Synthesis of the H-I-J tricyclic fragment of ciguatoxin, a marine polyether toxin

Article abstract of DOI:10.1055/s-2000-6507

During the course of our synthetic studies on ciguatoxin, synthesis of H-I-J tricyclic fragment has been stereoselectively achieved starting from a D-glucal derivative. The key steps are Sonogashira coupling reaction and cobalt complex-mediated oxocane cyclization.

Full text of DOI:10.1055/s-2000-6507

266
LETTER
Synthesis of the H-I-J Tricyclic Fragment of Ciguatoxin, a Marine Polyether
Toxin
Tong-Zhu Liu, Minoru Isobe*
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81-52-789-4111; E-mail: isobem@agr.nagoya-u.ac.jp
Received 29 November 1999
nection of the indicated bond in E furnishes the vinyl io-
Abstract: During the course of our synthetic studies on ciguatoxin,
dide F and the acetylene G. The stereogenic center in G
synthesis of H-I-J tricyclic fragment has been stereoselectively
derived from (S)-malic acid represents the C-12 (sugar
numbering) hydroxyl group in K-ring.
achieved starting from a D-glucal derivative. The key steps are So-
nogashira coupling reaction and cobalt complex-mediated oxocane
cyclization.
Key words: ciguatoxin, biscobalthexacarbonyl, oxocane cycliza-
tion, Sonogashira coupling
Ciguatera is one of the most widespread seafood poison-
ings which follows the consumption of warm water fish
contaminated with sodium channel neurotoxins known as
Ciguatoxin (CTX1B).1 The complex molecular structure
of CTX1B presents a formidable synthetic target mole-
cule, particularly with regard to the construction of its
trans-fused medium-sized ether rings.2 During the course
of our synthetic studies on ciguatoxin, we developed a
synthetic methodology for the construction of medium-
sized (7- to 10-membered) ether rings through cobalt
complex-mediated cyclization reaction.3 Recently, we
have achieved the model study on H-I-J ring system using
this methodology,4 we now report the synthesis of H-I-J
fragment 2. The retrosynthetic analysis of H-I-J fragment
2 (A) is illustrated in Scheme 1.
Retrosynthetic Analysis of H-I-J Ring Fragment
Scheme 1
Figure
Our synthesis plan began with Sonogashira reaction to es-
tablish all the requisite carbon framework;8 thus, coupling
of the vinyl iodide 33 with acetylenic chain9 4 in the pres-
ence of palladium(0) afforded the en-yne compound 5.
Acid-induced removal of the acetonide group, and subse-
quent protection of the corresponding primary alcohol as
TBDPS ether were followed by deacetylation and cobalt
complexation to provide the cobalt complex 6 (Scheme
2).
Retrosynthetic disconnection of the indicated C-O bond
of J-ring in lactone A provides dihydroxyl aldehyde B as
a potential precursor through a hemiacetal intermediate.5
The cis dihydroxyl group in B would be derived from the
corresponding olefin in C through osmium tetroxide-me-
diated dihydroxylation reaction.6 Olefin C should be ac-
cessible from cobalt complex D.7 The stereochemistry of
its methyl group has to be introduced. Opening the 8-
membered ring-I generates a precursor E. Retrosynthetic
removal of the biscobalthexacarbonyl group and discon-
Synlett 2000, No. 2, 266–268 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of the H-I-J Tricyclic Fragment of Ciguatoxin
267
tion of the newly-formed methyl group was determined by
comparison the NOESY data of these two compounds.12
Reductive decomplexation of 8a, and subsequent conver-
sion of the acetyl into benzyl group furnished the cis ole-
fin 9. Dihydroxylation of this olefin 9 with OsO4 in
acetone5 yielded a diol intermediate which was converted
to the corresponding acetonide, from which subsequent
removal of the TBDPS group and oxidation of the alcohol
afforded the corresponding aldehyde 10. Acidic hydroly-
sis of the acetonide group of 10 ended up with a subse-
quent ring-J formation in one step to afford a hemiacetal
intermediate, which was further transformed to the corre-
sponding lactone 11 through bromine oxidation. The sec-
ondary hydroxyl group on the I-ring was removed in 2
steps including 1) treatment of 11 with N,N'-thio-
carbonyldiimidazole13 in refluxing 1,2-dichloroethane to
provide the thioester 12 and 2) Barton's deoxygenation of
12 with tri-n-butyltin hydride14 in refluxing toluene. The
lactone 1315 showed the coupling constant (J9,10 = 9.5 Hz)
between the protons at the junction to indicate the trans
stereochemistry.
We have accomplished the synthesis of the H-I-J tricyclic
fragment directed toward the construction of the right
hand part of ciguatoxin. Further synthetic studies on the
construction of H-I-J-K ring fragment along this line are
now in progress and will be reported.
Acknowledgement
This research was financially supported by a Grant-In-Aids for Sci-
entific Research from the Ministry of Education, Science, Sports
and Culture and by JSPS-RFTF.
Reagents, conditions and yields: a) BuNH2, CuI, Pd(0), benzene, r.t.,
81%. b) MeOH, PPTS, 60 °C, 90%. c) TBDPSCl, Et3N, DMF, r.t.,
86%. d) MeOH, K2CO3, r.t., 91%. e) Co2(CO)8, CH2Cl2, 0 °C-r.t.,
98%. f) BF3∑OEt2, CH2Cl2, 0 °C, 50 min, 84%. g) Ac2O, Py. DMAP,
CH2Cl2, r.t., 90%. h) [HN = NH], MeOH, Et3N, r.t., [8a, 68%; 8b,
20%]. i) Bu3SnH, toluene, 50 °C, 87%. j) MeOH, K2CO3, r.t., 88%. k)
BnBr, NaH, DMF, -40-0 °C, 82%. l) OsO4, NMO, acetone-H2O (8:1),
0 °C-r.t., 80%. m) acetone, TsOH (cat), r.t., 93%. n) TBAF, THF, r.t.,
89%. o) DMSO, SO3∑Py, Et3N, 100%. p) 80% aq. AcOH, r.t., 98%.
q) Br2, DMF, NaOAc, 0 °C-r.t., 89%. r) thiocarbonyldiimidazole,
ClCH2CH2Cl, reflux, 77%. s) Bu3SnH, toluene, reflux, 88%.
References and Notes
(1) (a) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T.
J. Am. Chem. Soc. 1989, 111, 8929-8931. (b) Satake, M.;
Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.;
Yasumoto, T. J. Am. Chem. Soc. 1997, 119, 11325-11326.
c) Oguri, H.; Hishayama, S.; Sato. O.; Oishi, T.; Hirama, M.;
Murata, M.; Yasumoto, T.; Harada, N. Tetrahedron 1997, 53,
3057-3072.
(2) For recent synthetic studies from other groups, see: (a) Sasaki,
M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett. 1999, 40,
1337-1340. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.;
Tachibana, K. Organic Lett. 1999, 1, 1075-1077. (c) Oguri,
H.; Sakaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999,
40, 5405-5408. (d) Maeda, K.; Oishi, T.; Oguri, H.; Hirama,
M. Chem. Commun. 1999, 1063-1064. (e) Oishi, T.; Nagumo,
Y.; Shoji, M.; Brazidec, J.-Y. L.; Uehara, H.; Hirama, M.
Chem. Commun. 1999, 2035-2036. (f) Oka, T.; Murai, A.
Tetrahedron 1998, 54, 1-20. (g) Oka, T.; Fujiwara, K.; Murai,
A. Tetrahedron 1998, 54, 21-44.
Scheme 2
The cobalt complex 6 underwent smooth ring closure
upon treatment with boron trifluoride etherate in degassed
dichloromethane at 0 °C and acetylation to afford bicyclic
compound 7 as a single stereoisomer.10 The critical syn
stereochemistry of 7 was demonstrated by NOESY exper-
iments. The observation of cross peaks between H-4 (d
3.08, ddd, J = 11.0, 9.5, 4.8 Hz) and H-10 (d 4.79, dd,
J = 10.0, 3.0 Hz) indicated a syn relationship between
these protons. Reduction of the exo-cyclic olefin in 7 with
diimide11 afforded a 3:1 mixture of diastereoisomers 8a
and 8b, epimeric at C-7 (sugar numbering), which could
be separated by silica gel chromatography. The configura-
(3) (a) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett. 1994, 11, 916-
918. (b) Isobe, M.; Hosokawa, S.; Kira, K. Chem. Lett. 1996,
473-474. (c) Hosokawa, S.; Isobe, M. J. Org. Chem. 1999, 64
(1), 37-48. (d) Saeeng, R.; Isobe, M. Tetrahedron Lett. 1999,
40, 1911-1914. (e) For a review, see: Isobe, M.; Nishizawa,
R.; Hosokawa, S.; Nishikawa, T. J. Chem. Soc., Chem.
Commun. 1998, 2665-2676.
(4) Liu, T.-Z.; Li, J.-M.; Isobe, M. Tetrahedron 1999, to be
submitted.
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268
T.-Z. Liu, M. Isobe
LETTER
(5) Lewbart, M. L.; Schneider, J. J. J. Org. Chem. 1969, 34, 3505-
3512.
(4H, m, Ph). 13C NMR (100 MHz, CDCl3) d 14.0, 19.1, 21.2,
22.6, 26.6, 30.3, 31.5, 38.5, 40.3, 64.4, 7.9, 72.3, 77.2, 79.3,
80.4, 121.5, 127.8, 129.8, 133.1, 133.3, 135.6, 135.7, 141.2,
170.4, 199.7. MS (MALDI-TOF): calcd for C38H41Co2O11Si
m/z [M+H]+, 819.11; found, m/z 819.20.
(6) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40,
2247-2255. (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H.-L.;
Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org.
Chem. 1992, 57, 2768-2771.
(7) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609-
2612.
(8) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470.
(11) (a) Nicholas, K. M.; Pettit, R. Tetrahedron Lett. 1971, 37,
3475-3478. (b) Cusack, N. J.; Reese, C. B.; Roozpeikar, B. J.
Chem. Soc., Chem. Commun. 1972, 1132-1133. (c) Cusack, N.
J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron
1976, 32, 2157-2162.
(12) Cross peaks were observed between protons 7 and 4 as well as
7 and 10 in the NOESY experiments for compound 8b.
(13) Rasmussen, J. R. J. Org. Chem. 1980, 45, 2725-2727.
(14) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574-1585.
(9) Compound 4 was synthesized as follows:
(15) Data of the lactone 13: mp (°C):127-129. [a]D27 -59.2 (c 0.20,
CHCl3). 1H NMR (300 MHz, CDCl3) d 1.08 (3H, d, J = 7.0
Hz, CH3), 1.45-1.52 (1H, m, H-3a), 1.59-1.69 (4H, m,
H-2 x 2, H-6a, H-8a), 1.79-1.92 (2H, m, H-6b, H-7), 2.03-2.10
(3H, m, H-3b, H-8b, H-11a), 2.39 (1H, dt, J = 13.8, 7.8 Hz,
H-11b), 3.05 (1H, td, J = 10.0, 2.8 Hz, H-5), 3.15 (1H, td,
J = 10.0, 4.8 Hz, H-4), 3.23-3.31 (1H, m, H-1a), 3.64 (1H, td,
J = 9.5, 6.0 Hz, H-10), 3.83 (1H, br d, J = 11.0 Hz, H-1b), 3.95
(1H, dd, J = 8.5, 6.0 Hz, H-12), 4.35 (1H, ddd, J = 11.0, 9.5,
3.5 Hz, H-9), 4.66 (1H, d, J = 12.0 Hz, PhCH2O), 4.89 (1H, d,
J = 12.0 Hz, PhCH2O), 7.30-7.39 (5H, m, Ph). 13C NMR (75
MHz, CDCl3) d 25.8, 27.8, 32.4, 36.2, 45.2, 45.6, 67.5, 72.1,
72.3, 80.1, 81.9, 82.0, 85.3, 128.1, 128.5, 137.2, 169.8. IR
(KBr): nmax 1749, 1685, 1508, 1458, 1266, 1181, 1115, 947
cm-1. Anal. Calcd for C21H28O5: C, 69.98; H, 7.83. Found: C,
70.14; H, 8.02.
Reagents, conditions and yields: a) BH3∑SMe2, B(OMe)3,
THF, 0 °C, then MeOH workup. b) acetone, TsOH (cat), r.t.,
81% (2 steps). c) DMSO, (COCl)2, Et3N, CH2Cl2, -78-0 °C. d)
trimethylsilylacetylene, n-BuLi, THF, -78-0 °C, 53% (2
steps). e) DMSO, KOH powder, CH3I, 82%.
(10) Selected data of compound 7: [a]D26+26.0 (c 0.03, CHCl3). 1H
NMR (300 MHz, CDCl3) d 1.24-1.31 (1H, m, H-3a), 1.53-
1.56 (2H, m, H-2 x 3), 1.79 (1H, br d, J = 11.8, H-3b), 1.95
(1H, ddd, J = 14.2, 10.0, 5.2 Hz, H-11a), 2.06 (3H, s,
CH3CO), 2.39 (1H, ddd, J = 14.2, 10.0, 2.6 Hz, H-11b), 2.61
(1H, dd, J = 14.0, 2.0 Hz, H-6a), 2.72 (1H, dd, J = 14.0, 4.5
Hz, H-6b), 3.08 (1H, ddd, J = 11.0, 9.5, 4.8 Hz, H-4), 3.25-
3.33 (2H, m, H-1a, H-5), 3.78 (1H, dd, J = 12.0, 4.0 Hz, H-
13a), 3.83 (1H, dd, J = 12.0, 4.0 Hz, H-13b), 3.89 (1H, dt,
J = 11.8, 2.5 Hz, H-1b), 4.79 (1H, dd, J = 10.0, 3.0 Hz, H-10),
5.28 (1H, m, H-12), 5.42 (1H, d, J = 1.5 Hz, C=CH2), 5.54
(1H, d, J = 2.0 Hz, C=CH2), 7.35-7.43 (6H, m, Ph), 7.65-7.69
Article Identifier:
1437-2096,E;2000,0,02,0266,0268,ftx,en;Y20899ST.pdf
Synlett 2000, No. 2, 266–268 ISSN 0936-5214 © Thieme Stuttgart · New York