Synthesis of (+)-epiepoformin using the base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone

Article abstract of DOI:10.1016/S0040-4039(01)01871-8

Asymmetric total synthesis of (+)-epiepoformin was achieved in short steps using the base-catalyzed asymmetric Diels-Alder (DA) reaction of 3-hydroxy-2-pyrone with chiral acrylate. Since the synthesis produced Ogasawara's intermediate, it is also presented as a formal synthesis of (-)-theobroxide.

Full text of DOI:10.1016/S0040-4039(01)01871-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8649–8651
Synthesis of (+)-epiepoformin using the base-catalyzed
Diels–Alder reaction of 3-hydroxy-2-pyrone
a
b,
b
b
Hideki Shimizu, Hiroaki Okamura, * Naomi Yamashita, Tetsuo Iwagawa and
b
Munehiro Nakatani
a
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
b
Department of Chemistry and Bioscience, Faculty of Science, Kagoshima University, 1-21-35 Korimoto,
Kagoshima 890-0065, Japan
Received 10 September 2001; revised 1 October 2001; accepted 5 October 2001
Abstract—Asymmetric total synthesis of (+)-epiepoformin was achieved in short steps using the base-catalyzed asymmetric
Diels–Alder (DA) reaction of 3-hydroxy-2-pyrone with chiral acrylate. Since the synthesis produced Ogasawara’s intermediate, it
is also presented as a formal synthesis of (−)-theobroxide. © 2001 Elsevier Science Ltd. All rights reserved.
Naturally occurring highly oxygenated epoxycyclohex-
ane derivatives, known as cyclohexene oxides, are
attractive targets for synthetic chemists because of their
various biological activities, including anti-tumor and
glucosidase inhibition activities. Construction of the
saturated functionalities in the cyclohexane ring system
stereoselectively is also of great interest.
bond, oxygen functional groups at C-1 and C-4, and
carbonyl group at C-8 in 3 might be converted to the
respective epoxy group at C-2,3, oxygen functional
groups at C-1 and 4, and one-carbon side-chain at C-5
in typical cyclohexene oxides 4–7 (Scheme 2). Addition-
ally, since both enantiomers of 3 are easily obtained by
changing the chiral auxiliary of 2 and base-catalyst,
compound 3 should be a useful starting material for
asymmetric synthesis. Indeed, we have already reported
the synthesis of both enantiomers of eutypoxide B, a
1
The most important point in the efficient synthesis of
these small compounds with diverse oxygen functional
groups is the choice of a starting material with appro-
priate functional groups in the appropriate positions in
the cyclohexane ring or its equivalent. We reported a
base-catalyzed asymmetric Diels–Alder (DA) reaction
using 3-hydroxy-2-pyrone (1) with optically active acryl-
ate ((−)-2), which afforded a highly functionalized
adduct ((+)-3) in almost quantitative yield as an opti-
cyclohexene oxide with a C side-chain, from (+)- and
5
3
(
−)-3.
In our ongoing study of the application of 3 to cyclo-
hexene oxide synthesis, we chose two compounds, (+)-
4
5
epiepoformin (4) and (−)-theobroxide (5) as target
molecules. These compounds were isolated as metabo-
lites of phytotoxic pathogens and reported to be an
2
cally pure form (Scheme 1). As seen by its structure,
compound (+)-3 should be a useful starting material for
constructing cyclohexene oxides. The C-5,6 double
4
inhibitor of lettuce seed germination and an inducer of
Scheme 1.
Keywords: cyclohexene oxides; asymmetric synthesis; Diels–Alder reaction; base-catalyst.
*
Corresponding author. Tel.: +81-99-285-8116; fax: +81-285-8117; e-mail: okam@sci.kagoshima-u.ac.jp
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01871-8

8
650
H. Shimizu et al. / Tetrahedron Letters 42 (2001) 8649–8651
Scheme 2.
5
potato micro-tubers and morning-glory flower buds,
respectively. In 1982, Ichihara’s group first reported a
short, efficient synthesis of dl-4 using the DA reaction
observed. Only treatment with Pd/C that was pre-
treated in a H atmosphere afforded the desired (+)-
2
11
11. Although the yield was changeable, the isomerized
6
of dimethylfulven with p-quinone, and in 1995
product was obtained in fair yield (up to 70%).
Ogasawara’s group achieved the first asymmetric syn-
thesis of (+)-4 and both enantiomers of 5 using asym-
The resulting compound (+)-11 was the key intermedi-
7
metric
lipase-mediated
asymmetrization
of
a
ate of (+)-4 and (−)-5 in Ogasawara’s synthesis, and
7
meso-intermediate. Very recently, Maycock’s group
also reported a synthesis of (+)-4 and (−)-5 from (−)-
the optical rotation showed good agreement. To
confirm the structure, (+)-11 was converted to (+)-4 in
using the reported procedure. Since the optical rotation
8
quinic acid.
1
12
and H NMR spectrum of the resulting compound
showed good agreement with those reported for synthe-
Our synthesis of (+)-4 and (−)-5 started from hydroxy-
ketone (−)-8, which was obtained from adduct (+)-3
7
sized (+)-4, we accomplished efficient asymmetric syn-
3
following the preceding procedure (Scheme 3). Epoxi-
thesis of (+)-4 and a formal asymmetric synthesis of
(−)-5.
dation of (−)-8 was achieved by treatment of hydrogen
peroxide under basic conditions. Although the standard
H O –NaOH conditions only provided a complex mix-
As shown in this synthesis, compound 3 is a promising
starting material for various cyclohexene oxides. For
example, introducing a hydroxyl group on the methyl
2
2
ture, the combination of H O –Triton B was effective
2
2
in giving the desired epoxide 9, and the highest yield
up to 92%) was obtained using a catalytic amount (0.3
(
group at C-6 of (+)-4 and (−)-5 results in the efficient
7,9
4,13
equiv.) of Triton B. The stereochemistry of the epoxy
group results from the steric interaction between the
hydroperoxide nucleophile and the bulky TBSO-group,
which induced a attack of the hydroperoxide. Although
the base-induced enolization eliminated the stereochem-
istry of the hydroxymethyl group at this stage, this was
not disadvantageous because the stereochemistry disap-
peared in the next step.
synthesis of (+)-epiepoxydon
(6) and (−)-
14
phyllostine (7), respectively, and further oxidation
makes it possible to produce more highly oxidized
15
16
compounds, such as cyclophellitol and crotepoxide.
We are now examining the synthesis of such com-
pounds, including (+)-6 and (−)-7.
Dehydroxylation of the primary hydroxyl group in 9 in
almost quantitative yield was achieved by tosylation
and subsequent elimination. Isomerization of the exo-
olefin in (−)-10 was difficult. Several attempts using
Rh-complexes were made under various conditions,
but no efficient conversion to the endo-olefin (+)-11 was
Acknowledgements
The authors thank Dr. Ryo Irie, Kyushu University,
for performing the elemental analysis and the HRMS
measurements.
10
Scheme 3. Reagents and conditions: (a) 30% aq. H O , Triton B; (b) TsCl, Et N, DMAP; (c) Pd/C; (d) HF-CH CN.
2
2
3
3

H. Shimizu et al. / Tetrahedron Letters 42 (2001) 8649–8651
8651
References
9. Vang, N. C.; Finnegan, R. A. J. Am. Chem. Soc. 1958,
0, 5845–5848.
8
1
. (a) Thebtaranonth, C.; Thebtaranonth, Y. Acc. Chem.
Res. 1986, 19, 84–90; (b) Balci, M.; S u¨ tbeyaz, Y.; Secen,
H. Tetrahedron 1990, 46, 3715–3742.
10. (a) Birch, A. J.; Subba Rao, G. S. R. Tetrahedron Lett.
1968, 9, 3797–3798; (b) Andrieux, J.; Barton, D. H. R.;
Patin, H. J. Chem. Soc., Perkin Trans. 1 1977, 359–363;
(
1
c) Grieco, P. A.; Marinovic, N. Tetrahedron Lett. 1978,
9, 2545–2548.
2
3
4
5
. Okamura, H.; Morishige, K.; Iwagawa, T.; Nakatani, M.
Tetrahedron Lett. 1998, 39, 1211–1214.
1
1. A CꢀC double bond isomerization using Pd/C without
. Shimizu, H.; Okamura, H.; Iwagawa, T.; Nakatani, M.
Tetrahedron 2001, 57, 1903–1908.
. Nagasawa, H.; Suzuki, A.; Tamura, S. Agric. Biol. Chem.
the pretreatment in H was reported: Boss, R.; Scheffold,
2
R. Angew. Chem., Int. Ed. Engl. 1976, 15, 558–559.
1
1
2. H NMR of (+)-4 (400 MHz, CDCl ): 1.85 (br s, 3H),
3
1
978, 42, 1303–1304.
3.51 (dd, J=0.73, 3.7 Hz, 1H), 3.78 (br s, 1H), 4.66 (d,
. (a) Nakamori, K.; Matsuura, H.; Yoshihara, T.; Ichi-
hara, A.; Koda, Y. Phytochemistry 1994, 35, 835–839; (b)
Yoshihara, T.; Ohmori, F.; Nakamori, K.; Amanuma,
M.; Tsutsumi, T.; Ichihara, A.; Matsuura, H. J. Plant
Growth Regul. 2000, 19, 457–461.
J=4.0 Hz, 1H), 6.46 (br s, 1H).
1
1
1
3. Sekiguchi, J.; Gaucher, G. M. Biochem. J. 1979, 182,
4
45–453.
4. Sakamura, S.; Ito, J.; Sakai, R. Agric. Biol. Chem. 1971,
5, 105–110.
3
6
7
8
. Ichihara, A.; Kimura, R.; Oda, K.; Moriyasu, K.; Saka-
mura, S. Agric. Biol. Chem. 1982, 46, 1879–1883.
. Kamikubo, T.; Ogasawara, K. Tetrahedron Lett. 1995,
5. (a) Kupchan, S. M.; Hemingway, R. J.; Smith, R. M. J.
Org. Chem. 1969, 34, 3898–3902; (b) Takahashi, S. Phy-
tochemistry 1969, 8, 321–322.
3
6, 1685–1688.
16. Atsumi, S.; Umezawa, K.; Iinuma, H.; Nasanawa, H.;
Nakamura, H.; Iitaka, Y.; Takeuchi, T. J. Antibiot. 1990,
43, 49–53.
. Barros, M. T.; Maycock, C. D.; Ventura, M. R. Chem.
Eur. J. 2000, 6, 3991–3996.