWN conformers).
For the conformational assignments of 28, the experi-
mental methods including HOM2DJ and molecular me-
chanics calculation methods led us to conclude that the
major and minor conformers were assignable to those X
and Y, respectively.
a
The observed coupling constants were obtained from HOM2DJ
in Py-d5. On the other hand, the coupling constants of conformers
X and Y were obtained by Macromodel. The experimental error
was ( 0.2 Hz.
b
the case in E′FGH′ ring 5.36 The 1H NMR spectra
measured in pyridine-d5 at -20 °C of 28 exhibited a 3.5:1
mixture of two conformational isomers (UP conformer X
and DOWN conformer Y, Figure 3).37 Comparison of the
coupling constants observed by HOM2DJ with these of
conformers X and Y by Macromodel should predict the
majority to exist in similar conformation to UP conformer
X (Table 2).38 The trans stereochemistry of 28 should be
demonstrated by coupling constants (12.5 Hz) between
H29 and H30.
Further studies toward the total synthesis of CTX1B
are now in progress.
Ack n ow led gm en t. We thank J SPS for a DC schol-
arship to S.T. and Mr. K. Koga (Nagoya University) for
the NMR measurements.
(36) The broadening spectrum was shown in the Supporting Infor-
mation.
Su p p or tin g In for m a tion Ava ila ble: Synthetic scheme
toward H ring-aldehyde 20, experimental procedure, charac-
terization data, and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(37) When measured in CDCl3 at -20 °C, the 1H NMR spectra of
28 exhibited a 1:1 mixture of two conformational isomers (UP and
DOWN conformers).
(38) The parameters of conformer X and Y are shown in the
Supporting Information.
J O034021Y
J . Org. Chem, Vol. 68, No. 8, 2003 3231