Stereoselective total synthesis of (-)-α-eudesmol, a P/Q-type calcium channel blocker

Article abstract of DOI:10.1055/s-2001-16804

Practical and stereoselective total synthesis of (-)-αeudesmol 1, a P/Q-type calcium channel blocker, has been achieved with the key step being a cyclopropane ring opening accompanying introduction of a hydroxyl group. (+)-Carissone is used as a key intermediate.

Full text of DOI:10.1055/s-2001-16804

1452
LETTER
Stereoselective Total Synthesis of (–)- -Eudesmol, a P/Q-Type Calcium
Channel Blocker
Yasunori Aoyama,a* Yoshitaka Araki,b Toshiro Konoikeb*
aShionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan
bShionogi Research Laboratories, Shionogi & Co., Ltd., Amagasaki, Hyogo 660-0813, Japan
Tel. +81-6-6458-5861; Fax +81-6-6458-0987; E-mail: yasunori.aoyama@shionogi.co.jp
Received
(–)- -Eudesmol 1 possesses three asymmetric carbons (C-
5, C-7 and C-10), a double bond at the C3 C4 position and
a hydroxyl group at the C-11 position. Our synthetic de-
sign employs (+)-carissone 26 as a key intermediate be-
cause it has the same stereochemistry at C-7 and C-10 as
(–)- -eudesmol 1 and a hydroxyl group at the C-11 posi-
tion. (–)-Carvone 3 was chosen as the starting material,
because both enatiomers of carvone are readily available
commercially.
Abstract: Practical and stereoselective total synthesis of ( )- -
eudesmol 1, a P/Q-type calcium channel blocker, has been achieved
with the key step being a cyclopropane ring opening accompanying
introduction of a hydroxyl group. (+)-Carissone is used as a key in-
termediate.
Key words: -eudesmol, natural products, total synthesis, stereo-
selective, ring opening
The already-known sesquiterpene, -eudesmol, has been
isolated from many species of the plant kingdom.1 Re-
cently, in our laboratory, -eudesmol isolated from Juni-
perus virgantea was found to display a P/Q-type calcium
channel inhibitory activity.2 P/Q-type calcium channels
are only present in the central nervous system, especially
at the synaptic terminal, and participate in the release of
neurotransmitters. 3 As excess release of neurotransmit-
ters causes neuronal degeneration, the P/Q-type calcium
channel blocker is considered to be effective for treatment
of cerebral apoplexy, Alzheimer’s disease and migraine.
b
a
O
O
(–)-carvone 3
4
O
c
O
O
(–)-2-carone 5
6
Syntheses of -eudesmol have been achieved by some
groups, however, most use semi-synthesis from other nat-
ural products4 and do not allow synthesis of the antipode
of -eudesmol. Also, the total synthesis reported by the Li
group consists of many steps.5
Scheme 1 [a] Li, THF, t-BuOH, 85% (Ref 7); [b] HCl (gas), CHCl3
then KOH, MeOH, 82% (Ref 8); [c] EVK, KOH, EtOH, 85% (Ref 9).
First, (–)-carvone 3 was stereoselectively converted into
diketone 6 by known methods (Scheme 1).7–9 Because the
Michael reaction of (–)-2-carone 5 with ethyl vinyl ketone
(EVK) led stereoselectively to diketone 6 which pos-
sessed the desired stereochemistry at the C-10 position,9
these methods were applied to the synthesis of (+)-caris-
sone 2, the key intermediate. Robinson annulation of dike-
tone 6 was tried, but, the reaction did not proceed at all,
which may suggest that ring strain of the bicyclic structure
6 inhibits the cyclization reaction. Accordingly, cyclopro-
pane ring opening was next investigated.
We tried to develop a simpler total synthesis of both enan-
tiomers of -eudesmol for two purposes. The first was to
obtain a supply of -eudesmol for pharmacological eval-
uation, as it can not be obtained from Juniperus virgantea
in large quantities. The second was to determine the bio-
logical activity of the antipode of -eudesmol. We de-
scribe herein a practical and stereoselective total synthesis
of (–)- -eudesmol 1 with the key step being cyclopropane
ring cleavage accompanying introduction of a hydroxyl
group.
Some synthetic studies related to the ring opening of cy-
clopropyl ketone have been reported.10 What was neces-
sary was to develop a method for the cyclopropyl ketone
ring opening followed by introduction of a hydroxyl
group at the C-11 position. The results of acid-catalyzed
cyclopropane ring opening are summarized in the Table.
Treatment of diketone 6 with acids such as boron trifluo-
ride diethyl etherate (BF3•OEt2), sulfuric acid (H2SO4)
and acetic acid (AcOH) led to (+)- -cyperone 9, an undes-
ired product (entry 1, 2 and 3). However, by using para-
1
9
8
7
2
10
5
3
O
4
6
11
OH
H
OH
(–)-α-eudesmol 1
(+)-carissone 2
Figure 1
Synlett 2001, No. 9, 1452–1454 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselective Total Synthesis of (–)- -Eudesmol
1453
Table Cyclopropane ring opening followed by cyclization.
O
O
+
O
O
O
OH
OH
(+)-carissone 2
7a
6
+
O
O
(+)-α-cyperone 8
(+)-β-cyperone 9
Entry
Isolated yields
Conditions
9 (68%)
BF3•OEt2 (10 eq.), AcOH, r.t., 2 h
1
2
3
4
5
6
9 (70%)
9 (65%)
H2SO4 (1.0 eq.), AcOH, r.t., 1 h
H2SO4 (1.0 eq.), dioxane, r.t., 2 h
TsOH•H2O (1.5 eq.), dioxane, r.t., 24 h
2 (12%), 8 (33%), 9 (14%)
7a (63%)
TsOH•H2O (1.5 eq.), H2O (200 eq.), dioxane, r.t., 18 h
TsOH•H2O (1.5 eq.), H2O (200 eq.), dioxane, 60 ºC, 15 h
2 (81%)
toluenesulfonic acid monohydrate (TsOH•H2O), (+)-
carissone 2, a desired product and (+)- -cyperone 8, a de-
hydrated product of (+)-carissone 2, were obtained as ma-
jor products (entry 4). Based on these results, the
proposed mechanism of the transformation of cyclopropyl
ketone 6 into (+)- -cyperone 9 and (+)-carissone 2 is pre-
sented in Scheme 2. In the presence of H2SO4 and/or
AcOH and/or TsOH, nucleophilic addition against the C-
11 carbocation of ring-opening intermediate II leads to
compounds 7b-d (Nu = OSO3H, OAc, OTs). The elimina-
tion reaction of 7b-d to 10 smoothly proceeds and then the
acid-catalyzed cyclization of 10 occurs to afford (+)- -
cyperone 8. The acid-catalyzed isomerization of (+)- -
cyperone 8 to (+)- -cyperone 9 has already been report-
ed.11 The use of TsOH•H2O as an acid gives 7a and 7b,
because both TsOH and H2O act as nucleophiles. Com-
pound 7a is converted into (+)-carissone 2 without dehy-
dration. Accordingly, in the presence of excess of H2O,
acid-catalyzed ring opening followed by cyclization of 6
was expected to selectively lead to 2. As expected, in the
presence of excess of H2O (200 equiv.), TsOH-catalyzed
ring opening of 6 selectively afforded 7a, a precursor of 2
(entry 5). Increasing the reaction temperature accelerated
cyclization of 7a to give (+)-carissone 2 in 81% yield (en-
O
O
H+
6
+
O
HO
+
H
I
II
O
7a: Nu = OH
Nu
7b: Nu = OTs
7c: Nu = OAc
7d: Nu = OSO3H
O
Nu
O
H+
–HNu
(+)-α-cyperone 8
7b-d
7a
H+
O
10
(+)-β-cyperone 9
H+
(+)-carissone 2
Scheme 2 Proposed mechanism of the transformation of cyclo-
propyl ketone 6 into (+)- -cyperone 9 and (+)-carissone 2.
try 6).12 This method of introducing a hydroxyl group at Finally, conversion of (+)-carissone 2 into (–)- -eudes-
the C-11 position enabled practical and stereoselective mol 1 was investigated.4a The crucial generation of trans
synthesis of (+)-carissone 2.
decalin 1 was effected by palladium-catalyzed hydro-
genolysis of allylic carbonate 12 (Scheme 3).13 Reduction
Synlett 2001, No. 9, 1452–1454 ISSN 0936-5214 © Thieme Stuttgart · New York

1454
Y. Aoyama et al.
LETTER
(4) a) Humber, D. C.; Pinder, A. R.; Williams, R. A. J. Org.
Chem. 1967, 32, 2335. b) Kutney, J. P.; Singh, A. K. Can, J.
Chem. 1984, 62, 1407. C) Toyota, M.; Yonehara, Y.; Horibe,
I.; Minagawa, K.; Asakawa, Y. Phytochemistry 1999, 52, 689.
(5) Chen, Y.; Xiong, Z.; Zhou, G.; Yang, J.; Li, Y. Chem. Lett.
1997, 1289.
(6) a) Barton, D. H. R.; Tarlton, E. J. J. Chem. Soc. 1954, 3492.
b) Pinder, A. R.; Williams, R. A. J. Chem. Soc. 1963, 2773.
c) Kutney, J. P.; Singh, A. K. Can. J. Chem. 1982, 60, 1842.
d) Liu, L.; Xiong, Z.; Nan, F.; Li, T.; Li, Y. Bull. Soc. Chim.
Belg. 1995, 104, 73.
(7) Hua, D. H.; Venkataraman, S. J. Org. Chem. 1988, 53, 1095.
(8) Dauben, W. G.; Shaffer, G, W.; Deviny, E. J. J. Am. Chem.
Soc. 1970, 92, 6273.
of the carbonyl group of 2 with NaBH4-CeCl3 gave the
corresponding 3 -alcohol 11 (92%) as a major product.14
Compound 11 was regioselectively transformed into al-
lylic carbonate 12. The palladium-catalyzed regioselec-
tive and stereospecific decarboxylation hydrogenolysis
of allylic carbonate 12 afforded (–)- -eudesmol 1 without
hindrance of the reaction by the non-protected hydroxyl
group of 12.15 Total synthesis of (–)- -eudesmol 1 has
been achieved in seven steps with an overall yield of 42%
from (–)-carvone 3.16 The antipode 13 of (–)- -eudesmol
1 was synthesized from (+)-carvone by the above proce-
dures.
(9) Hebda, C.; Szykula, J.; Orpiszewski, J.; Fohlisch, B. Monatsh.
Chem. 1991, 122, 1029.
The inhibition of calcium influx in rat cerebral synapto-
some by the P/Q-type calcium channel blocker -eudes-
mol was examined. The activities of both enantiomers of
-eudesmol 1 and 13 were almost same (IC50 = 2.6 and 2.0
M., respectively).2
(10) a) Nakai, T.; Wada, E.; Okawara, M. Tetrahedron Lett. 1975,
1531. b) Tsuge, O.; Kanemasa, S.; Otsuka, T.; Suzuki, T. Bull.
Chem. Soc. Jpn. 1988, 61, 2897. C) Park, H.; Lee, Y. S.; Jung,
S. H.; Shim, S. C. Synth. Commun. 1992, 22, 1445.
d) Imanishi, T.; Hirokawa, Y.; Yamasita, M.; Tanaka, T.;
Miyashita, K.; Iwata, C. Chem. Pharm. Bull. 1993, 41, 31.
(11) Howe, R.; McQuillin, F. J. J. Chem. Soc. 1955, 2423.
(12) Preparation of (+)-carissone 2: A solution of 6 (411 mg, 1.74
mmol) and para-toluenesulfonic acid monohydrate (496 mg,
2.61 mmol) in H2O (6.3 mL, 350 mmol) and 1,4-dioxane
(6.0 mL) was heated for 15 h at 60 °C. After cooling, sodium
bicarbonate solution (20 mL) was added and the reaction
mixure was extracted with ethyl acetate (2 20 mL). The
organic phase was washed with brine and dried over Na2SO4.
Removal of solvent and chromatographic purification (n-
hexane/ethyl acetate = 3/1) yielded 2 (333 mg, 81%) as a
colorless solid; mp 76.0 77.0 °C; [ ]D22 = +138.7°+11.0° (c
0.163, CHCl3) (lit. (Ref 6c)+136.6° (CHCl3)); IR max: 3609,
1654, 1608 cm−1; 1H NMR (300 MHz, CDCl3): 1.21 (s, 3H),
1.25 (s, 3H), 1.26 (s, 3H), 1.31 1.60 (m, 4H, including OH),
1.66 1.84 (m, 4H), 1.78 (d, 3H, J = 1.2 Hz), 1.91 (dt, 1H,
J = 1.2 and 13.5 Hz), 2.39 (dt, 1H, J = 16.5 and 4.2 Hz), 2.52
(ddd, 1H, J = 7.5, 12.0 and 17.1 Hz), 2.86 (dt, 1H, J = 13.8
and 2.7 Hz); 13C NMR (75 MHz, CDCl3): 10.8 (q), 22.3 (q),
22.5 (t), 26.6 (q), 27.4 (q), 28.7 (t), 33.7 (t), 35.8 (s), 37.2 (t),
41.8 (t), 49.6 (d), 72.2 (s), 128.7 (s), 162.9 (s), 199.1 (s);
FABMS m/e 237 [(M+H)+]; Anal. Calcd. for C15H24O2: C,
76.23; H, 10.24. Found: C, 76.05; H, 10.17.
a
b
(+)-carissone 2
HO
OH
11
O
c
(–)-α−eudesmol 1
MeO
O
OH
12
Scheme 3 [a] NaBH4, CeCl3•7H2O, EtOH H2O, 40 0 °C, 92%;
[b] ClCO2Me, pyridine, CH2Cl2, 0 °C, >99%; [c] Pd(OAc)2 (0.2 eq.),
n-Bu3P (0.2 eq.), HCO2NH4 (2.0 eq.), THF, r.t., 2 h, 95%.
In summary, practical and stereoselective total synthesis
of (–)- -eudesmol 1, a P/Q-type calcium channel blocker,
has been achieved with the key step being the cyclopropyl
ketone ring opening followed by introduction of a hydrox-
yl group at the C-11 position This method of introducing
a hydroxyl group may be applicable to syntheses of other
natural products
(13) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J.
Tetrahedron 1993, 49, 5483.
(14) a) The corresponding 3 -alcohol was obtained as a minor
product (8%). b) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc.
1979, 101, 5848.
(15) To the best of our knowledge, this is the first example of
application of an allylic carbonate with a non-protected
hydroxyl group, such as 12, to the palladium-catalyzed
hydrogenolysis of an allylic carbonate (or formate).
Acknowledgement
We thank Dr. T. Kanemasa and Dr. K. Asakura (Shionogi & Co.,
Ltd.) for the biological evaluation of both enantiomers of -eu-
desmol.
(16) An analytical sample of ( )- -eudesmol 1 was recrystallized
24
from n-pentane, mp 85.0 86.0 °C; [ ]D
= 8.1°+0.5° (c
1.008, CHCl3) (lit. (Ref 4c) 8.0° (CHCl3)); 1H NMR (300
MHz, CDCl3): 0.77 (s, 3H), 0.91 1.17 (m, 2H), 1.21 (s, 3H),
1.22 (s, 3H), 1.28 1.66 (m, 7H, including OH), 1.62 (brs, 3H),
1.82 2.20 (m, 4H), 5.32 (brs, 1H); 13C NMR (75 MHz,
CDCl3): 15.5 (q), 21.2 (q), 22.4 (t), 22.9 (t), 24.3 (t), 26.8 (q),
27.6 (q), 32.2 (s), 37.8 (t), 40.1 (t), 46.6 (d), 50.0 (d), 73.0 (s),
121.0 (d), 135.2 (s); LSIMS m/e 222 [M+]; Anal. Calcd. for
C15H26O: C, 81.02; H, 11.79. Found: C, 80.86; H, 11.73.
References and Notes
(1) The first isolation of -eudesmol was reported from
Eucalyptus species (McQuillin, F. J.; Parrack, J. D. J. Chem.
Soc. 1956, 2973).
(2) Kanemasa, T.; Kagawa, K. Japan Kokai Tokkyo Koho,
JP08198745, 1999.
(3) a) Mintz, I. M.; Adams, M. E.; Bean, B. P. Neuron 1992, 9, 85.
b) Mintz, I. M.; Venema, V. J.; Swiderek, K. M.; Lee, T. D.;
Bean, B. P.; Adams, M. E. Nature 1992, 355, 827.
Article Identifier:
1437-2096,E;2001,0,09,1452,1454,ftx,en;Y12101ST.pdf
Synlett 2001, No. 9, 1452–1454 ISSN 0936-5214 © Thieme Stuttgart · New York