Synthesis of marine sesterterpenoid dysidiolide

Article abstract of DOI:10.1016/S0040-4039(99)02175-9

Dysidiolide, a novel sesterterpenoid isolated from the Caribbean sponge Dysidia etheria de Laubenfels, has been shown an inhibitor of protein phosphatase cdc25A. The authors established a stereocontrolled total synthesis of (±)-dysidiolide using an intramolecular Diels-Alder reaction as the key step. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02175-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 911–914
Synthesis of marine sesterterpenoid dysidiolide
Hiroaki Miyaoka, Yasuhiro Kajiwara and Yasuji Yamada ∗
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 29 October 1999; revised 10 November 1999; accepted 12 November 1999
Abstract
Dysidiolide, a novel sesterterpenoid isolated from the Caribbean sponge Dysidia etheria de Laubenfels, has
been shown an inhibitor of protein phosphatase cdc25A. The authors established a stereocontrolled total synthesis
of (±)-dysidiolide using an intramolecular Diels–Alder reaction as the key step. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: marine metabolites; natural products; terpenes; terpenoids; antitumour compounds.
Dysidiolide (1), isolated in 1996 from the Caribbean sponge, Dysidia etheria de Laubenfels by
Gunasekera and Clardy et al. is a marine sesterterpenoid, possessing a novel carbon skeleton with
unique structural features.1,2 Dysidiolide is the first naturally derived inhibitor of protein phosphatase
cdc25A (IC50 9.4 µM). Dysidiolide was noted to inhibit the growth of A-549 human lung carcinoma
and P388 murine leukemia cell lines at IC50 4.7 and 1.5 µM, respectively. The relative configuration
of dysidiolide was determined based on single-crystal X-ray results and the absolute configuration was
determined by enantioselective total synthesis.3,4 Three total syntheses3–5 of and two synthetic studies6,7
on dysidiolide have been reported. The biological activity and rare structural features of dysidiolide
prompted the authors to undertake its total synthesis. A stereocontrolled total synthesis of (±)-dysidiolide
was established using an intramolecular Diels–Alder reaction as the key step.
Cyclohexenone 28 was converted to α,β,γ,δ-unsaturated ketone 4 in three steps: (i) alkylation
of 2 with LDA and 3-iodo-1-(tert-butyldimethylsilyl)oxypropane; (ii) further alkylation with LDA
and iodomethane to give enone 3; and (iii) vinylation of 3 with vinylmagnesium bromide followed
by treatment with silica gel to form α,β,γ,δ-unsaturated ketone 4 (Scheme 1). α,β,γ,δ-Unsaturated
ketone 4 was treated with thiophenol in the presence of Et3N to produce α,β-unsaturated ketone,
which was subsequently reduced with DIBAL-H to give a mixture of β-alcohol 5a and α-alcohol 5b
(5a:5b=1.6:1).9,10 Following separation of these compounds, oxidation of sulfide in β-alcohol 5a with
mCPBA and then acylation with propiolic acid, DCC and DMAP in toluene provided sulfoxide ester 7.
Sulfoxide ester 7 was also obtained from α-alcohol 5b by the oxidation of sulfide in 5b with mCPBA
followed by Mitsunobu inversion11 with propiolic acid. Sulfoxide ester 7 was refluxed in toluene in
∗
Corresponding author. Tel: +81 426 76 3046; fax: +81 426 76 3069; e-mail: yamaday@ps.toyaku.ac.jp (Y. Yamada)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02175-9
tetl 16103

912
Scheme 1. Reagents and conditions: A: (i) LDA, HMPA, TBDMSOCH2CH2CH2I, THF, −78°C–rt, 76%; (ii) LDA, MeI, THF,
96%; B: vinyl magnesium bromide, THF, 0°C, then silica gel, 92%; C: (i) PhSH, Et3N, benzene, rt, 90%, (ii) DIBAL-H,
toluene, −78°C, quant.; D: mCPBA, CH2Cl2, −78°C, 99%; E: propiolic acid, DCC, DMAP, toluene, rt, quant.; F: mCPBA,
CH2Cl2, −78°C, 96%; G: propiolic acid, DEAD, Ph3P, THF, rt, 97%; H: pyridine, toluene, reflux, 78%; I: Me2CuLi, Et2O,
−15°C, 91%; J: (i) TBAF, THF, rt, 90%, (ii) Bn-Br, NaH, THF:DMF (4:1), rt, 87%; K: LDA, THPOCH2CH2I, THF, 92%; L:
(i) DIBAL-H, toluene, −78°C, (ii) LiBH4, MeOH–THF, 0°C, 90% (two steps); M: TBDMS-Cl, imidazole, DMF, rt, 97%; N:
(i) PON-Cl, MeLi, TMEDA, THF, 0°C–rt, 87%, (ii) Li, EtNH2, tBuOH, 0°C–rt, 94%; O: (i) Bn-Br, NaH, THF–DMF, quant.,
(ii) TBAF, THF, reflux, quant.; P: (i) PON-Cl, MeLi, TMEDA, THF, 0°C–rt, 87%, (ii) Li, EtNH2, tBuOH, 0°C, 72%; Q: (i) I2,
Ph3P, imidazole, 2-methyl-2-butene, CH2Cl2, rt, 96%, (ii) 2-bromopropene, tBuLi, CuI, Et2O, rt, 80%; R: (i) AcOH:H2O (4:1),
n
i
rt, 95%, (ii) TPAP, NMO, CH2Cl2, rt, 86%; S: 3-bromofuran, BuLi, THF, −78°C, 93%; T: O2, hν, Rose Bengal, Pr2NEt,
CH2Cl2, −78°C, 88%

913
the presence of pyridine to afford decalin 812 as the sole product with elimination of sulfoxide and
intramolecular Diels–Alder reaction. α,β-Unsaturated lactone 8 was treated with Me2CuLi to give
stereoselectively 7α-methyl lactone 9a with a small amount of 7α-methyl lactone 9b (9a:9b=9:1).
Compound 9a was converted to lactone 1113 in three steps: (i) TBAF, THF; (ii) BnBr, NaH, THF–DMF
to give lactone 10; and (iii) alkylation with LDA and 1-iodo-2-(tetahydropyranyl)oxyethane. Lactone
11 was reduced by a two-step sequence: (i) DIBAL-H and (ii) LiBH4 to give diol 12. Deoxygenation
of two hydroxyl groups in diol 12 was successively carried out according to Ireland’s phosphoramidate
method.14 The primary hydroxyl group in diol 12 was selectively protected by treatment with TBDMS-
Cl and imidazole to give mono-TBDMS ether 13. Deoxygenation of secondary hydroxyl group in 13 was
carried out by treatment with (Me2N)2P(O)Cl (PON–Cl) to give phosphoramidate followed by Benkeser
reduction (Li/EtNH2) to afford alcohol 14. The hydroxyl group in 14 was protected as the benzyl
ether and the TBDMS protecting group was removed to give alcohol 15. The primary alcohol 15 was
converted to phosphoramidate followed by Benkeser reduction to give alcohol 16. Iodination15 of alcohol
t
16 followed by cross-coupling with 2-lithiopropene, prepared from 2-bromopropene and BuLi, in the
presence of CuI afforded compound 17. By cleavage of the THP protecting group in 17 by treatment with
acetic acid and subsequent oxidation with TPAP and NMO,16 aldehyde 182,3,5 was obtained. Finally, the
total synthesis of dysidiolide was performed essentially according to Corey’s procedure.3 The addition
n
of 3-lithiofuran, prepared from 3-bromofuran and BuLi, to aldehyde 18 gave epimeric alcohols 19a3
and 19b (19a:19b=1:1). The photochemical oxidation of 19a furnished (±)-dysidiolide ((±)-1). Spectral
data (NMR and IR) of synthesized (±)-1 were identical to those reported.1,5
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research (Grant No. 09672165) from
the Ministry of Education, Science, Sports and Culture of Japan.
References
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oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) to give decalin 8 (15%) and ester ii (64%). α-Alcohol ib, also prepared
from dienone 4 by DIBAL-H reduction, was treated with propiolic acid in the presence of DEAD and Ph3P according to the
Mitsunobu procedure to give ester ii in 92% yield as the sole product. The diene portion of dienone 4 was thus shown to be
protected as the phenyl sulfide.

914
10. The relative configuration of alcohols 5a and 5b was determined from the NOESY spectrum of decalin 8, which was derived
from 5a and 5b, respectively.
11. Mitsunobu, O. Synthesis 1981, 1–28.
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