A very short route to the functionalized A-ring moiety of ciguatoxin

Article abstract of DOI:10.1016/S0040-4039(99)02185-1

The functionalized AB-ring moiety of ciguatoxin has been synthesized in a highly convergent manner via transition metal catalysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02185-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 975–978
A very short route to the functionalized A-ring moiety of
ciguatoxin
Hiroki Oguri, Shin-ichiro Tanaka, Tohru Oishi and Masahiro Hirama ∗
Department of Chemistry, Graduate School of Science, Tohoku University, and CREST, Japan Science and Technology
Corporation (JST), Sendai 980-8578, Japan
Received 26 October 1999; accepted 24 November 1999
Abstract
The functionalized AB-ring moiety of ciguatoxin has been synthesized in a highly convergent manner via
transition metal catalysis. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: ciguatoxin; coupling reaction; transition metal catalysis; olefin metathesis.
Ciguatoxin (CTX1B, 1) is the principal toxin of ‘ciguatera’ sea-food poisoning.1 Every year, more
than 20 000 people in the tropics and subtropics suffer from ciguatera which causes gastro-intestinal,
neurological, and cardiovascular disorders.2 The extremely limited availability of 1 (0.35 mg of 1
from 4000 kg of moray eels)1a has hampered further pharmacological studies and development of an
immunoassay system for detecting poisonous fish.3 The total synthesis of 1 is one of the most challenging
targets in modern organic synthesis.4 The structural features of 1 which distinguish it from other
trans-fused polyether marine toxins5 such as the brevetoxins include the acid-sensitive A-ring structure
possessing a 1-butene-3,4-diol side-chain, which makes 1 the most potent among the congeners.6 While
several synthetic efforts to construct the A-ring of 1 have been reported, most of these syntheses are
linear and lengthy.7 Connecting the side-chain fragment (2) with the core (3) at C4–C5 should be the
most convergent approach (Scheme 1).8 However, it has not yet been realized. This approach would
facilitate the total synthesis of 1 because it should allow us to construct such a labile system in the later
stages of the total synthesis. We report herein an efficient methodology to synthesize the A-ring moiety
of 1 in a highly convergent manner.
We first attempted a Heck coupling reaction of vinyl iodide (2) and cyclic enol ether (6) (Scheme
2). The synthesis of 6 commenced with 4, which is available from tri-O-benzyl-D-glucal in two steps.9
Allylation of the secondary alcohol (4) followed by the ruthenium-catalyzed ring-closing metathesis
reaction gave allylic ether (5) in good yield. Isomerization of 5 to the cyclic enol ether (6) was achieved
using Wilkinson’s catalyst in 55% yield.10 The Heck reaction of 6 with 211 was performed under Larock’s
∗
Corresponding author. Fax: +81-22-217-6566; e-mail: hirama@ykbsc.chem.tohoku.ac.jp (M. Hirama)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02185-1
tetl 16113

976
Scheme 1.
conditions12 at 80°C. However, the undesired C5-epimer (7) was obtained predominantly in only low
yield (10% yield based on 2). Neither the utilization of Jeffery’s conditions [cat. Pd(OAc)2, nBu4NCl,
and KOAc in DMF at 40°C]13 nor the use of BINAP as a chiral phosphine ligand14 gave the desired
5R-isomer.
Scheme 2. Reagents and conditions: (a) allylbromide, KH, THF, 0°C to rt, 90%; (b) Cl2(PCy3)2Ru_CHPh (5 mol%), CH2Cl2,
rt, 95%; (c) (PPh3)3RhCl (10 mol%), DABCO (30 mol%), EtOH:H2O (9:1), reflux, 55%; (d) 2 (0.2 equiv.), Pd(OAc)2 (3 mol%),
PPh3 (9 mol%), Ag2CO3 (2 equiv.), CH3CN, 80°C, 7 (10%)
We next examined a palladium-catalyzed coupling reaction of the allylic acetal (10) with the vinyl me-
tal species (12) (Scheme 3).15 The secondary alcohol (4) was reacted with 1-phenoxy-1,2-propadiene16
according to the Rutjes’s procedure17 to yield a mixture of allylic acetals, 8 and 9, in 53% and 17% yields,
respectively. After separation, ring-closing olefin metathesis reactions of 8 and 9 yielded 1018 and 11,
respectively, in good yields. The C5 stereochemistry was determined by NOE experiments. Palladium-
catalyzed coupling of 10 with 12,19 however, yielded a γ-adduct (13) selectively.
This problem was solved by applying Kobayashi’s nickel-catalyzed reaction (Scheme 4).20 The
coupling of 10 with borate (14)21 was conducted in the presence of NiCl2(PPh3)2 (10 mol%), NaI (1
equiv.), and t-BuCN (2 equiv.) in THF. The reaction proceeded smoothly below room temperature to give
1522 and the regioisomer (13) in 40% and 49% yields, respectively.23 The C5 stereochemistry of 15 was
confirmed by NOE experiments.
Thus, we succeeded in the synthesis of the AB-ring moiety (15) of 1 in only three steps from the
D-glucose derivative (4). The present methodology should provide an extremely expeditious entry to
construct the labile A-ring system of 1. Further efforts directed towards the total synthesis of ciguatoxin
(1) are currently underway in our laboratory.

977
Scheme 3. Reagents and conditions: (a) Pd(OAc)2 (5 mol%), Ph2P(CH2)3PPh2 (5 mol%), 1-phenoxy-1,2-propadiene (5 equiv.),
Et3N (1.5 equiv.), CH3CN, 80°C, 9 h, 8 (53%) and 9 (17%); (b) Cl2(PCy3)2Ru_CHPh (5 mol%), CH2Cl2, reflux, 89%; (c)
Cl2(PCy3)2Ru_CHPh (10 mol%), CH2Cl2, reflux, 68%; (d) 12 (1.5 equiv.), Pd(PPh3)4 (10 mol%), 0°C to 35°C, THF, 13 (70%)
Scheme 4.
Acknowledgements
We thank Dr. Jean-Yves Le Brazidec for valuable discussions and Yumi Shindo for preparing 2. This
work was supported in part by the Ministry of Education, Science, Sports, and Culture of Japan.
References
1. For structural elucidation of 1, see: (a) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J. Am. Chem.
Soc. 1990, 112, 4380. (b) Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T. J. Am.
Chem. Soc. 1997, 119, 11325.
2. For recent reviews, see: (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897. (b) Scheuer, P. J. Tetrahedron 1994, 50, 3.
3. Oguri, H.; Tanaka, S.; Hishiyama, S.; Oishi, T.; Hirama, M.; Tumuraya, T.; Tomioka, Y.; Mizugaki, M. Synthesis 1999, SI,
1431 and references cited therein.
4. Maeda, K.; Oishi, T.; Oguri, H.; Hirama, M. Chem. Commun. 1999, 1063; Oishi, T.; Nagumo, Y.; Shoji, M.; Blazidec, J.-Y.
L.; Uehara, H.; Hirama, M. Chem. Commun. 1999, 2035, and references cited therein.
5. Alvarez, E.; Candenas, M.-L.; Pérez, R.; Ravelo, J. L.; Martín, J. D. Chem. Rev. 1995, 95, 1953.
6. Yasumoto, T.; Satake, M. J. Toxicol.-Toxin Reviews 1996, 15, 91.
7. Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405 and references cited therein.
8. Carbon numbering corresponding to that of 1 has been used throughout this paper.
9. Rainier, J. D.; Allwein, S. J. Org. Chem. 1998, 63, 5310.

978
10. Clark J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 127.
11. The fragment (2) was synthesized from (R)-1-benzyl glycerol as follows: (i) TBSCl, imidazole, DMF, 97%; (ii) Pd(OH)2,
H2, 97%; (iii) Dess–Martin periodinane, CH2Cl2; (iv) CrCl2, CHI3, THF, 0°C to rt, 58% (two steps); synthesis of (R)-1-
benzyl glycerol, see: Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Heterocycles 1981, 16, 381.
12. Larock, R. C.; Gong, W. H. J. Org. Chem. 1989, 54, 2047.
13. Jeffery, T.; David, M. Tetrahedron Lett. 1998, 39, 5751.
14. Hayashi, T.; Kubo, A.; Ozawa, F. Pure Appl. Chem. 1992, 64, 421.
15. Dunkerton, L. V.; Serino, A. J. J. Org. Chem. 1982, 47, 2814.
16. Moghaddam, F. M.; Emami, R. Synth. Commun. 1997, 27, 4073.
17. (a) Rutjes, F. P. J. T.; Kooistra, T. M.; Hiemstra, H.; Schoemaker, H. E. Synlett 1998, 192. (b) Okuro, K.; Alper, H. J.
Org. Chem. 1997, 62, 1566. (c) Ovaa, H.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 1998, 39, 3025.
18. Compound 10: 1H NMR (500 MHz, CDCl3) δ 2.59 (1H, m, H8), 2.80 (1H, dt, J=17.5, 6.0 Hz, H8), 3.49 (1H, m, H13), 3.52
(1H, m, H9), 3.54 (1H, t, J=9.5 Hz, H12), 3.62 (1H, dd, J=10.0, 5.0 Hz, H14), 3.64 (1H, t, J=9.0 Hz, H11), 3.70 (1H, dd,
J=10.5, 2.0 Hz, H14), 4.21 (1H, t, J=9.0 Hz, H10), 4.42 (1H, d, J=11.0 Hz, OCH2Ph), 4.54 (1H, d, J=12.5 Hz, OCH2Ph),
4.58 (1H, d, J=12.5 Hz, OCH2Ph), 4.61 (1H, d, J=11.0 Hz, OCH2Ph), 4.68 (1H, d, J=11.0 Hz, OCH2Ph), 4.70 (1H, d, J=11.0
Hz, OCH2Ph), 5.80 (1H, m, H6), 5.86 (1H, ddd, J=11.5, 6.0, 4.0 Hz, H7), 5.97 (1H, d, J=3.5 Hz, H5), 6.85–7.34 (20H, m);
FT-IR (film) νmax 3029, 2911, 2867, 1597, 1493, 1452, 1357, 1220, 1150, 1101, 1068, 1027, 991, 946, 754, 735, 697 cm−1
;
29
[α]D +46.3 (c 1.02, CHCl3); ESI-MS, calcd for C37H38O6Na (M+Na+) 601.257, found 601.253.
19. The vinyl zinc (12) was synthesized from 2: n-BuLi (1.5 equiv.) in THF at −78°C for 2 h; then ZnCl2 (1.2 equiv.) from
−78°C to 0°C.
20. Usmani, S. B.; Takahisa, E.; Kobayashi, Y. Tetrahedron Lett. 1998, 39, 601 and references cited therein.
21. The borate (14) was prepared from 2 as follows: (i) n-BuLi (1.5 equiv.), THF, −78°C, 2 h, then B[OCH(CH3)2]3 (1.5 equiv.),
−78°C to rt, then NH4Cl; (ii) 2,3-butanediol, MgSO4, toluene, rt, 69% (two steps); (iii) n-BuLi (1.1 equiv.), THF, 0°C, 15
min.
22. Compound 15: 1H NMR (500 MHz, CDCl3) δ 0.02 (6H, s), 0.03 (3H, s), 0.05 (3H, s), 0.87 (9H, s) 0.88 (9H, s) 2.46 (1H,
m, H8), 2.70 (1H, m, H8), 3.26 (1H, td, J=9.5, 3.5 Hz, H9), 3.43 (1H, dd, J=10.5, 5.5 Hz, H1), 3.46 (1H, dd, J=10.5, 4.0 Hz,
H1), 3.48 (1H, m, H13), 3.54 (1H, t, J=9.5 Hz, H12), 3.57 (1H, t, J=9.5 Hz, H10), 3.62 (1H, dd, J=10.5, 5.5 Hz, H14), 3.68
(1H, t, J=9.5 Hz, H11), 3.70 (1H, dd, J=10.5, 1.5 Hz, H14), 4.17 (1H, m, H2), 4.49 (1H, d, J=10.5 Hz, OCH2Ph), 4.54 (1H,
d, J=12.0 Hz, OCH2Ph), 4.57 (1H, d, J=12.0 Hz, OCH2Ph), 4.62 (1H, m, H5), 4.75 (1H, d, J=10.5 Hz, OCH2Ph), 4.83 (1H,
d, J=10.5 Hz, OCH2Ph), 5.00 (1H, d, J=10.5 Hz, OCH2Ph), 5.77–5.83 (3H, m, H3, H6, H7), 5.87 (1H, dd, J=15.5, 5.0 Hz,
H4), 7.10–7.40 (15H, m); 13C NMR (125 MHz, CDCl3) δ −5.37, −5.27, −4.65, −4.64, 18.29, 18.38, 25.72, 25.88, 25.97,
34.15, 68.07, 69.25, 73.45, 73.54, 75.01, 75.46, 75.71, 77.83, 78.05, 78.46, 85.43, 87.32, 115.28, 120.70, 127.24, 127.53,
127.59, 127.65, 127.74, 127.84, 127.90, 127.97, 128.11, 128.34, 129.63, 130.61, 131.35, 135.50, 138.12, 138.26, 138.82;
28
FT-IR (film) νmax 2955, 2928, 2857, 1471, 1361, 1255, 1102, 1028, 970, 835, 777, 734, 697 cm−1; [α]D +20.3 (c 0.776,
CHCl3); MALDI-TOF-MS, calcd for C47H68O7Na (M+Na+) 823.440, found 823.462.
23. The phenoxy group in 10 as a leaving group was crucial to attain 15. A similar reaction of the corresponding methyl acetal
with 14 did not proceed at room temperature; the tetrahydrooxepin ring opening occurred when heated.24
24. Guagnano, V.; Lardicci, L.; Malanga, C.; Menicagli, R. Tetrahedron Lett. 1998, 39, 2025.