Concise asymmetric synthesis of dysidiolide

Article abstract of DOI:10.1016/S0040-4039(00)00078-2

The cdc25A protein phosphatase inhibitor dysidiolide (1) has been synthesized via intermolecular Diels-Alder reaction of the triene 4 with crotonaldehyde and construction of a quaternary carbon center by methylation of the exocyclic enolate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00078-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2111–2114
Concise asymmetric synthesis of dysidiolide
Masato Takahashi,a Kosuke Dodo,a Yuichi Hashimoto a and Ryuichi Shirai b,∗
aInstitute of Molecular and Cellular Biosciences (IMCB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku,
Tokyo 113-0032, Japan
bResearch and Education Center for Materials Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho,
Ikoma-shi, Nara 630-0101, Japan
Received 17 November 1999; revised 15 December 1999; accepted 7 January 2000
Abstract
The cdc25A protein phosphatase inhibitor dysidiolide (1) has been synthesized via intermolecular Diels–Alder
reaction of the triene 4 with crotonaldehyde and construction of a quaternary carbon center by methylation of the
exocyclic enolate. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: terpene; anti-cancer agent; asymmetric synthesis; Diels–Alder reaction; alkylation.
Dysidiolide (1), a novel sesterterpene from the Caribbean marine sponge Dysidea etheria de
Laubenfels,1 inhibits the protein phosphatase cdc25A (IC50=9.4 µM) that promotes the G1/S transition of
the cell cycle by dephosphorylation of the cyclin–cyclin dependent kinase complex.2 Dysidiolide inhibits
the growth of human lung carcinoma cells and murine leukemia cells, probably due to inhibition of
cdc25A, which is known to be oncogenic and overexpressed in a number of tumor cell lines.3 Therefore,
the cdc25A-specific inhibitor dysidiolide is regarded as a novel candidate agent for the treatment of
cancer and other proliferative diseases.
Although three groups have already reported total syntheses of natural,4 unnatural5 and racemic6 dy-
sidiolide, a synthetic approach to its structure–activity relationship has not been reported yet. Therefore,
we planned to develop an efficient synthetic route to dysidiolide and its analogs in order to investigate
the structure–activity relationship and to create novel potentially useful compounds with higher activities.
Our synthetic strategy described below should afford dysidiolide and a variety of analogs having different
configurations and functionalities.
The retrosynthetic analysis is shown in Scheme 1. The decalin framework, the core structure of
dysidiolide, could be constructed by intermolecular Diels–Alder reaction of the chiral triene 4 with
crotonaldehyde. Subsequently, the quaternary center at C-6 could be created by methylation of the
exocyclic enolate generated from the aldehyde 3. The γ-hydroxybutenolide residue, regarded as a
surrogate phosphate, could be created by 1,2-addition of 3-furyllithium7 to the aldehyde 2 and subsequent
photochemical oxidation of the furan ring.7,8
∗
Corresponding author. Tel: +81-743-72-6171; fax: +81-743-72-6179; e-mail: rshirai@ms.aist-nara.ac.jp (R. Shirai)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00078-2
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Scheme 1.
The starting ketone 5 was prepared from racemic 2-methylcyclohexanone by d’Angelo’s procedure.9
Optically pure 5 was obtained by recrystallization of corresponding semicarbazone followed by regener-
29
29
ation of the original ketone ([α] −35.9 (c 2.93, EtOH), lit. [α] −33.8 (c 2.95, EtOH)9). Protection
D
D
of the ketone as the ethylene acetal followed by reduction afforded the corresponding alcohol 6, which
was converted to the iodide 7 via the tosylate, followed by cross-coupling with 2-propenylmagnesium
bromide in the presence of a catalytic amount of CuI. Removal of the ketal with pyridinium p-
toluenesulfonate gave the ketone 8. Then, 1,2-addition of vinylcerium reagent to the carbonyl group
5
of 8 and dehydration of the corresponding carbinol with anhydrous CuSO4 afforded the desired triene
4 along with 10% of the alkenyl side chain isomer. These products were readily separated by AgNO3-
coated silica gel column chromatography (Scheme 2).
Scheme 2. Reagents and conditions. (a) Ethylene glycol, benzene, reflux (96%); (b) LiAlH4, THF, 0°C (90%); (c) TsCl, pyridine,
0°C (92%); (d) NaI, acetone, reflux (90%); (e) 2-propenylmagnesium bromide, CuI, THF, −30°C→0°C (92%); (f) pyridinium
p-toluenesulfonate, acetone, reflux (94%); (g) vinylmagnesium bromide, anhydrous CeCl3, THF, rt (89%); (h) anhydrous
CuSO4, benzene, reflux (89%)
Intermolecular Diels–Alder reaction of the triene 4 and crotonaldehyde proceeded smoothly at −30 to
0°C, catalyzed by EtAlCl2·THF, to give an inseparable adduct mixture of four isomers in 83% yield.10
Reduction of the mixture with AlH3 provided a mixture of four alcohols 9a–9d (9a (endo-6S,7R,11R):9b
(endo-6R,7S,11S):9c (exo-6R,7S,11R):9d (exo-6S,7R,11S)=47:23:21:9), and the pure alcohol 9a derived
from the endo major isomer 3 was obtained.
Next, the alcohol 9a was reoxidized to the previous aldehyde 3, which was methylated with t-
BuOK–MeI to give an inseparable mixture of 10 and epi-10 in 80% yield with moderate α-selectivity.
The course of stereoselectivity is understood that the β-methyl group at the quaternary carbon center
blocked β-face of exocyclic enolate by model analysis. The absolute configuration of 10 and epi-10
was established as Diels–Alder reaction of triene 4 with tiglic aldehyde (trans-2-methyl-2-butenal)
gave epi-10.10 Reduction of the mixture of 10 and epi-10 with NaBH4 provided the easily separable
alcohols 11 and epi-11 in yields of 16% and 45% from 3, respectively. Although epi-11 has the
wrong stereochemistry for the synthesis of 1, this is still a valuable intermediate to synthesize novel
stereoisomers of dysidiolide. Next, compound 11 was converted to the tosylate, which was displaced by
cyanide ion in HMPA solvent.11 Subsequently, DIBAL reduction of the nitrile gave the known synthetic

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intermediate (2) of dysidiolide.4–6 Treatment of 2 with excess 3-furyllithium7 provided 12 and epi-12,
which were separated by silica gel chromatography. Finally, photochemical oxidation7,8 of 12 afforded
dysidiolide 1 as colorless crystals (Scheme 3). The 1H NMR and MS/HRMASS spectra, optical rotation
and melting point of synthetic 1 were identical to those reported.1
Scheme 3. Reagents and conditions: (a) EtAlCl2·THF (1:1), CH2Cl2, −30°C→0°C (83%); (b) AlH3, THF, 0°C and separation
(25% from 4); (c) TPAP, NMO, MS4 Å, rt (90%); (d) CH3I, t-BuOK, THF, rt (80%); (e) NaBH4, MeOH, 0°C, 11 (16% from
3) and epi-11 (45% from 3); (f) TsCl, pyridine, 0°C (89%); (g) NaCN, HMPA, 90°C (90%); (h) DIBAL-H, CH2Cl2, −78°C
(72%); (i) 3-bromofuran, n-BuLi, THF, −78°C (88% 1:1, 12:epi-12); (j) O2, hν, Rose Bengal, i-Pr2EtN, CH2Cl2, −78°C (85%)
This synthetic approach provided a facile route to dysidiolide and could be applicable for preparing
a wide range of novel derivatives. Synthesis of such analogs and studies of the structure–activity
relationships are in progress.

2114
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture, Japan.
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