A new stereocontrolled route to (+)-curcuphenol, a phenolic sesquiterpene from the marine sponge Didiscus flavus

Article abstract of DOI:10.1016/S0957-4166(98)00234-1

Using a synthetic equivalent of chiral 2-cyclopentenol, (+)- curcuphenol, a cytotoxic bisabolane type sesquiterpene isolated from the marine sponge Didiscus flavus, has been synthesized through a concurrent retro-Diels-Alder reaction and Claisen rearrange

Full text of DOI:10.1016/S0957-4166(98)00234-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2215–2217
A new stereocontrolled route to (+)-curcuphenol, a phenolic
sesquiterpene from the marine sponge Didiscus flavus
Tsutomu Sugahara and Kunio Ogasawara ∗
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 27 May 1998; accepted 10 June 1998
Abstract
Using a synthetic equivalent of chiral 2-cyclopentenol, (+)-curcuphenol, a cytotoxic bisabolane type sesquiter-
pene isolated from the marine sponge Didiscus flavus, has been synthesized through a concurrent retro-Diels–Alder
reaction and Claisen rearrangement reaction. © 1998 Elsevier Science Ltd. All rights reserved.
Enantiomerically pure ketodicyclopentadiene 1, accessible in both enantiomeric forms, is used in the
construction of a variety of natural products as a synthetic equivalent of chiral cyclopentadienone.1,2 It
has also been used as a synthetic equivalent of chiral 2-cyclopentenol after chemo- and stereoselective
reduction3 to chiral endo-alcohol4 2. We report here an alternative utilization of 2 as an equivalent
of chiral 2-cyclopentenol tolerated under the Mitsunobu reaction conditions. Although the Mitsunobu
reaction5 is one of the best methods for the preparation of aryl ethers from phenols and alcohols with
inversion of the latter’s configuration, a considerable racemization is sometimes observed when chiral
allylic alcohols are used as substrates.6,7 We describe here a new synthesis of a cytotoxic bisabolane
sesquiterpene (+)-curcuphenol 3, isolated from the marine sponge Didiscus flavus,8–11 starting with the
Mitsunobu reaction of the allyl alcohol equivalent (−)-2 which proceeded without any racemization
(Scheme 1).
Scheme 1.
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Thus, the reaction of (−)-2, mp 96°C, [α]D −13.1 (c 0.5, CHCl3) (prepared from enantiomerically
pure (+)-KDP 1: >99% ee by HPLC 12), with two equivalents each of 3-methylphenol, diisopropyl
∗
Corresponding author. Fax: +81-22-217-6845; e-mail: konol@mail.cc.tohoku.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00234-1

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T. Sugahara, K. Ogasawara / Tetrahedron: Asymmetry 9 (1998) 2215–2217
azodicarboxylate (DIPAD) and triphenylphosphine (TPP) in THF at room temperature furnished the
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exo-aryl ether 4, [α]D +44.7 (c 1.2, CHCl3), in 77% yield after 24 h (Scheme 2). The reaction was
found to proceed without losing the original chiral integrity of (−)-2 as confirmed by HPLC analysis
using a chiral column12 (>99% ee).
Scheme 2. Reagents and conditions: (i) 3-MeC6H4OH (2 equiv.), DIPAD (2 equiv.), TPP (2 equiv.), THF, room temp., 24 h
(77%); (ii) diphenyl ether, reflux, 50 min (51%; 68% based on consumed 4); (iii) O3, MeOH, −78°C, then NaBH4, −78°C to
0°C (88%); (iv) Me2C(OMe)2, PPTS (cat.), CH2Cl2, room temp., then benzene, ∼70°C; (v) SiO2, CH2Cl2, room temp. (∼6 h)
(76% from 7); (vi) SO3–pyridine, DMSO, Et3N, room temp., 40 min; (vii) iPrP+Ph3I−, BuLi, THF, 0°C, 45 min (78% from
9); (viii) 1 N HCl:THF (1:2), room temp., 45 min (94%); (ix) NaOH (2 equiv.), (C8H17)3N+MeCl−(0.1 equiv.), MeOCH2Cl (4
equiv.), room temp., 1 h (47%; 66% based on consumed 12); (x) TsCl, Et3N, DMAP (cat.), CH2Cl2, room temp., 24 h; (xi)
NaBH4, DMSO, 70°C, 1.5 h (90% from 13); (xii) conc. HCl (cat.), MeOH:THF (1:4), room temp., 24 h (88%)
29
Upon thermolysis in boiling diphenyl ether (∼280°C) for 50 min, the 3-arylcyclopentene 6, [α]D
+105.5 (c 1.1, CHCl3), was obtained in 51% yield in one step as the single product with some recovery
of the starting material (∼20%) by concurrent retro-Diels–Alder reaction and Claisen rearrangement.13
Prolonged heating did not increase the amount of 6 significantly though the starting material disappeared.
Since 3-methylphenol was detected from the reaction mixture, a competitive elimination reaction of the
allyl ether 4 was presumed to occur under the thermolysis conditions. Regioselective generation of the
single 2,5-disubstituted phenol 6 may be reasoned by preferential intervention of the less hindered 5b
of two possible transition states (5a and 5b) having orbitally favored chair-like conformations14 in the
Claisen rearrangement. Disappointingly, the enantiomeric excess of the product 6 was found to be 88%
ee indicating about 6% loss of the original chiral integrity during the thermolysis conditions which may
be due to a competitive [1,3]-sigmatropic rearrangement15 in the Claisen rearrangement.
In order to confirm the absolute configuration as well as to utilize the rearrangement product, the
cyclopentene 6 thus obtained was transformed into (+)-curcuphenol8 3 whose absolute configuration
had already been established.11 On sequential single-flask ozonolysis and sodium borohydride reduction,
29
6 afforded the triol 7, [α]D +19.3 (c 1.6, MeOH), in 88% yield. To discriminate the three hydroxy
functionalities in the molecule, 7 was reacted with 2,2-dimethoxypropane in the presence of PPTS16 to
afford the diacetonide 8, which on brief exposure to silica gel suspended in dichloromethane allowed
29
specific deacetalization to give selectively the primary alcohol 9, [α]D −18.4 (c 1.4, CHCl3), in

T. Sugahara, K. Ogasawara / Tetrahedron: Asymmetry 9 (1998) 2215–2217
2217
satisfactory overall yield. Oxidation17 of 9 followed by the Wittig reaction of the resulting aldehyde
29
10 gave the isopropylidene product 11, [α]D +4.8 (c 0.7, CHCl3), which, on acid-hydrolysis, afforded
the diol 12, [α]D27 +32.6 (c 1.0, CHCl3). The overall yield of 12 from 7 was 55%. The phenolic hydroxy
functionality of 12 was selectively protected by treating with methoxymethyl chloride in the presence of a
phase transfer catalyst18 to give the aryl ether 13 in 47% yield with some recovery of the starting material
(∼20%), although the yield of 13 was less than satisfactory. While the phenolic hydroxy functionality
was blocked, the primary hydroxy functionality was removed by its tosylation followed by borohydride
reduction19 of the resulting tosylate 14 to give the penultimate intermediate 15, [α]D +7.9 (c 0.1,
27
CHCl3), bearing a secondary methyl functionality, in 90% yield. Finally, 15 was acid-hydrolyzed to give
(+)-curcuphenol 3, [α]D +26.0 (c 0.3, CHCl3), ([α]D +24.6ꢀ2 for the natural product;8 [α]D +29.5
(c 0.2, CHCl3) for the enantiomerically pure sample after purification by preparative HPLC using a chiral
column12), in 88% yield. Enantiomeric excess of the product was determined to be 90% ee by HPLC12
using a chiral column which corresponded to that of the thermolysis product 6.
27
29
References
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