Optimization of ring-contraction of the meso enedione epoxide for chiral building block synthesis

Article abstract of DOI:10.1016/S0040-4039(02)00750-5

The ring-contraction of the enedione epoxide obtained from the adduct of benzoquinone and cyclopentadiene is mainly affected by the amount of base used. Excellent yields (>80%) of the ring-contracted product were consistently obtained when the epoxide was

Full text of DOI:10.1016/S0040-4039(02)00750-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4175–4178
Optimization of ring-contraction of the meso enedione epoxide
for chiral building block synthesis
Hideyuki Tanaka, Yoshihiro Kozuki and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 24 March 2002; revised 11 April 2002; accepted 17 April 2002
Abstract—The ring-contraction of the enedione epoxide obtained from the adduct of benzoquinone and cyclopentadiene is mainly
affected by the amount of base used. Excellent yields (>80%) of the ring-contracted product were consistently obtained when the
epoxide was treated with a 0.5 equiv. of ethanolic sodium hydroxide in ethanol. The versatility of the chiral building block
accessible from the ring-contracted product has also been demonstrated by an alternative diastereocontrolled synthesis of
(+)-tanikolide, a toxic and antifungal marine natural product isolated from Lyngbya majuscula. © 2002 Published by Elsevier
Science Ltd.
We have developed1 a chiral production of the tricyclic
diol 1 in both enantiomeric forms by employing lipase-
mediated resolution of the racemic precursor ( )-1
obtained from the known tricyclic keto-ester ( )-22
(Scheme 1). Owing to its sterically biased framework
allowing convex-face selective modification and its ther-
mal lability to generate a cyclopentene double bond
with extrusion of a cyclopentadiene molecule, the diol 1
was used as a synthetic equivalent of a functionalized
chiral cyclopentadienol. It allowed the efficient prepara-
tion of a naturally occurring antiviral carbocyclic
nucleoside (–)-neplanocin3 and two monoterpenes, (–)-
iridolactone4 and (+)-pedicularis-lactone,4 in an enan-
tio- and diastereocontrolled manner due to its inherent
steric and chemical nature. Although the keto-ester
( )-2 was easily formed from the meso-enedione epox-
ide 3, generated from the Diels–Alder adduct between
benzoquinone and cyclopentadiene, by a Favorskii-type
ring-contraction as originally reported by Herz and
co-workers,2 the reaction was very capricious, affording
the ring-contracted product ( )-2 in a range of yields
which made the consistent production of the chiral
building block very difficult. We therefore, sought opti-
mal conditions for the ring-contraction of the enedione
epoxide 3 to achieve the consistent production of the
chiral building block 1 and thereby widen its utilization
in the enantioselective construction of a variety of
chiral materials. We report here good conditions for the
satisfactory production of the keto-ester ( )-2 and its
transformation into both of the enantiomeric diols 1 in
an enantiopure state, one of which has never been
obtained in a pure state at this stage before.1 The use of
the enantiopure product (–)-1 for an alternative synthe-
sis of (+)-tanikolide,5,6 a toxic and antifungal marine
natural product isolated from Lyngbya majuscula, was
also described to demonstrate the versatility of the
chiral building block.
Based on the procedure by Herz and co-workers,2 we
examined the reaction extensively using sodium hydrox-
ide in ethanol as well as sodium ethoxide in ethanol and
sodium methoxide in methanol. As shown, it was found
that sodium hydroxide was superior to the others and
that the amount of the base was the most important
CO2Et
OH
OH
OH
:
HO
O
(–)-1
(+)-1
(±)-2
Scheme 1.
* Corresponding author. E-mail: konol@mail.cc.tohoku.ac.jp
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00750-5

4176
H. Tanaka et al. / Tetrahedron Letters 43 (2002) 4175–4178
CO2R
OH
O
5N NaOH (0.5 equiv)
Bui2AlH
ROH, r.t., 3 h
(R = Et : 80%)
CH2Cl2, –78 °C, 30 min
O
(77%)
HO
O
O
meso-3
(±)-1
(±)-2
Scheme 2.
carried out in the presence of 0.5 equiv. of sodium
hydroxide, the ring-contracted product ( )-2 was
obtained cleanly in good yield. Thus, stirring the epox-
ide 3 (19.0 g, 100 mmol) in EtOH (480 ml) with 20%
ethanolic NaOH (10 ml, 50 mmol) at room temperature
for 3 h afforded the keto-ester (+)-2 (17.4 g, 80%) after
the standard work-up and purification by silica gel
column chromatography. Reduction of the product 2
using lithium aluminum hydride afforded the desired
diol ( )-1, but was accompanied by a considerable
amount of by-products presumably due to a concurrent
[3,3]-sigmatropic rearrangement under these condi-
tions.1,7 However, the reduction of the keto-ester ( )-2
using diisobutylaluminum hydride (DIBAL) at –78°C
in dichloromethane1 allowed the desired reduction to
give the crystalline diol ( )-1, mp 122–124°C, in satis-
factory yield (Scheme 2).
hydroxy functionalities in the molecule, the diol 9 was
treated with N-bromosuccinimide (NBS) to form the
bromo-ether 10, [h]2D4 –58.4 (c 1.4, CHCl3), leaving the
exo-hydroxy functionality intact. After protection of
the exo-hydroxy functionality as the MOM–ether 11,
[h]2D4 +6.9 (c 1.5, CHCl3), the bromo-ether functionality
was cleaved reductively with zinc and acetic acid in
methanol to liberate the endo-hydroxy functionality to
give rise to the endo-alcohol 12, [h]2D2 +21.1 (c 1.1,
CHCl3). The overall yield of 12 from the starting diol
(–)-1 was 46% in seven steps (Scheme 4).
To construct the quaternary stereogenic center required
for the target molecule 20, the endo-alcohol 12 was
refluxed with
4 equiv. of N,N-dimethylacetamide
dimethyl acetal11 in diphenyl ether. Under these condi-
tions, we expected that a concurrent retro-Diels–Alder
reaction, ketene aminoacetal formation and an Eschen-
moser rearrangement would occur to generate the
cyclopentene 14 having the requisite quaternary center
presumably via the transient monocyclic intermediate
13. The expected reaction did indeed take place within
60 min to furnish the cyclopentene 14, [h]2D4 +35.7 (c
1.5, CHCl3), in 63% yield. Transformation of the
product 14 into the target molecule (+)-tanikolide 20
was carried out in a straightforward manner. Thus, the
tertiary amide functionality of 14 was reduced with
lithium triethylborohydride12 to give the primary alco-
hol 15, [h]2D3 +41.9 (c 0.6, CHCl3), which was converted
Resolution of the racemic diol ( )-1 (5.0 g, 28.2 mmol)
was carried out in ether (240 ml) containing vinyl
acetate (3.9 ml, 42 mmol) in the presence of immobi-
lized lipase (Lipase LIP, Toyobo, 1.25 g) at ꢀ30°C for
3.5 h to give the diacetate (–)-4, [h]2D6 –112.2 (c 1.2,
CHCl3) (95% ee),8 (3.18 g, 43%) and the monoacetate
(+)-5, [h]2D6 +133.9 (c 1.0, CHCl3) (>99% ee),8 (2.73 g,
44%) after silica gel column chromatography. The diac-
etate (–)-4 gave the enantiopure diol (–)-1,8 mp 136–
138°C, [h]2D7 –187.0 (c 0.4, EtOH),6 in 78% yield after
methanolysis with potassium carbonate followed by
recrystallization of the optically enriched diol (–)-1
from MeOH–CHCl3. Alkaline methanolysis of the
monoacetate (+)-5 afforded the enantiopure diol (+)-1,8
mp 134–136°C, [h]2D6 +175.1 (c 1.0, EtOH), quantita-
tively (Scheme 3).
1
into the inseparable diene mixture 17 (E/Z=1:10 by H
NMR) via the aldehyde 16 by sequential pyridinium
dichromate (PDC) oxidation, Wittig reaction and
MOM-deprotection.13 The resulting mixture 17 was
oxidized to the cyclopentenone mixture 18 which, on
catalytic hydrogenation over palladium on charcoal in
ethanol containing chloroform,14 afforded the single
keto-alcohol 19, [h]2D5 –8.1 (c 1.0, CHCl3), by concurrent
hydrogenation and hydrogenolysis. Finally, Baeyer–Vil-
To demonstrate the capability of the diol 1 for con-
structing a quaternary stereogenic center in a diastere-
ocontrolled manner, we conducted an alternative
synthesis of (+)-tanikolide 20 the absolute structure of
which was recently established unambiguously by our
laboratory6 through an enantiocontrolled procedure
employing the catalytic asymmetric synthesis.9,10 Thus,
the diol (–)-1 was oxidized chemoselectively using man-
ganese(IV) oxide to give the keto-alcohol 6, [h]2D6 –15.9
(c 1.0, CHCl3), quantitatively. After benzylation, the
resulting benzyl ether 7, [h]2D2 –61.8 (c 0.9, CHCl3), was
treated with 30% hydrogen peroxide in methanol con-
taining 1N NaOH to give the exo-epoxide 8 which, on
reflux with lithium aluminum hydride in dioxane,
afforded the single diol 9, [h]2D1 –14.9 (c 1.0, CHCl3), by
concurrent diastereoselective selective reduction of the
ketone functionality and regioselective cleavage of the
epoxide ring. To differentiate the two secondary
Table 1. Ring-contraction reactiona of the meso-enedione
epoxide 3
Entry
Base (equiv.)
Solvent
Product (R) (%)b,c
1
2
3
4
5
6
NaOEt (1.0)
NaOMe (1.0)
NaOH (1.0)
NaOH (0.7)
NaOH (0.5)
NaOH (0.3)
EtOH
MeOH
EtOH
EtOH
EtOH
EtOH
Et: 29
Me: 32
Et: 61d
Et: 75d
Et: 80d
Et: 62d
a All reactions were carried out at room temperature.
b Isolated yield after silica gel column chromatography.
c Virtually, no starting material was recovered.
d None of the hydrolysis products from 3 and 1 was isolated.

H. Tanaka et al. / Tetrahedron Letters 43 (2002) 4175–4178
4177
1) K2CO3-MeOH
r.t., 35 h
OH
OH
OAc
OAc
2) recrystallized
from MeOH-CHCl3
(>99% ee)
Lipase LIP
vinyl acetate (1.5 equiv)
(–)-1
(43%:>95% ee)
(78%)
(–)-4
(±)-1
+
Et2O, ~30 °C, 3.5 h
OAc
OH
K2CO3-MeOH
r.t., 12 h
(100%)
HO
HO
(>99% ee)
(44%:>99% ee)
(+)-1
(+)-5
Scheme 3.
i
iii
OBn
O
OBn
OH
OR
O
iv
(–)-1
O
OH
8
9
6: R=H
7: R=Bn
ii
OBn
vii
OBn
v
Br
OH
O
OR
OMOM
12
10: R=H
11: R=MOM
vi
Scheme 4. Reagents and conditions: (i) MnO2, CH2Cl2, rt (100%); (ii) Bn–Br, Bu4NHSO4 (cat.), 50% NaOH, benzene (80%); (iii)
30% H2O2, 1N NaOH, MeOH rt; (iv) LiAlH4, dioxane, reflux (70%, two steps); (v) NBS, CH2Cl2, rt (86%); (vi) Zn, AcOH–MeOH
(1:10), reflux (95%).
liger oxidation of the keto-alcohol 19 was carried out
under the conditions using m-chloroperbenzoic acid in
the presence of triflic acid15 to give (+)-tanikolide 20,
mp 39–41°C, [h]D25 +3.0 (c 0.8, CHCl3){natural:5 [h]D25
+2.3 (c 0.7, CHCl3); synthetic:6 mp 38–40°C, [h]D25 +2.9
(c 0.65, CHCl3)}, which was identical with an authentic
sample in all respects. The overall yield of (+)-
tanikolide 20 from the tricyclic alcohol 12 was 30% in
seven steps; therefore, the total yield from the chiral
building block (–)-1 was 14% in fourteen steps (Scheme
5).
In conclusion, we have found that the optimal condi-
tions for the ring-contraction of the enedione epoxide
obtained from the adduct of benzoquinone and
cyclopentadiene gave the tricyclic keto-ester, which
OMOM
OBn
OR2
OBn
OBn
MOMO
O
i
ii
12
R1
NMe2
O
15: R1=CH2OH, R2=MOM
16: R1=CHO, R2=MOM
17: R1=CH=CHC8H17,R2=H
iii
iv
NMe2
14
13
OH
OBn
OH
O
O
O
O
vii
vi
v
C11H23
C8H17
C11H23
(+)-tanikolide 20
19
18
Scheme 5. Reagents and conditions: (i) MeC(NMe2)(OMe)2, Ph2O, reflux (63%); (ii) LiEt3BH, THF (99%); (iii) PDC, CH2Cl2, rt;
(iv) C9H19PPh3I, NaHMDS, THF, then satd HCl–MeOH (72%, two steps); (v) PCC, CH2Cl2 (95%). (vi) H2, 10% Pd–C (cat.),
EtOH–CHCl3 (3:1) (83%); (vii) m-CPBA, TfOH (cat.), CH2Cl2 (85%).

4178
H. Tanaka et al. / Tetrahedron Letters 43 (2002) 4175–4178
served as the precursor of the versatile cyclopentenol
chiral building block, in satisfactory yield. The versatil-
ity of the chiral building block has also been demon-
strated by an alternative diastereocontrolled synthesis
of (+)-tanikolide, a toxic and antifungal marine natural
product isolated from Lyngbya majuscula.
sis, see: Kanada, R. M.; Taniguchi, T.; Ogasawara, K.
Synlett 2000, 1019.
7. (a) Klunder, A. J. H.; Lange, J. H. M.; Zwanenburg, B.
Tetrahedron Lett. 1987, 28, 3027; (b) Suri, S. C.; Rogers,
S. L.; Lauderdale, W. J. Tetrahedron Lett. 1996, 37, 7827;
(c) Chavan, S. P.; Ethiraj, K. S.; Kamat, S. K. Tetra-
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8. Optical purity was determined by HPLC equipped with a
chiral column (CHIRALCEL OD, elution with PriOH–
hexane 5:95) after transformation into the dibenzoate.
9. (a) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsuura, K.;
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Acknowledgements
We are grateful to the Ministry of Education, Culture,
Sports, Science and Technology, Japan for support of
this research.
10. (a) Kanada, R. M.; Taniguchi, T.; Ogasawara, K. Chem.
Commun. 1998, 1755; (b) Iura, Y.; Sugahara, T.;
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