Enantioselective syntheses of decursinol angelate and decursin

Article abstract of DOI:10.1016/S0040-4039(01)00642-6

The practical enantioselective syntheses of decursinol angelate and decursin were achieved in eight steps from resorcinol. The stereochemistry was addressed using the catalytic asymmetric epoxidation of 7-acetoxy-2,2-dimethylchromene by chiral (salen)Mn complexes as the key step.

Full text of DOI:10.1016/S0040-4039(01)00642-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4001–4003
Enantioselective syntheses of decursinol angelate and decursin
a
b
b
c
a,
Jongdoo Lim, Ik-Hwan Kim, Hyeon Ho Kim, Kyung-Seop Ahn and Hogyu Han *
a
Department of Chemistry, Korea University, Seoul 136-701, South Korea
b
Graduate School of Biotechnology, Korea University, Seoul 136-701, South Korea
c
Korea Research Institute of Bioscience and Biotechnology, PO Box 115, Yusong, Taejon 305-333, South Korea
Received 28 February 2001; revised 12 April 2001; accepted 13 April 2001
Abstract—The practical enantioselective syntheses of decursinol angelate and decursin were achieved in eight steps from
resorcinol. The stereochemistry was addressed using the catalytic asymmetric epoxidation of 7-acetoxy-2,2-dimethylchromene by
chiral (salen)Mn complexes as the key step. © 2001 Elsevier Science Ltd. All rights reserved.
Protein kinase C (PKC) is a target of great interest in
the development of antitumor agents because of its
crucial role in cellular signal transduction and tumor
(+)-decursin and its analogues were reported by the
Shibasaki group. Here, we report a novel and efficient
route to the enantioselective syntheses of decursinol
angelate and decursin. Our strategy employed the cata-
lytic asymmetric epoxidation of 7-acetoxy-2,2-
dimethylchromene (7) as the key step.
4
1
promotion. Decursinol angelate (1) and decursin (2)
are novel cancer chemotherapeutic candidates isolated
from Angelica gigas Nakai. They have more effective
cytotoxic activity against various human cancer cell
2
lines than normal fibroblasts (Fig. 1). Initial studies
The construction of the requisite epoxidation precursor
showed that both decursinol angelate and decursin
exhibit PKC activating activity, suggesting that their
7
is illustrated in Scheme 1. Our synthesis began with
the condensation of resorcinol 3 and 3-methyl-2-
butenoic acid in the presence of methanesulfonic acid
2b,c
cytotoxicity may be related to the PKC activation.
Recent data indicate that decursinol angelate has
and phosphorus pentoxide, providing the chromanone
2d
stronger activity than decursin in PKC activation.
5
4
in 96% yield. The subsequent reduction of 4 using
The combined cytotoxic and PKC activating properties
of these pyranocoumarins are similar to those of bryo-
statins and thus make them attractive targets for total
LiAlH in THF afforded the chroman 5 in 83% yield.
4
The dehydration step was carried out using p-TsOH in
3
THF
under
reflux
to
give
7-hydroxy-2,2-
synthesis. Recently, the first asymmetric syntheses of
6
dimethylchromene (6) in 88% yield.
O
O
O
O
O
O
O
O
Preliminary attempts to epoxidize the chromene 6
under a variety of standard conditions using m-CPBA,
NaOCl, t-BuOOH or dioxiranes as the oxidant were
unsuccessful due to the rapid decomposition of the
presumed epoxide. This problem was effectively cir-
cumvented via acetylation of the hydroxyl group of 6.
O
O
1
: (+)-decursinol angelate
2: (+)-decursin
7
Figure 1. Structure of decursinol angelate and decursin.
HO
OH
HO
O
HO
O
RO
O
a
b
c
O
OH
6. R = H
. R = Ac
3
4
5
d
7
Scheme 1. Reagents and conditions: (a) 3-methyl-2-butenoic acid, MeSO H, P O , 70°C, 96%; (b) LAH, THF, D, 83%; (c)
3
2
5
p-TsOH, THF, D, 88%; (d) acetic anhydride, pyridine, DMAP, CH Cl , rt, 98%.
2
2
Keywords: decursinol angelate; decursin; decursinol; catalytic asymmetric epoxidation; protein kinase C.
*
Corresponding author. Tel.: +82-2-3290-3134; fax: +82-2-3290-3121; e-mail: hogyuhan@mail.korea.ac.kr
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00642-6

4
002
J. Lim et al. / Tetrahedron Letters 42 (2001) 4001–4003
AcO
O
HO
O
O
c
a
OH
OH
AcO
O
O
8
a
9a
9b
b
AcO
O
HO
7
d
O
8
b
Scheme 2. Reagents and conditions: (a) Jacobsen’s (S,S)-salen-Mn(III) catalyst, n-Bu NHSO , buffered solution/CH CN, 1,1,1-
4
4
3
®
trifluoroacetone, Oxone , NaHCO , 0°C, 83%; (b) Jacobsen’s (R,R)-salen-Mn(III) catalyst, n-Bu NHSO , buffered solution/
CH CN, 1,1,1-trifluoroacetone, Oxone , NaHCO , 0°C, 83%; (c) LAH, THF, 0°C, 81%; (d) identical conditions with (c), 81%.
3
4
4
®
3
3
a
O
O
O
b, c
O
O
O
9a
OH
OR
O
1
0a
O
+
2. R=
1. R=
O
O
O
OH
10b
Scheme 3. Reagents and conditions: (a) ethyl propiolate, zinc chloride, 110°C, 40%; (b) angelic acid, DCC, DMAP, CH Cl , rt,
2
2
(
1, 74%); (c) 3,3-dimethylacryloyl chloride, pyridine, CH Cl , rt, (2, 92%).
2 2
The chromene 7 was readily epoxidized under buffered
neutral reaction conditions (Jacobsen’s (S,S)-(+)- or
absolute stereochemistry was established by using
Jacobsen’s (salen)Mn catalysts. This practical approach
should provide access to a series of new analogues that
will be useful to elucidate the molecular basis for the
role of decursinol angelate and decursin in PKC
activation.
(
R,R)-(−)-salen-Mn(III) catalysts 4 mol%, 1,1,1-trifl-
®
uoroacetone, Oxone , and NaHCO ) to allow the facile
3
production of the epoxide 8a in good yield (83%) and
8
–10
enantioselectivity (92% ee) (Scheme 2).
Protection of
the hydroxyl group of 6 as tert-butyldimethylsilyl ether
followed by epoxidation proved to be unsuccessful.
Despite its stability to silica gel chromatography, 8a
was immediately reduced without further purification.
Acknowledgements
Reduction of 8a with LiAlH in THF at 0°C proceeded
4
with concomitant removal of the acetyl group to
This work was supported by the Highly Advanced
Program (G7) from the Ministry of Science and Tech-
nology, Korea (Grant No. 00-G-NB-01-C-008). Fellow-
ship support from the BK21 Program (J.L.) is
gratefully acknowledged. The authors would like to
thank Professor Nakcheol Jeong for his insightful com-
ments about this work.
provide the alcohol 9a (67% yield, two steps from
1
1–13
7
).
The exclusive regioselectivity of ring opening by
LiAlH was consistent with that previously found for
4
11b
simple chroman epoxides.
prepared by reduction of the epoxide 8b obtained from
using Jacobsen’s (R,R)-salen-Mn(III) catalyst.
The alcohol 9b could be
7
(
+)-Decursinol (10a) was obtained in 40% yield from
the condensation of 9a with ethyl propiolate in the
1
4
presence of zinc chloride (Scheme 3). This transforma-
tion provided a separable mixture (ca. 1:1) of regioiso-
mers 10a and 10b. The regioselectivity of the cyclization
step was not favorably influenced by employing Pd-cat-
References
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Personal communication.
15
alyzed addition, or AlCl as the Lewis acid. Finally,
3
esterification of the hydroxyl group of 10a with angelic
acid or 3,3-dimethylacryloyl chloride provided (+)-
decursinol angelate (1) and (+)-decursin (2) in 74 and
16
92% yield, respectively.
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tive route to the syntheses of (+)-decursinol angelate
and (+)-decursin. The synthesis proceeds in eight steps
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1
2. (3S)-3,7-Dihydroxy-2,2-dimethylchroman (9a): To a sus-
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mmol) in dry THF (15 mL) under nitrogen at 0°C was
added dropwise a solution of 8a (345 mg, 1.47 mmol) in
THF (25 mL). After the addition was completed the
reaction mixture was stirred for 2 h at 0°C. The reaction
was quenched with water at 0°C and extracted with ethyl
acetate. The combined organic layers were washed with
1
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brine, dried over MgSO , and concentrated in vacuo. The
4
residue was purified by flash chromatography
8
9
. (a) Adam, W.; Jeko
3 , J.; L e´ vai, A.; Nemes, C.; Patonay,
(
EtOAc:hexane=1:2) to afford 9a (0.23 g, 81%) as a
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3
1
white solid. TLC (EtOAc:hexane=1:1): R =0.41;
H
f
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NMR (300 MHz, CDCl ): l 6.91 (d, J=8.4 Hz, 1H), 6.39
3
(
dd, J=8.1, 2.7, 1H), 6.32 (d, J=2.7, 1H), 4.80 (brs, 1H),
3
2
3
1
2
1
.78 (dd, J=10.8, 5.4, 1H), 3.00 (dd, J=16.2, 4.8, 1H),
. (3S,4S)-7-Acetoxy-3,4-epoxy-2,2-dimethylchroman (8a):
To a solution of 7 (360 mg, 1.65 mmol), (S,S)-(+)-N,N%-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-
manganese(III) chloride (Jacobsen’s (S,S)-salen-Mn(III)
catalyst, 43 mg, 0.068 mmol) and n-Bu NHSO (20 mg,
.70 (dd, J=16.5, 5.4, 1H), 1.75 (d, J=7.5, 1H), 1.35 (s,
13
H), 1.30 (s, 3H); C NMR (75 MHz, CDCl ): l 155.27,
3
53.16, 130.58, 110.39, 108.56, 103.73, 76.81, 69.79, 30.48,
+
4.71, 22.36; HRMS (FAB) calcd for C H O (M ):
11
14
3
4
4
23
94.0943. Found: 194.0947; [h] =+11.5 (c 1.03, CHCl ).
D
3
0
.059 mmol) in CH CN (18 mL) was added a buffer
3
13. The ee values of products were determined by analytical
solution of 50 mM Na B O ·10H O in 0.4 mM aqueous
2
4
7
2
HPLC on a chiral column (Chiralpak AD, 4.6×250 mm,
Na EDTA (12 mL), and the reaction mixture was cooled
2
Daicel) under isocratic conditions (2-propanol:hexane=
to 0°C. 1,1,1-Trifluoroacetone (0.2 mL) was added, fol-
−1
1
5:85, 1 mL min flow rate, u=254 nm). Retention time:
lowed by portionwise addition of two solutions of
9a, 12.50 min; 9b, 14.88 min.
®
Oxone (3.8 g, 6.2 mmol) in 0.4 mM aqueous Na EDTA
2
14. Kaufman, K. D.; Kelly, R. C. J. Heterocyclic Chem.
(
18 mL) and NaHCO (1.2 g, 14.3 mmol) in H O (18 mL)
3
2
1965, 2, 91–92.
with stirring over the reaction period (1.5 h). The reaction
mixture was then treated with water and extracted with
diethyl ether. The combined organic layers were dried
1
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over MgSO , filtered, and concentrated in vacuo. The
4
residue was purified by flash chromatography
(
8
EtOAc:hexane=1:2) to give 8a as a yellow oil (0.32 g,
16. (a) Nelson, T. D.; Meyers, A. I. J. Org. Chem. 1994, 59,
1
26
3%). TLC (EtOAc:hexane=1:1): R =0.57; H NMR
2577–2580; (b) Compound 1: [h] =+73.6 (c 1.42,
f
D
26
(
300 MHz, CDCl ): l 7.32 (d, J=8.1 Hz, 1H), 6.67 (dd,
CHCl ). Compound 2: [h] =+121.3 (c 1.08, CHCl ).
3 D 3
3
.