Synthetic studies on a marine polyether toxin, gambierol: Stereoselective synthesis of the FGH ring system via B-alkyl Suzuki coupling

Article abstract of DOI:10.1016/S0040-4039(00)01483-0

A synthetic route to the FGH ring system of gambierol, a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features B-alkyl Suzuki coupling of the F and H rings, followed by ring-closure of the G ring and stereoselective installation of 1,3-diaxial methyl groups at C21 and C23. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01483-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8371–8375
Synthetic studies on a marine polyether toxin, gambierol:
stereoselective synthesis of the FGH ring system via B-alkyl
Suzuki coupling
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
Received 3 August 2000; revised 30 August 2000; accepted 1 September 2000
Abstract
A synthetic route to the FGH ring system of gambierol, a marine polyether toxin isolated from the
dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features B-alkyl Suzuki
coupling of the F and H rings, followed by ring-closure of the G ring and stereoselective installation of
1,3-diaxial methyl groups at C21 and C23. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: coupling reactions; polyethers; Suzuki reactions; toxins.
Gambierol (1) was isolated as a toxic constituent from the ciguatera causative dinoflagellate,
Gambierdiscus toxicus and showed toxicity against mice (LD50 50 mg/kg, mice, i.p.).1 The mice
symptoms resemble those shown by ciguatoxins, implying the possibility that it is also impli-
cated in ciguatera fish poisoning, which is one of the most widespread seafood poisonings.
Complete stereochemical assignments have been accomplished by extensive NMR analysis1 and
application of a chiral anisotropic reagent.2 Its characteristic polyether structure, potent
biological activity, and extremely limited availability from natural sources make gambierol an
intriguing synthetic target molecule.3 We have recently reported a new methodology for the
convergent assembly of a polyether structure utilizing B-alkyl Suzuki coupling of lactone-
derived enol phosphates and disclosed its potential in the synthesis of ciguatoxin fragments.4 In
this letter, we describe a stereocontrolled construction of the FGH ring system (2) of gambierol
based on the B-alkyl Suzuki coupling strategy.5
A convergent synthetic approach to gambierol (1) involves construction of two fragments
representing the ABC and EFGH ring systems. The latter compound was to be derived from the
precursor FGH ring system (2). Our strategy for the synthesis of 2 was based on B-alkyl Suzuki
* Corresponding author. Tel: +81-3-5841-4357; fax: +81-3-5841-8380; e-mail: msasaki@chem.s.u-tokyo.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01483-0

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coupling of the F and H ring precursors and then ring-closure of the G ring (Scheme 1; 4+5“3).
A formidable challenge in synthesizing 2 appeared to be the introduction of the 1,3-diaxial
dimethyl groups at C21 and C23 positions on the F ring. We could solve the problem by a
preliminary introduction of the C23 methyl group, followed by installation of a quaternary
center at C21 (3“2).
Scheme 1.
Synthesis of exo-olefin 4 started with alcohol 6,6 which was converted into bis(benzyl)ether 7
by a three-step procedure involving protection as the benzyl ether, hydroboration-oxidation, and
benzylation. Following removal of the benzylidene acetal, the resultant diol was converted into
alcohol 8 by silylation of both hydroxyl groups and subsequent selective mono-desilylation.
Iodination of 8, followed by base treatment provided the desired exo-olefin 4 (Scheme 2).
Scheme 2. Reagents and conditions: (a) NaH, BnBr, Bu4Nl, DMF, rt, 97%; (b) 9-BBN, THF, rt, then H2O2, NaOH,
rt, 95%; (c) KH, BnBr, Bu4Nl, THF, reflux, 76%; (d) p-TsOH, MeOH–CH2Cl2, rt, 86%; (e) TBSCl, imidazole, DMF,
50°C; (f) CSA, MeOH–CH2Cl2, 0°C, 96% (two steps); (g) I2, PPh3, imidazole, benzene, rt, 95%; (h) KO–t-Bu, THF,
0°C, 96%
In our previous B-alkyl Suzuki coupling,4b,c excess amounts (2 equiv.) of the phosphate
coupling partners and elevated reaction temperature were required to realize the coupling
reaction in high yield. These problems prompted us to explore the optimum reaction conditions
for the hydroboration-Suzuki coupling of 4 and 5. Hydroboration of the B-alkyl Suzuki
coupling partner 4 and direct subjection of the resultant alkylborane to enol phosphate 5 under
the previously reported conditions (aqueous 1 M NaHCO3 (3 equiv.), Pd(PPh3)4 (10 mol%),
DMF, 50°C)4b afforded cross-coupled product 9 in 87% yield (Table 1, entry 1). Use of
PdCl2(dppf) (dppf=1,1%-bis(diphenylphosphino)ferrocene) as a catalyst improved the yield of 9
(entry 2) and allowed the coupling reaction to proceed at room temperature in high yield (entry
3).7 On the other hand, use of PdCl2(PCy3)28 with an electron-rich ligand lowered the yield of the
coupling reaction (entry 4).9 It has recently been reported that Pd(OAc)2/o-(di-tert-butylphos-
phino)biphenyl efficiently promotes the room temperature Suzuki coupling of aryl chlorides;7e,f
however, this catalyst system was also less effective in the present case (entry 5).

8373
Table 1a
Run
Catalyst
Conditions
% Yield
1
2
3
Pd(PPh3)4
DMF, 50°C, 20 h
DMF, 50°C, 20 h
DMF, rt, 24 h
DMF, 50°C, 20 h
Dioxane, rt, 24 h
87
93
97
50
58
PdCl2(dppf)
PdCl2(dppf)
PdCl2(PCy3)2
Pd(OAc)2/
4
5b
a Reactions were carried out using 10 mol% of Pd catalyst, 3 equiv. of base, and 1.2 equiv. of 5; reaction times have
not been minimized.
b 20 mol% of ligand was used.
Ring-closure of the G ring and installation of the C23 angular methyl group is summarized
in Scheme 3. Hydroboration of 9 with BH3·THF, followed by oxidative workup proceeded
stereoselectively to give an alcohol (77%),10 which was then protected as the p-methoxybenzyl
(PMB) ether. Desilylation and oxidation of the resultant alcohol with TPAP/NMO11 provided
ketone 10 in 83% yield for the three steps. We first attempted to install an angular methyl group
at C2312 via nucleophilic attack to an oxocarbenium ion generated from methyl acetal 11.
Removal of the PMB group, followed by methyl acetal formation and acetylation afforded 11
as a single stereoisomer. However, upon treatment of 11 with Me3Al or Me2Zn in the presence
of BF3·OEt2,13 none of the desired methylated product 3 was obtained. Thus, ketone 10 was
transformed into hemithioketal 12. Following removal of the PMB group, treatment of the
14
resulting hemiacetal with EtSH and Zn(OTf)2 and in situ acetylation provided 12 in 86%
overall yield. Oxidation of 12 to the corresponding sulfone and subsequent reaction with
Me3Al15 led exclusively to the desired 3 in 86% overall yield. The relative configuration of 3 was
unambiguously established by NOE experiments, as shown in Scheme 3.
Final installation of the quaternary carbon center at C21 could be accomplished, as shown in
Scheme 4. Routine protective group manipulation allowed for transformation of 3 into alcohol
13, which was then oxidized with TPAP/NMO to give ketone 14. Initial attempts to introduce
a methyl group at C21 by nucleophilic addition were unsuccessful, and the undesired b-methyl
isomer was obtained as the major product due to the serious steric congestion of the angular
methyl group at C23. However, dihydroxylation of exo-olefin 15, derived from 14 by Wittig
reaction, afforded diol 16 as a single stereoisomer in high yield.16 In this reaction, excess
amounts of OsO4 (3 equiv.) and NMO (10 equiv.) were required to obtain a high yield of 16.
Selective tosylation of the primary hydroxyl group in 16 gave monotosylate 17, where the

8374
Scheme 3. Reagents and conditions: (a) BH3·THF, THF, −30°C; then H2O2, NaOH, rt“40°C, 77%; (b) KH, PMBCl,
,
Bu4Nl, THF, rt, 88%; (c) Bu4NF, THF, rt, quant.; (d) TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt, 94%; (e) DDQ,
CH2Cl2–phosphate buffer (pH 7), rt; (f) p-TsOH·H2O, CHCl3–MeOH, rt, 82% (two steps); (g) Ac2O, DMAP,
CH2Cl2, 0°C, 97%; (h) DDQ, CH2Cl2–phosphate buffer (pH 7), rt; (i) EtSH, Zn(OTf)2, NaHCO3, CH2Cl2, rt; then
Ac2O, Et3N, DMAP, 86% (three steps); (j) mCPBA, NaHCO3, CH2Cl2, rt, 96%; (k) Me3Al, CH2Cl2, −78°C, 90%
Scheme 4. Reagents and conditions: (a) NaOMe, MeOH, rt; (b) Me2C(OMe)2, PPTS, DMF, rt, 98% (two steps); (c)
,
H2, Pd(OH)2/C, EtOAc, rt; (d) TIPSCl, imidazole, CH2Cl2, rt, 89% (two steps); (e) TPAP, NMO, 4 A molecular
sieves, CH2Cl2, rt, 99%; (f) Ph3P+CH3Br−, NaHMDS, THF, −78°C“rt, 92%; (g) OsO4 (3 equiv.), NMO (10 equiv.),
t-BuOH–H2O (1:1), rt, 96%; (h) TsCl, DMAP, (CH2Cl)2, rt, 99%; (i) LiAlH4, THF, 0°C“rt, 75%
stereochemistry at C21 was established by NOE experiment. Finally, reduction of 17 with
LiAlH4 at 0°C yielded the corresponding epoxide, which upon warming to room temperature
delivered the desired FGH ring system 2 in 75% yield.17,18
In conclusion, we have completed the synthesis of the FGH ring system of gambierol. In the
present synthesis we have demonstrated that PdCl2(dppf) promotes the room temperature
B-alkyl Suzuki coupling of lactone-derived enol phosphate. The mild reaction conditions
described herein should tolerate the presence of a wide variety of functional groups and thus
enhance the practicality and usefulness of the B-alkyl Suzuki coupling strategy for the synthesis
of a polyether system. Also, 1,3-diaxial dimethyl groups with serious steric congestion were
successfully introduced. Further efforts directed toward a total synthesis of gambierol are
underway and will be reported in due course.

8375
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D
-ribose in nine steps: (i) Ph3PꢀCHCO2Me, THF, reflux; (ii)
PhCH(OMe)2, CSA, CH2Cl2, rt, 77% (two steps); (iii) TBSCl, imidazole, DMF, 50°C, 93%; (iv) DIBALH, CH2Cl2,
,
−78°C, 98%; (v) t-BuOOH, Ti(Oi-Pr)4, (−)-diethyl tartrate, 4 A molecular sieves, CH2Cl2, −20°C, 86%; (vi) SO3·pyr,
Et3N, DMSO, CH2Cl2, 0°C; (vii) Ph3P+CH3Br−, NaHMDS, THF, 0°C, 86% (two steps); (viii) Bu4NF, THF, rt,
99%; (ix) PPTS, CH2Cl2, rt, 90%.
7. Examples of Suzuki coupling reactions that proceed at room temperature are rare, see: (a) Campi, E. M.; Jackson,
W. R.; Marcuccio, S. M.; Naeslund, C. G. M. J. Chem. Soc., Chem. Commun. 1994, 2395. (b) Anderson, J. C.;
Namli, H.; Roberts, C. A. Tetrahedron 1997, 53, 15123–15134. (c) Uenishi, J.-I.; Beau, J.-M.; Armstrong, R. W.;
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(f) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550–9561.
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halides to Pd(0), see: Spessard, G. O.; Meisser, G. L. Organometallic Chemistry; Prentice Hall: Upper Saddle River,
New Jersey, 1996; pp. 171–175.
10. Undesired isomer was obtained in 10% yield. Hydroboration of 5 with thexylborane was much slower, and the
product alcohol was obtained in 67% yield after 4 days.
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12. The numbering of carbon atoms of all compounds in this paper corresponds to that of gambierol.
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16. Epoxidation of 15 with mCPBA (Na2HPO4, 4,4%-thiobis(6-t-butyl-m-cresol), ClCH2CH2Cl or toluene, 90°C)
provided the corresponding epoxide in poor selectivity (a-epoxide and b-epoxide=2:3).
17. LiAlH4 reduction of 17 at 0°C gave the corresponding epoxide in 92% yield.
18. Selected data for compound 2: 1H NMR (500 MHz, C6D6) l 3.94–3.86 (m, 2H, 18-H, 32-H), 3.84 (m, 1H, 18-Hr),
3.71 (m, 1H, 30-H), 3.64 (dd, 1H, J=11.3, 8.93 Hz, 32-H), 3.51–3.46 (m, 2H, 20-H, 27-H), 3.24 (ddd, 1H, J=8.9,
8.9, 5.5 Hz, 31-H), 3.07 (dd, 1H, J=12.8, 4.0 Hz, 24-H), 3.02 (ddd, 1H, J=11.0, 9.2, 5.2 Hz, 26-H), 2.17 (ddd,
1H, J=11.6, 5.2, 4.0 Hz, 25-H), 2.05–1.90 (m, 4H, 19-H, 22-H, 28-H, 29-H), 1.84–1.66 (m, 5H, 22-H, 25-H, 28-H,
29-H, OH), 1.62 (m, 1H, 19-H), 1.60 (s, 3H, acetonide), 1.45 (s, 3H, acetonide), 1.18–1.03 (m, 27H, 41-Me, 42-Me,
SiCHMe2×3); 13C NMR (125 MHz, C6D6) l 98.4, 85.1, 80.5, 76.0, 73.2, 73.1, 72.0, 70.1, 63.5, 61.1, 54.6, 33.1,
32.5, 30.2, 29.8, 28.8, 24.7, 19.5, 18.2, 15.8, 12.3; HRMS (FAB) calcd for C29H54O7SiNa [(M+Na)+] 565.3537, found
565.3527.