Synthesis of the EF-ring of ciguatoxin 3C based on the [2,3]-wittig rearrangement and ring-closing olefin metathesis

Article abstract of DOI:10.1021/ol702231j

The EF-ring segment of Ciguatoxin 3C, a causative toxin of ciguatera fish poisoning, was synthesized in three major steps: 1,4-addition for the C20O-C27 bond connection, chirality transferring anti selective [2,3]-Wittig rearrangement for the construction of the anti-2-hydroxyalkyl ether part, and ring-closing olefin metathesis for the F-ring formation.

Full text of DOI:10.1021/ol702231j

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5373-5376
Synthesis of the EF-Ring of Ciguatoxin
3C Based on the [2,3]-Wittig
Rearrangement and Ring-Closing Olefin
Metathesis
Akiyoshi Goto,† Kenshu Fujiwara,*,† Ayako Kawai,† Hidetoshi Kawai,†,‡ and
Takanori Suzuki†
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan, and PRESTO, Japan Science and Technology Agency (JST),
4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
fjwkn@sci.hokudai.ac.jp
Received September 11, 2007
ABSTRACT
The EF-ring segment of ciguatoxin 3C, a causative toxin of ciguatera fish poisoning, was synthesized in three major steps: 1,4-addition for
the C20O C27 bond connection, chirality transferring anti selective [2,3]-Wittig rearrangement for the construction of the anti-2-hydroxyalkyl
−
ether part, and ring-closing olefin metathesis for the F-ring formation.
Ciguatoxin 3C (1, Figure 1), isolated from cultured di-
noflagellate Gambierdiscus toxicus, is a member of the
ciguatera-toxin family that causes widespread seafood poi-
soning in circumtropical areas.1 The potent toxicity of 1
(MLD ) 1.3 µg/kg, ip, in mice)1 is attributed to unrelenting
activation of voltage-gated sodium channels by strong
binding of 1 to the channel (Ki ) 0.81 × 10-4 µM).2 This
strong binding suggests that 1 could be a potentially useful
biological tool.3 Despite the demand for significant quantities
of 1 for biological research into preventing ciguatera toxic-
ity,4 its supply is limited due to low productivity of the toxin
by G. toxicus (0.7 mg of 1 from 1100 L of culture).1
† Hokkaido University.
Figure 1.
‡ PRESTO.
(1) Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett. 1993, 34,
1975.
(2) (a) Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto, T.
Toxicon 2003, 41, 469. (b) Nicholson, G. M.; Lewis, R. J. Mar. Drugs
2006, 4, 82.
Therefore, chemical synthesis is a logical approach for
generating an adequate supply of 1.
10.1021/ol702231j CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/04/2007

The structure of 1 consists of 12 trans-fused cyclic ethers,
a spirocyclic acetal, and 30 stereocenters. This structure is
extremely complex in molecular size, topology, and stere-
ochemistry, making 1 an attractive and difficult synthetic
challenge. Hence, many chemists,5,6 including our group,7
have long investigated the synthesis of 1 and its congeners.
The Hirama group achieved the first total synthesis of 1 in
2001;8 now the challenge is focused on increasing the
efficiency of the synthesis.9 As a part of our program toward
the total synthesis of 1, we describe here an efficient synthesis
of the EF-ring segment (2, Scheme 1).
Scheme 1
Our plan for the synthesis of the EF-ring segment (2) of
1 is shown in Scheme 1. F-ring construction from intermedi-
ate 3 by ring-closing olefin metathesis (RCM)10,11 was
scheduled at the final stage of the synthesis. To establish
the anti-relationship of the two oxygen functional groups at
C26 and C27 of 3,12 the [2,3]-Wittig rearrangement of (3-
alkoxyallyloxy)acetate 5 to anti-3-alkoxy-2-hydroxyester 4
was used. This would readily lead to 3 in a chirality-
transferring manner.13 Although only a few examples of anti-
preference in the [2,3]-Wittig rearrangement of allyloxyac-
etate esters have been reported,14 we succeeded in finding
conditions for providing the desired 1,2-anti product 4
selectively. We chose to synthesize allyl alcohol 6, a
precursor of 5, by the 1,4-addition of 815 (the E-ring segment
of 1) to an alkynone under mild conditions.16 This was
followed by the subsequent stereoselective reduction of the
resulting ketone 7 with the assistance of the R2 group as a
chiral auxiliary. Here, a 2,2-dimethyl-1,3-dioxolan-4-yl
group, previously reported to be efficient for stereoselective
reduction of the adjacent ketone,17 was employed as a chiral
auxiliary. Therefore, the synthesis was started from alkynone
9,18 readily accessible from (R)-2,3-O-isopropylideneglyc-
eraldehyde.19
At first, in order to establish the above-mentioned process
toward an anti-3-alkoxy-2-hydroxy ester, acetylene ketone
9 was examined with simple alcohols (10) (Scheme 2). 1,4-
Addition, initiated by the portionwise addition of Bu3P (0.2-
0.7 equiv) to a solution of an alcohol (10a-e) and 9 in
CH2Cl2 at 0 °C, provided adducts 11a-e with high E-
selectivity. Although primary alcohols 10a,b and simple
(3) Manger, R. L.; Leja, L. S.; Lee, S. Y.; Hungerford, J. M.; Kirkpatrick,
M. A.; Yasumoto, T.; Wekell, M. M. J. AOAC Int. 2003, 86, 540.
(4) For the detection of ciguatoxins, see: (a) Hokama, Y.; Takenaka,
W. E.; Nishimura, K. L.; Ebesu, J. S. M. A. J. AOAC Int. 1998, 81, 727.
(b) Oguri, H.; Hirama, M.; Tsumuraya, T.; Fujii, I.; Maruyama, M.; Uehara,
H.; Nagumo, Y. J. Am. Chem. Soc. 2003, 125, 7608. (c) Tsumuraya, T.;
Fujii, I.; Inoue, M.; Tatami, A.; Miyazaki, K.; Hirama, M. Toxicon 2006,
48, 287 and references cited therein.
(5) For the total syntheses of related trans-fused polycyclic ethers, see:
brevetoxin A: (a) Nicolaou, K. C.; Yang, Z.; Shi, G.-Q.; Gunzner, J. L.;
Agrios, K. A.; Ga¨rtner, P. Nature 1998, 392, 264. For brevetoxin B, see:
(b) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 589. (c) Matsuo,
G.; Kawamura, K.; Hori, N.; Matsukura, H.; Nakata, T. J. Am. Chem. Soc.
2004, 126, 14374. (d) Kadota, I.; Takamura, H.; Nishii, H.; Yamamoto, Y.
J. Am. Chem. Soc. 2005, 127, 9246. For gambierol, see: (e) Kadota, I.;
Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 46. (f) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki,
M. J. Am. Chem. Soc. 2002, 124, 14983. (g) Johnson, H. W. B.; Majumder,
U.; Rainier, J. D. J. Am. Chem. Soc. 2005, 127, 848. For gymnocin A: (h)
Tsukano, C.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2005, 127, 4326.
Reviews: (i) Nakata, T. Chem. ReV. 2005, 105, 4314. (j) Inoue, M. Chem.
ReV. 2005, 105, 4379. (k) Sasaki, M. In Topics in Heterocyclic Chemistry;
Springer: Berlin, Germany, 2006; Vol. 5, pp 149-178.
(6) For recent synthetic studies on ciguatoxins, see: (a) Bond, S.;
Perlmutter, P. Tetrahedron 2002, 58, 1779. (b) 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. (c) Fuwa, H.; Fujikawa, S.; Tachibana, K.;
Takakura, H.; Sasaki, M. Tetrahedron Lett. 2004, 45, 4795. (d) Inoue, M.;
Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma, Y.; Kawada, Y.; Komano,
K.; Yamashita, S.; Lee, N.; Hirama, M. J. Am. Chem. Soc. 2006, 128, 9352.
(e) Clark, J. S.; Grainger, D. M.; Ehkirch, A. A.-C.; Blake, A. J.; Wilson,
C. Org. Lett. 2007, 9, 1033. (f) Nonoyama, A.; Hamajima, A.; Isobe, M.
Tetrahedron 2007, 63, 5886.
(12) For related stereoselective construction of 2,3-dialkoxy alkanamides
for cyclic ether synthesis: (a) Crimmins, M. T.; McDougall, P. J. Org.
Lett. 2003, 5, 591. (b) Crimmins, M. T.; She, J. Synlett 2004, 1371. (c)
Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005, 7,
4033. (d) Kobayashi, S.; Takahashi, Y.; Komano, K.; Alizadeh, B. H.;
Kawada, Y.; Oishi, T.; Tanaka, S.; Ogasawara, Y.; Sasaki, S.; Hirama, M.
Tetrahedron 2004, 60, 8375.
(7) (a) Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7011. (b)
Domon, D.; Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron
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Kawai, H.; Suzuki, T. Tetrahedron 2006, 62, 7408.
(8) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri,
H.; Satake, M. Science 2001, 294, 1904.
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(14) Fujimoto, K.; Nakai, T. Tetrahedron Lett. 1994, 35, 5019.
(15) The alcohol 8 was prepared from a known compound (ref 7a). The
synthesis is described in the Supporting Information.
(9) (a) Inoue, M.; Uehara, H.; Maruyama, M.; Hirama, M. Org. Lett.
2002, 4, 4551. (b) Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.;
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R. J.; Siedlecki, J.; O’Neil, S. A.; Sun, H. J. Am. Chem. Soc. 1997, 119,
6919. (b) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548.
See, also: (c) Clark, J. S. Chem. Commun. 2006, 3571.
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5374
Org. Lett., Vol. 9, No. 26, 2007

Scheme 2
Table 1.
entry
substrate
yield, %
ratioa 14:15:16:17
1
2
3
4
5
6
7
13a
13b
13c
13d
13e
13f
85
74
71
73
60
81
86
3.6:1:0:0
3.5:1:0:0
4:1:0:0
6:1:0:0
11:1:0:0
anti:syn ) 1:3
1:1.1:0:0.4
13gb
1
a Each ratio was determined by H NMR. b Racemic 13g was used.
14 and 15 in good yield with exclusive E-selectivity and
reasonable anti-selectivity (14a:15a ) 3.6:1; 14b:15b )
3.5:1) (entries 1 and 2). While diphenylmethyl ether 13c gave
a similar result to that of 13a (entry 3), (1S,5S)- and (1R,5R)-
carveyl ethers 13d and 13e displayed excellent ratios of 14
(14:15 ) 6-11:1) (entries 4 and 5). These results indicated
that increasing the bulkiness of the R1 group would enhance
the preference for 14. Therefore, higher anti-selectivity in
the [2,3]-Wittig rearrangement in the synthesis of the EF-
ring of 1 was predicted if a bulky oxocene ring (E-ring) for
the R1 group of the substrate was used. Notably, R2-modified
substrates 13f (R2 ) H) and 13g (R2 ) iPr) showed syn-
selectivity (entry 6) and production of 14, 15, and 17 with
low selectivity (entry 7), respectively. These results suggested
that the 2,2-dimethyl-1,3-dioxolanyl group at R2 also con-
tributed to the preference for 14 in the [2,3]-Wittig rear-
rangement, even though the mechanism of this contribution
is presently unclear.
secondary alcohol 10c showed moderate yields of 11a-c
(51-67%) in their reaction with an equimolar amount of 9,
the use of 2 equiv of 9 improved the yields (62-81%)
(entries 1-6). The low yields in the reactions of (1S,5S)-
and (1R,5R)-carveols (10d and 10e) with 1 equiv of 9 (entries
7 and 9) are attributable to slow reaction rates due to steric
hindrance of carveols and competition of catalyst deactivation
caused by the side reaction of Bu3P with 9.20 These yields
were also improved significantly by the use of 2 or more
equiv of 9 (entries 8 and 10). The chiral-auxiliary-assisted
stereoselective reduction of 11a-e was achieved by NaBH4
in the presence of CeCl3 to produce 12a-e with relatively
high selectivity (>7:1).21 The resulting alcohols were reacted
with tert-butyl bromoacetate under phase-transfer conditions
to give 13a-e in good yield.22,23
Encouraged by the above results, we next synthesized the
EF-ring segment (24) of 1 (Scheme 3). The 1,4-addition of
8 to 9 successfully provided 18, although the reaction had
to be repeated for complete consumption of 8. The reduction
of 18 with NaBH4/CeCl3 exclusively gave 19 (99% from
8), which was reacted with tert-butyl bromoacetate to afford
20 (94%). The [2,3]-Wittig rearrangement of 20, performed
by treatment with LHMDS in THF at -78 °C followed by
warming to 0 °C, provided 21 in high yield (86%) with
almost complete stereoselectivity, in accordance with the
above prediction. The ester 21 was reduced with LiBH4 to
an alcohol, which was converted to epoxide 22 by regiose-
lective tosylation25 followed by base treatment (77% from
21). The reaction of 22 with vinyl cyano-cuprate in the
presence of Et2O‚BF3 successfully produced 23 (87%).26
Representative results from the [2,3]-Wittig rearrangement
of 13 are shown in Table 1. The rearrangement was typically
carried out by deprotonation of 13 with 3 equiv of LHMDS24
in THF at -78 °C followed by warming to -20 °C. The
rearrangement of primary alkyl ethers 13a and 13b produced
(20) The portionwise addition of 0.4 equiv of Bu3P to 9 in the absence
of an alcohol resulted in complete consumption of 9 and production of a
mixture of highly polar compounds. This side reaction is serious in the
case of secondary alkyl alcohols (i.e., cyclohexanol and 3-pentanol), which
hardly reacted with 9. Secondary alcohols that have at least one sp2 carbon
adjacent to a carbinol group can react with excess 9 to produce the
corresponding adducts in moderate yields.
(21) Gemal, A. L.; Luche, J.-L. J Am. Chem. Soc. 1981, 103, 5454.
(22) Pietraszkiewicz, M.; Jurczac, J. Tetrahedron 1984, 40, 2967.
(23) Since the reactions of 12f and 12g with tert-butyl bromoacetate were
accompanied by significant ester hydrolysis, the reactions were halted after
35-45 min at about 50% conversion to avoid the loss of 13f and 13g.
(24) When NHMDS or KHMDS was used instead of LHMDS in
preliminary experiments with 13a, low E/Z and anti/syn selectivities were
observed (NHMDS: 14a:15a:16a:17a ) 1.5:2.3:1:2.3; KHMDS: 14a:15a:
16a:17a ) 5:1:0:6.5).
(25) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidynathan, R. Org. Lett. 1999, 1, 447.
(26) Alexakis, A.; Jachiet, D.; Normant, J. F. Tetrahedron 1986, 42, 5607.
Org. Lett., Vol. 9, No. 26, 2007
5375

Scheme 3
Finally, RCM of 23 with first-generation Grubbs’ catalyst27
rearrangement, and RCM. Further studies toward the total
in refluxing CH2Cl2 furnished the desired 24 in high yield
(92%). Remarkably, metathesis proceeded only between the
two vinyl groups of 23 despite the presence of four reactive
olefinic bonds. The stereochemistry at C26 and C27 of 24,
introduced during the [2,3]-Wittig rearrangement, was con-
firmed by 1H NMR analysis after acetylation of 24. The NOE
between H20 and H27 and large JH26-H27 (8.5 Hz) showed
the 20,27-cis-26,27-trans configuration of 24. Thus, stereo-
selective construction of the F-ring was achieved in nine steps
in 50% overall yield from 8.
synthesis of 1 are in progress in this laboratory.
Acknowledgment. We thank Mr. Kenji Watanabe and
Dr. Eri Fukushi (GC-MS and NMR Laboratory, Graduate
School of Agriculture, Hokkaido University) for the mea-
surements of mass spectra. This work was supported by a
Global COE Program (B01) and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology of Japanese Government.
In conclusion, the EF-ring segment (24) of 1 was ef-
ficiently synthesized from 8 through a key process including
1,4-addition, chirality-transferring anti-selective [2,3]-Wittig
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
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