Synthetic entry to the ABCD ring fragment of gymnocin-A, a cytotoxic marine polyether

Article abstract of DOI:10.1016/S0040-4039(03)00949-3

Synthetic entry to the ABCD ring fragment of gymnocin-A, a cytotoxic marine polyether, has been achieved based on the B-alkyl Suzuki-Miyaura coupling-based strategy and radical cyclization for the construction of the tetrahydrofuran ring A.

Full text of DOI:10.1016/S0040-4039(03)00949-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4351–4354
Synthetic entry to the ABCD ring fragment of gymnocin-A, a
cytotoxic marine polyether
Makoto Sasaki,a,* Chihiro Tsukanob and Kazuo Tachibanab
aLaboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Tsutsumidori-Amamiya, Aoba-ku,
Sendai 981-8555, Japan
bDepartment 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 March 2003; revised 7 April 2003; accepted 11 April 2003
Abstract—Synthetic entry to the ABCD ring fragment of gymnocin-A, a cytotoxic marine polyether, has been achieved based on
the B-alkyl Suzuki–Miyaura coupling-based strategy and radical cyclization for the construction of the tetrahydrofuran ring A.
© 2003 Elsevier Science Ltd. All rights reserved.
Gymnocin-A (1) was recently isolated from the notori-
ous red tide dinoflagellate, Karenia mikimotoi, by Satake
and co-workers.1 The toxin displays in vitro cytotoxicity
against P388 cancer cells (EC50=1.3 mg/mL).1,2 The
structure of gymnocin-A, including the relative and
absolute stereochemistry, has been determined by a
combination of NMR analyses, FAB collision-induced
dissociation MS/MS experiments, and modified Mosh-
er’s method (Fig. 1).1 Structurally, gymnocin-A is char-
acterized by 14 contiguous and saturated ether rings,
including two repeating 6/6/7/6/6 ring systems, and a
2-methyl-2-butenal side chain. The number of contigu-
ous ether rings exceeds those of other polycyclic ethers
hitherto known.3 Given the structural complexity along
with intriguing biological activity, we have been
engaged in the synthesis of gymnocin-A, culminating in
the synthesis of the FGHIJKLMN ring fragment 3
(Scheme 1).4 Herein we describe a synthetic route to the
ABCD ring fragment 2 that features the B-alkyl
Suzuki–Miyaura coupling of the B and D rings5–7 and
radical cyclization for constructing the A ring.
Assembly of the BCD ring system began with the
preparation of exocyclic enol ether 7 (Scheme 2). Seven-
membered lactone 4 was converted to alcohol 5
through Pd(0)-mediated carbonylation of the corre-
sponding enol phosphate.8,9 Desilylation with tetra-n-
butylammonium fluoride (TBAF) followed by
benzylation and reductive opening of the anisilydene
acetal gave alcohol 6 (78% overall yield), which was
readily converted to exocyclic enol ether 7 via iodina-
tion and base treatment (91% for the two steps).
Figure 1. Structure of gymnocin-A.
Keywords: gymnocin-A; polycyclic ethers; B-alkyl Suzuki–Miyaura coupling; radical cyclization.
* Corresponding author. Tel.: +81-22-717-8828; fax: +81-22-717-8897; e-mail: msasaki@bios.tohoku.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00949-3

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M. Sasaki et al. / Tetrahedron Letters 44 (2003) 4351–4354
With the requisite 13 in hand, we next focused on
introduction of the C1013 hydroxyl group (Scheme 3).
Thus, reductive removal of the benzyl groups within 13
with lithium di-tert-butylbiphenylide (LiDBB)14 was
followed by selective protection of the primary
hydroxyl group as the pivalate ester (85% overall yield).
The residual secondary alcohol was then oxidized to
ketone 14 in 94% yield. Conversion to the enone via the
Ito–Saegusa protocol15 and subsequent Luche
reduction16 gave allylic alcohol 15 in 84% overall yield.
Directed epoxidation with mCPBA followed by oxida-
tion gave a,b-epoxy ketone 16 (67% yield for the two
steps), which was then reduced with Na[PhSeB(OEt)3]17
to provide b-hydroxy ketone 17 in quantitative yield.
The stereochemistry of the C10 hydroxyl group was
assigned by the small coupling constant, J=2.4 Hz,
between 10-H and 11-H. Protection of the hydroxyl
group as its tetrahydropyranyl (THP) ether followed by
stereoselective reduction of the ketone with L-Selec-
tride® and removal of the pivalate ester gave diol 18 in
85% yield for the three steps.
Scheme 1. Retrosynthetic analysis of gymnocin-A (1).
Hydroboration of 7 with 9-BBN and in situ coupling of
the derived alkylborane with enol phosphate 85h pro-
vided cross-coupled product 9 (1 M aqueous NaHCO3,
Pd(PPh3)4, DMF, 50°C). Subsequent hydroboration of
the enol ether moiety (BH3·SMe2, then H2O2, NaOH)
gave the desired alcohol 10 in 54% overall yield from 7,
along with the diastereomeric alcohol (not shown, 12%
from 7). Protection of 10 as its triethylsilyl (TES) ether,
oxidative removal of the p-methoxybenzyl (PMB)
group, and oxidation of the resultant alcohol with
TPAP/NMO10 gave ketone 11 in 86% overall yield.11
Treatment of 11 with EtSH and Zn(OTf)2 effected
removal of the TES and benzylidene acetal groups and
concomitant mixed thioketal formation. The resulting
diol was reprotected as the acetonide to give 12 in 87%
yield for the two steps. Finally, desulfurization under
radical conditions4,5f,g,i,j,12 furnished tricyclic ether 13 in
93% yield. The stereostructure of 13 was unambigu-
ously confirmed by NOEs and coupling constants as
shown.
For construction of the 2,3-disubstituted tetra-
hydrofuranyl ring A, we envisioned radical cyclization
of b-alkoxy acrylate.18,19 Thus, regioselective tosylation
of the primary hydroxyl group of 18 (81% yield) fol-
lowed by reaction of the residual secondary alcohol
with methyl propiolate in the presence of N-methyl
morpholine (NMM) afforded b-alkoxy acrylate, which
was then treated with sodium iodide in reflux acetone
to give a radical cyclization precursor, iodide 19 (72%
yield for the two steps). Treatment of 19 with tributyl-
stannane in the presence of triethylborane20 in toluene
at −78°C effected cyclization of the tetrahydrofuranyl
ring to provide 20 in nearly quantitative yield. Ester 20
Scheme 2. Reagents and conditions: (a) TBAF, THF, rt; (b) KOt-Bu, BnBr, THF, rt; (c) DIBALH, CH2Cl2, 0°C, 78% (three
steps); (d) I2, PPh3, imidazole, THF, rt, 95%; (e) KOt-Bu, THF, 0°C, 96%; (f) 7, 9-BBN, THF, rt, then 1 M aq. NaHCO3,
Pd(PPh3)4, 8, DMF, 50°C; (g) BH3·SMe2, THF, rt, then H2O2, NaOH, 0°C“rt, 54% (two steps); (h) TESOTf, 2,6-lutidine,
,
CH2Cl2, 0°C, 89%; (i) DDQ, pH 7.0 phosphate buffer, CH2Cl2, rt, 97%; (j) TPAP, NMO, MS 4 A, CH2Cl2, rt, quant.; (k) EtSH,
Zn(OTf)2, CH2Cl2, rt; (l) Me2C(OMe)2, CSA, CH2Cl2, rt, 87% (two steps); (m) Ph3SnH, AIBN, PhMe, 100°C, 93% (+
diastereomer, 7%).

M. Sasaki et al. / Tetrahedron Letters 44 (2003) 4351–4354
4353
Scheme 3. Reagents and conditions: (a) LiDBB, THF, −78°C; (b) PivCl, pyridine, CH2Cl2, rt, 85% (two steps); (c) TPAP, NMO,
,
MS 4 A, CH2Cl2, rt, 94%; (d) LiHMDS, TMSCl, Et3N, THF, −78°C; (e) Pd(OAc)2, MeCN, rt, 96% (two steps); (f) NaBH4,
,
CeCl3·7H2O, MeOH/CH2Cl2, rt, 88%; (g) mCPBA, NaHCO3, CH2Cl2, rt, 83%; (h) TPAP, NMO, MS 4 A, CH2Cl2, rt, 81%; (i)
Na[PhSeB(OEt)3], AcOH, EtOH, 0°C“rt, quant.; (j) DHP, CSA, CH2Cl2, rt, 81%; (k) L-Selectride®, THF, −78°C; (l) LiAlH4,
THF, 0°C, 85% (three steps); (m) TsCl, Et3N, DMAP, CH2Cl2, rt, 81%; (n) methyl propiolate, NMM, CH2Cl2, 35°C; (o) NaI,
acetone, reflux, 72% (two steps); (p) Bu3SnH, Et3B, PhMe, −78°C, quant.; (q) LiAlH4, THF, 0°C; (r) KOt-Bu, BnBr, THF, rt;
(s) CSA, MeOH, rt; (t) p-MeOPhCH(OMe)2, CSA, CH2Cl2, rt, 71% (four steps); (u) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 95%; (v)
DIBALH, CH2Cl2, 0°C, 93%; (w) I2, PPh3, imidazole, THF, rt, 86%; (x) KOt-Bu, THF, 0°C, quant.
was then converted into alcohol 21 (71% overall yield)
via benzylation of the resulting alcohol, acid hydrolysis
of the acetal protective groups, and reprotection as the
anisilydene acetal. Silylation of the C10 alcohol was
followed by reductive opening of the anisilydene acetal.
Iodination of the resultant primary hydroxyl group
followed by base treatment furnished the desired
ABCD ring exocyclic enol ether 2 in 76% overall
yield.21 The stereostructure of 2 was unambiguously
established by NOE experiments as shown.
2. Analogues of 1 of yet unknown structures showed far
stronger cyctotoxicity than 1; a private communication
from Prof. M. Satake of Tohoku University.
3. For reviews on marine polycyclic ethers, see: (a)
Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897–
1909; (b) Murata, M.; Yasumoto, T. Nat. Prod. Rep.
2000, 293–314; (c) Yasumoto, T. Chem. Rec. 2001, 3,
228–242.
4. Sasaki, M.; Tsukano, C.; Tachibana, K. Org. Lett. 2002,
4, 1747–1750.
5. (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)
Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett.
2000, 41, 8371–8375; (e) Fuwa, H.; Sasaki, M.;
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Takakura, H.; Noguchi, K.; Sasaki, M.; Tachibana, K.
Angew. Chem., Int. Ed. 2001, 40, 1090–1093; (g) Fuwa,
H.; Sasaki, M.; Tachibana, K. Org. Lett. 2001, 3, 3549–
3552; (h) Sasaki, M.; Ishikawa, M.; Fuwa, H.;
Tachibana, K. Tetrahedron 2002, 58, 1889–1911; (i)
Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K.
Org. Lett. 2002, 4, 2771–2774; (j) Fuwa, H.; Kainuma,
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In conclusion, we have developed a synthetic route to
the ABCD ring fragment 2 of gymnocin-A (1) utilizing
the B-alkyl Suzuki–Miyaura coupling-based methodol-
ogy and radical cyclization for constructing the A ring.
Coupling of 2 with the FGHIJKLMN ring fragment
leading to the total synthesis of 1 is currently under way
and will be reported in due course.
Acknowledgements
We thank Professor M. Satake of Tohoku University
for valuable discussions. This work was financially sup-
ported in part by a grant from Suntory Institute for
Bioorganic Research (SUNBOR).
6. For reviews on Suzuki cross-coupling reaction, see: (a)
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(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168;
(c) Suzuki, A.; Brown, H. C. In Organic Syntheses Via
Boranes; Aldrich Chem.: Wisconsin, 2003; Vol. 3.
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J=11.5 Hz, 1H), 4.44 (ddd, J=9.5, 7.8, 6.4 Hz, 1H), 4.34
(ddd, J=11.5, 8.9, 5.1 Hz, 1H), 4.29 (d, J=12.6 Hz, 1H),
4.26 (d, J=12.6 Hz, 1H), 4.21 (d, J=11.5 Hz, 1H), 4.19
(m, 1H), 4.05 (br d, J=6.3, 1.0 Hz, 1H), 4.00 (s, 1H),
3.97 (ddd, J=11.9, 8.8, 4.4 Hz, 1H), 3.89 (br d, J=6.3,
1.0 Hz, 1H), 3.62 (ddd, J=8.8, 7.8, 7.8 Hz, 1H), 3.48 (m,
1H), 3.41(m, 1H), 3.32 (s, 3H), 3.05 (ddd, J=10.6, 8.9,
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1.96–1.78 (m, 6H), 1.72 (m, 1H), 1.55 (m, 1H), 0.96 (s,
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