Synthetic studies toward gambierol. Convergent synthesis of the octacyclic polyether core.

Article abstract of DOI:10.1021/ol0166597

[structure: see text]. A convergent synthetic route to the octacyclic polyether core of gambierol, a marine polycyclic ether toxin, has been developed. The synthesis involves construction of two fragments representing the ABC and EFGH ring systems followe

Full text of DOI:10.1021/ol0166597

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3549-3552
Synthetic Studies toward Gambierol.
Convergent Synthesis of the Octacyclic
Polyether Core
Haruhiko Fuwa,† Makoto Sasaki,*,†,‡ and Kazuo Tachibana†
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo,
and CREST, Japan Science and Technology Corporation (JST), Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Department of Biomolecular Science,
Graduate School of Life Science, Tohoku UniVersity, Tsutsumidori-Amamiya,
Aoba-ku, Sendai 981-8555, Japan
msasaki@chem.s.u-tokyo.ac.jp
Received August 28, 2001
ABSTRACT
A convergent synthetic route to the octacyclic polyether core of gambierol, a marine polycyclic ether toxin, has been developed. The synthesis
involves construction of two fragments representing the ABC and EFGH ring systems followed by their coupling via a B-alkyl Suzuki reaction.
The fused polyether class of marine natural products,
exemplified by brevetoxins, ciguatoxins, and maitotoxin, has
received much attention due to the biological potency and
structural complexity of these molecules.1,2 Gambierol (1)
was isolated as a toxic constituent from cultured cells of the
ciguatera causative dinoflagellate Gambierdiscus toxicus and
exhibits mouse lethality with an LD50 value of 50 µg/kg (ip).3
The symptoms caused in mice resemble those shown for the
ciguatoxins, which are the principal toxins responsible for
ciguatera fish poisoning, implying the possibility that gam-
bierol is also implicated in ciguatera. The biological basis
of the toxicity, however, remains unknown, mainly due to
an extremely limited availability. The gross structure, includ-
ing relative stereochemistry, has been determined by Yasu-
moto and co-workers on the basis of extensive NMR
analysis.3 Recently, the absolute configuration has been
unambiguously established by application of a chiral aniso-
tropic reagent.4 Its characteristic polyether structure and
potent biological activity, as well as the scarcity from natural
sources, make gambierol an intriguing synthetic target
molecule.5 In the course of our studies toward the total
synthesis of gambierol (1), we have reported the convergent
(4) Morohashi, A.; Satake, M.; Yasumoto, T. Tetrahedron Lett. 1998,
39, 97-100.
(5) (a) Kadota, I.; Park, C.-H.; Ohtaka, M.; Oguro, N.; Yamamoto, Y.
Tetrahedron Lett. 1998, 39, 6365-6368. (b) Kadota, I.; Kadowaki, C.;
Yoshida, N.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 6369-6372. (c)
Kadota, I.; Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 6373-6376. (d) Kadowaki, C.; Chan, P. W. H.; Kadota, I.;
Yamamoto, Y. Tetrahedron Lett. 2000, 41, 5769-5772. (e) Kadota, I.;
Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 6702-
6703. (f) Kadota, I.; Takamura, H.; Sato, K.; Yamamoto, Y. Tetrahedron
Lett. 2001, 42, 4729-4731. (g) Sakamoto, Y.; Matsuo, G.; Matsukura, H.;
Nakata, T. Org. Lett. 2001, 3, 2749-2752. (h) Cox, J. M.; Rainier, J. D.
Org. Lett. 2001, 3, 2919-2922. (i) Kadota, I.; Park, C.-H.; Sato, K.;
Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6195-6198. (j) Kadota, I.;
Kadowaki, C.; Takamura, H.; Yamamoto, Y. Tetrahedron Lett. 2001, 42,
6199-6202.
† The University of Tokyo, and CREST, JST.
‡ Tohoku University.
(1) For recent reviews on marine polycyclic ether toxins, see: (a)
Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909. (b) Scheuer,
P. J. Tetrahedron 1994, 50, 3-18. (c) Murata, M.; Yasumoto, T. Nat. Prod.
Rep. 2000, 293-314. (d) Yasumoto, T. Chem. Rec. 2001, 3, 228-242.
(2) For recent reviews on polyether synthesis, see: (a) Alvarez, E.;
Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J. D. Chem. ReV. 1995,
95, 1953-1980. (b) Mori, Y. Chem. Eur. J. 1997, 3, 849-852.
(3) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115,
361-362.
10.1021/ol0166597 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/10/2001

synthesis of the EFGH ring system.6 Herein we describe the
synthesis of the ABC ring system and its union with the
EFGH ring system via the B-alkyl Suzuki coupling-based
strategy,7-9 leading to the octacyclic polyether core 2 of
gambierol.
Synthesis of the ABC ring exo-olefin 3 started with the
known compound 510 and followed substantial literature
precedent5a (Scheme 2). Oxidative cleavage of the double
We envisioned that the polyether core of gambierol (1)
could be constructed by hydroboration-Suzuki cross-
coupling of two fragments representing the ABC and EFGH
ring systems (3 and 4,6 respectively) (Scheme 1). With the
Scheme 2a
Scheme 1. Structure and Retrosynthetic Analysis of
Gambierol (1)
a Reagents and conditions: (a) OsO4, NMO, THF-H2O; then
NaIO4; (b) (i-PrO)2P(O)CH2CO2Et, t-BuOK, THF, -78 f 0 °C;
(c) DIBALH, CH2Cl2, -78 °C, 85% (four steps); (d) t-BuOOH,
Ti(Oi-Pr)4, (-)-DET, 4 Å molecular sieves, CH2Cl2, -20 °C; (e)
Red-Al, THF, -40 f 0 °C, quantitative (two steps); (f)
p-MeOC6H4CH(OMe)2, PPTS, CH2Cl2, rt; (g) DIBALH, CH2Cl2,
-40 f 0 °C, 80% (two steps); (h) SO3‚pyr, Et3N, DMSO, CH2Cl2,
0 °C; (i) Ph3PdCHCO2Me, toluene, 80 °C, quantitative (two steps);
(j) TBAF-HOAc (1:1), THF, rt f 35 °C, 1.5 days, 91%; (k) NaH,
THF, rt, 86%; (l) DIBALH, CH2Cl2, -78 °C; (m) Ph3PCH3Br,
NaHMDS, THF, 0 °C, 91% (two steps); (n) 9-BBN, THF, rt; then
aqueous NaHCO3, H2O2; (o) t-BuOK, BnBr, THF, TBAI, rt, 93%
(two steps); (p) DDQ, pH 7 buffer-CH2Cl2, rt; (q) t-BuOK, BnBr,
TBAI, THF, rt, 93% (two steps).
polyether core in hand, functionalization of the H ring and
installation of the triene side chain would complete the total
synthesis of 1.
bond followed by Horner-Emmons reaction and DIBALH
reduction gave allylic alcohol 6 (Scheme 2). The C6 hydroxyl
group11 was installed by Sharpless asymmetric epoxidation
and subsequent reduction with Red-Al12 to afford 1,3-diol 7
as the sole product. Diol 7 was converted to an anisilidene
derivative, which was treated with DIBALH to induce
regioselective reductive opening to give primary alcohol 8.
Oxidation to the aldehyde followed by Wittig elongation gave
R,â-unsaturated ester 9. After removal of the TBS group,
treatment of the derived alcohol 10 with NaH in THF induced
hetero-Michael reaction to afford ester 11 in 86% yield.
DIBALH reduction and Wittig methylenation of the derived
aldehyde gave terminal olefin 12, which upon hydro-
boration-oxidation and protection provided benzyl ether 13.
The PMB group was then replaced with the benzyl group to
give 14.
(6) (a) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 2000, 41,
8371-8375. (b) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron 2001,
57, 3019-3033.
(7) (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron Lett.
1998, 39, 9027-9030. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana,
K. Org. Lett. 1999, 1, 1075-1077. (c) Sasaki, M.; Noguchi, K.; Fuwa, H.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 1425-1428. (d) Takakura, H.;
Noguchi, K.; Sasaki, M.; Tachibana, K. Angew. Chem., Int. Ed. 2001, 40,
1090-1093.
(8) The B-alkyl Suzuki coupling has been successfully used in natural
product syntheses, see: (a) Johnson, C. R.; Braun, M. P. J. Am. Chem.
Soc. 1993, 115, 11014-11015. (b) Ohba, M.; Kawase, N.; Fujii, T. J. Am.
Chem. Soc. 1996, 118, 8250-8257. (c) Narukawa, Y.; Nishi, K.; Onoue,
H. Tetrahedron 1997, 53, 539-556. (d) Trost, B. M.; Lee, C. B. J. Am.
Chem. Soc. 1998, 120, 6818-6819. (e) Balog, A.; Harris, C.; Savin, K.;
Zhang, K.-G.; Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998,
37, 2675-2678. (f) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
7885-7892. (g) Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072-
3080. (h) Meng, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999, 38,
1485-1488. (i) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 1999, 38, 3542-3545. (j) Zhu, B.; Panek, J. S. Org. Lett.
2000, 2, 2575-2578. (k) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000, 2,
2687-2690. (l) Chelmer, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695-
2698. (m) Lee, C. B.; Chou, T.-C.; Zhang, X.-G.; Wang, Z.-G.; Kuduk, S.
D.; Chappell, M. D.; Stachel, S. J.; Danishefsky, S. J. J. Org. Chem. 2000,
65, 6525-6533 and references therein.
(10) Compound 5 is available in 12 steps from 2-deoxy-D-ribose, see:
Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K. Tetrahedron
1990, 46, 4517-4552.
(11) The numbering of carbon atoms of all compounds in this paper
corresponds to that of gambierol.
(9) For reviews on Suzuki cross-coupling reaction, see: (a) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147-168.
(12) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719-2722.
3550
Org. Lett., Vol. 3, No. 22, 2001

The synthesis of the C ring was envisioned to occur via
acid-catalyzed ring opening of hydroxy epoxide (Scheme
3).13 Toward this end, 14 was converted to alcohol 15 in a
Scheme 4a
Scheme 3a
a Reagents and conditions: (a) p-TsOH‚H2O, MeOH, rt; (b)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (c) CSA, MeOH, rt, 86%
(three steps); (d) TPAP, NMO, 4 Å molecular sieves, CH2Cl2, rt,
95%; (e) Tebbe reagent, THF, 0 °C, 96%; (f) 9-BBN, THF, rt;
then aqueous NaHCO3, H2O2; (g) SO3‚pyr, Et3N, DMSO, CH2Cl2,
0 °C; (h) (i-PrO)2P(O)CH2CO2Et, t-BuOK, THF, -78 f 0 °C, 90%
(three steps); (i) DIBALH, CH2Cl2, -78 °C, 99%; (j) t-BuOOH,
Ti(O-i-Pr)4, (+)-DET, 4 Å molecular sieves, CH2Cl2, -28 °C, 92%;
(k) SO3‚pyr, Et3N, DMSO, CH2Cl2, 0 °C; (l) Ph3PCH3Br, NaH-
MDS, THF, 0 °C, 90% (6:1, two steps); (m) TBAF, THF, rt, 96%;
(n) PPTS, CH2Cl2, rt, 79%; (o) t-BuOK, PMBCl, TBAI, THF, rt;
(p) OsO4, NMO, THF-H2O; then NaIO4, rt; (q) NaBH4, MeOH, 0
°C f rt, 86% (two steps); (r) I2, PPh3, imidazole, benzene, rt; (s)
t-BuOK, THF, 0 °C, 86% (two steps).
a Reagents and conditions: (a) KHMDS (3 equiv), (PhO)2P(O)Cl
(10 equiv), THF-HMPA (10:1), -78 °C, quantitative; (b) 3,
9-BBN, THF, rt; then 3 M aqueous Cs2CO3, 4, PdCl2(dppf)‚CH2Cl2,
DMF, 50 °C, 22 h, 86%; (c) BH3‚THF, THF, 0 °C f rt; then 3 M
aqueous NaOH, H2O2, rt, 87%; (d) TPAP, NMO, 4 Å molecular
sieves, CH2Cl2, rt, 98%; (e) DDQ, pH 7 buffer-CH2Cl2, rt; (f)
EtSH, Zn(OTf)2, CH2Cl2, rt; (g) Ac2O, Et3N, DMAP, CH2Cl2, rt,
75% (three steps); (h) Ph3SnH, AIBN, toluene, 110 °C, 95%.
requisite 4 was prepared from the precursor lactone 216b by
treatment with KHMDS and (PhO)2P(O)Cl in THF-HMPA
(10:1, 10 mM) at -78 °C. Hydroboration of 3 with 9-BBN-
H16 and subjection of the resultant alkylborane to 4 under
the previously reported conditions using aqueous 3 M
Cs2CO3 and PdCl2(dppf)‚CH2Cl2 (50 mol %) in DMF at 50
°C for 22 h6,8b furnished the desired cross-coupled product
22 in excellent yield. Subsequent hydroboration with BH3‚
THF (THF, 0 °C f rt) proceeded stereoselectively to give,
after oxidative workup, an alcohol (87%), which was then
oxidized with TPAP/NMO17 to afford ketone 23 in 98%
yield.18 The stereochemistry of 23 was unambiguously
determined by the large coupling constant, J13,14 ) 9.0 Hz,
and NOE between 16-H and 24-Me as shown. Oxidative
removal of the PMB group provided the corresponding
hemiketal, which upon exposure to EtSH and Zn(OTf)2
effected formation of the mixed thioketal with concomitant
conventional three-step sequence. Oxidation of 15 followed
by treatment of the derived aldehyde with Tebbe reagent14
gave olefin 16,15 which was then converted into R,â-
unsaturated ester 17 in a three-step sequence as shown.
DIBALH reduction, asymmetric epoxidation, oxidation, and
Wittig reaction produced vinyl epoxide 18 as an inseparable
6:1 mixture of diastereomers. After desilylation, cyclization
of the resultant epoxy alcohol with PPTS afforded a mixture
of the desired tricyclic 19 and its diastereomer, which was
readily separated by silica gel chromatography. The structure
of 19 was confirmed by coupling constant, J13,14 ) 9.2 Hz,
and NOE experiments as shown. Protection as the PMB ether
was followed by oxidative cleavage of the double bond and
subsequent reduction of the derived aldehyde with NaBH4
to give alcohol 20, which was then converted to the desired
exo-olefin 3 without incident.
With the ABC ring 3 in hand, the crucial coupling reaction
with enol phosphate 4 was next attempted (Scheme 4). The
(16) 9-BBN-H dimer was recrystallized from anhydrous dimethoxyethane
prior to use.
(17) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(18) Stereochemistry of the alcohol was not determined. So, we cannot
exclude a possibility that exclusive formation of ketone 23 results from an
equilibration reaction after oxidation with TPAP/NMO.
(13) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J.
Am. Chem. Soc. 1989, 111, 5330-5334.
(14) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611-3613.
(15) Wittig methylenation of the aldehyde resulted in a low yield (26%)
of 16.
Org. Lett., Vol. 3, No. 22, 2001
3551

loss of the acetonide group. Subsequent acylation provided
diacetate 24 in 75% yield over three steps. Finally, radical
reduction7d,19 proceeded cleanly to furnish the octacyclic
polyether core 2 of gambierol (1) in 95% yield.
In conclusion, the first synthesis of the octacyclic polyether
core of gambierol (1) has been achieved in a convergent
manner. The present synthesis has demonstrated the general-
ity of our B-alkyl Suzuki coupling-based approach for the
convergent assembly of a fused polyether structure. Further
studies toward the total synthesis of gambierol (1) are
currently underway and will be reported in due course.
Acknowledgment. A fellowship (to H.F.) from the Japan
Society for the Promotion of Science is gratefully acknowl-
edged.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321-5330.
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