An efficient synthesis of (+)-decursinol from umbelliferone

Article abstract of DOI:10.1016/j.tetlet.2007.02.088

An efficient, practical and enantioselective total synthesis of (+)-decursinol, which has diverse range of biological properties including anti-cancer, anti-Helicobacter pylori, and strong antinociceptive activities, has been achieved in five steps with 41.4% overall yield from umbelliferone. The improved ring construction from coumarin to linear pyranocoumarin has been obtained through quinonemethide intermediate by using phenylboronic acid with propionic acid.

Full text of DOI:10.1016/j.tetlet.2007.02.088

Tetrahedron Letters 48 (2007) 2889–2892
An efficient synthesis of (+)-decursinol from umbelliferone
Jung Ho Lee, Hyun Bae Bang, Su Young Han and Jong-Gab Jun*
Department of Chemistry and Institute of Applied Chemistry, Hallym University, Chunchon 200-702, Republic of Korea
Received 18 January 2007; revised 9 February 2007; accepted 19 February 2007
Available online 22 February 2007
Abstract—An efficient, practical and enantioselective total synthesis of (+)-decursinol, which has diverse range of biological prop-
erties including anti-cancer, anti-Helicobacter pylori, and strong antinociceptive activities, has been achieved in five steps with 41.4%
overall yield from umbelliferone. The improved ring construction from coumarin to linear pyranocoumarin has been obtained
through quinonemethide intermediate by using phenylboronic acid with propionic acid.
Ó 2007 Elsevier Ltd. All rights reserved.
Coumarins have important biological effects including
anti-oxidant, anti-inflammatory, anti-allergic, hepato-
protective, antiviral, anticarcinogenic, enzyme inhibitor,
and precursor of toxic substances; however, many of
them are not suitable for therapeutic use due to their
low overall yield. We have focused on the practical and
efficient total synthesis of 1, and reported herein the
shortest step and the highest yield of enantioselective
total synthesis for (+)-decursinol (Fig. 1).
1
toxic, carcinogenic and mutagenic properties. (+)-
Our previous total synthesis of (+)-decursinol from res-
orcinol showed regioisomeric problem during ring con-
struction from chroman (3) with ethyl propiolate
(1.5 equiv) to give linear pyranochromen (4) as shown
Decursinol (1) is a linear dihydrocoumarin isolated from
2
the root of Angelica gigas Nakai (Umbelliferae) and
3
has known to have cytotoxic activity, anti-Helicobacter
pylori activity, and strong antinociceptive activity.5
4
in Scheme 1. We could not find the regioselective reac-
9
Several asymmetric total syntheses of 1 were reported
by using esculetin, resorcinol, or umbelliferone (2)
as a starting material with a relatively long step resulting
tion condition to minimize the equimolar amount of by-
product (5).
6
7
8
Direct ring formation reaction of commercially avail-
able umbelliferone (2) with 2-methyl-3-butene-2-ol to
xanthyletin (13) was unsuccessful due to conjugation
6
5
4
HO
7
3
stability. Umbelliferone was reduced at rt with H /Pd–
8
2
2
O
O
C (10 wt %) for 10 h in 94% yield to produce 6 as shown
in Scheme 2, and subsequent ring formation reaction
with 2-methyl-3-butene-2-ol (10.5 equiv) afforded pyra-
nochroman 7 (Table 1). The best condition for the ring
formation gave 38% yield of 7 by using p-TsOH
O
O
HO
O
9
10
1
2
umbelliferone
1
(+)-decursinol
Figure 1.
ethyl propiolate
ZnCl
+
O
O
O
O
OH
2
O
O
o
1
10 C, 1.5 h
3
4
(38% : 38%)
5
O
Scheme 1. Reaction of chroman with ethyl propiolate.
Keywords: Decursinol; Umbelliferone; Coumarin; Quinonemethide; Phenylboronic acid.
*
Corresponding author. Tel.: +82 33 248 2075; fax: +82 33 256 3421; e-mail: jgjun@hallym.ac.kr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.088

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J. H. Lee et al. / Tetrahedron Letters 48 (2007) 2889–2892
change to dichloromethane in this reaction decreased
the yield to 26% (entry 6).
Pd-C/H2
AcOH, rt
2
O
HO
O
1
0 h, 94%
Phenylboronic acid is known as a useful reagent to pro-
duce quinonemethide intermediate from phenol with
6
1
0
Scheme 2. Reduction of umbelliferone.
aldehyde. Ring formation reaction of phenol 6 with
-methyl-2-butenal (1.5 equiv) by using phenylboronic
3
acid (2 equiv) with excess acetic acid produced 8 in
56% yield as shown in Table 2 (entry 2), and no reaction
occurred without AcOH (entry 3) or phenylboronic acid
(
0.2 equiv) in dichloroethane (entry 2), however pro-
duced an equimolar amount of regioisomer. Solvent
Table 1. Ring formation reaction with 2-methyl-3-butene-2-ol
OH
O
O
O
O
HO
O
reflux
6
7
a
Entry
Acid
Equivalents
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
0.1
0.2
0.3
0.5
1.0
0.2
Cat.
Cat.
Cat.
Solvent
3.0
3.0
1.0
1.5
0.5:2.5
Dichloroethane
Dichloroethane
Dichloroethane
Dichloroethane
Dichloroethane
Dichloromethane
Dichloroethane
Dichloroethane
Benzene
AcOH
Dichloroethane
Benzene
Dichloroethane
Dichloroethane
Dichloroethane
8
8
4
4
8
8
2
2
2
12
20
8
20
16
3
20
38
37
34
24
26
20
22
19
5
10
10
0
8
15
H
2
SO
4
MeSO
MeSO
3
H
H
3
1
1
1
1
1
1
AcOH
ZnCl
ZnCl
2
2
AlCl
3
BF
BF
3
ÆEt
ÆEt
2
O
3
2
O–TMSOMs
a
Isolated yield.
Table 2. Ring formation reaction with 3-methyl-2-butenal using phenylboronic acid
O
H
O
O
HO
O
PhB(OH)2
reflux
O
O
6
8
a
Entry
PhB(OH)
2
(equiv)
Acid (equiv)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1.0
2.0
1.0
0
AcOH (88)
AcOH (88)
None
Toluene
Toluene
Toluene
Toluene
Benzene
Toluene
Toluene
Toluene
Benzene
Toluene
Benzene
Toluene
Toluene
Benzene
Benzene
Benzene
24
24
24
24
36
36
36
36
24
36
36
36
36
24
24
24
42
56
0
AcOH (88)
0
1.5
1.5
1.5
1.5
1.0
1.5
1.5
1.5
1.5
1.0
1.0
1.0
Propionic acid (110)
Propionic acid (45)
Propionic acid (110)
Propionic acid (cat.)
Formic acid (88)
Butyric acid (110)
Valeric acid (110)
Benzoic acid (2)
50
57
62
15
0
47
41
32
45
0
1
1
1
1
1
1
1
Phenyl acetic acid (2)
H
2
SO
MeSO
4
(cat.)
H (cat.)
3
0
0
p-TsOH (1)
a
Isolated yield.

J. H. Lee et al. / Tetrahedron Letters 48 (2007) 2889–2892
2891
H
H
PhB(OH)2
Ph
B
O
O
6
Ph
B
O
O
O
O
O
HO
O
OH
9
10
PhB(OH)2
O
B
8
Ph
O
O
O
O
O
O
OH
12
11
Scheme 3. Ring formation mechanism with phenylboronic acid.
O
a
b
c
8
1
O
O
O
O
O
O
13
14
Scheme 4. Reagents and conditions: (a) DDQ (2 equiv), PhH, reflux, 8 h, 92%; (b) Jacobsen’s (S,S)-salen-Mn(III) catalyst (4 mol %), n-Bu
4
NHSO
4
,
Ò
buffered solution/CH CN, 1,1,1-trifluoroacetone, Oxone , NaHCO , 0 °C, 1.5 h, 83%; (c) NaBH CN (1 equiv), BF ÆOEt , THF, rt, 0.5 h, 93%.
3 3 3 3 2
(
entry 4). Propionic acid (1.5 equiv) instead of acetic
a previous regioisomer problem, and gave the highest
yield and the shortest total synthesis of (+)-decursinol.
acid using in the reaction with phenylboronic acid in-
1
1
creased the product to 62% yield (entry 7); however,
the other acids (entries 9–16) showed no advantage.
Phenylboronic acid adduct 9 was reacted with aldehyde
to form benzodioxaborine 11, which rearranged to pro-
duce quinonemethide intermediate 12 as shown in
Scheme 3. Intramolecular hetero electrocyclization of
the exo-quinonemethide 12 gave the desired product 8
without forming a regioisomer.
Acknowledgements
This work was supported by the Ministry of Commerce,
Industry and Energy through the Center for Efficacy
Assessment and Development of Functional Foods
and Drugs at Hallym University, and in part by Grant
No. (R01-2005-000-10916-0) from the Basic Research
Program of Korea Science and Engineering Foundation.
Lactone 8 is dehydrogenated by DDQ (2 equiv) in
refluxing benzene to give xanthyletin (13) in 92% yield
1
2
within 8 h (Scheme 4), however, the dehydrogenation
reaction of 7 required excess amount of DDQ (5 equiv)
with longer reaction time (36 h) to give only 82% yield of
References and notes
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3
6
7
8
9
(
1 equiv) at rt for 0.5 h gave (+)-decursinol in 93%
1
3
yield.
In conclusion, an efficient, practical and enantioselective
total synthesis of (+)-decursinol has been achieved from
commercially available umbelliferone in five steps with
4
1.4% overall yield including reduction (94%), conden-
sation (62%), oxidation (92%), asymmetric epoxidation
83%), and reduction (93%). This methodology resolved
(

2892
J. H. Lee et al. / Tetrahedron Letters 48 (2007) 2889–2892
1
1. Pettigrew, J. D.; Cadieux, J. A.; So, S. S. S.; Wilson, P. D.
br t, J = 5.4 Hz, C7–H), 6.19 (1H, d, J = 9.3 Hz, C3–H),
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6.76 (1H, s, C10–H), 7.16 (1H, s, C5–H), 7.56 (1H, d,
1
3
1
J = 9.3 Hz, C4–H). C NMR (75 MHz, CDCl ): d 22.4
3
1
3. Compound 1: R
f
0.13 (EtOAc–hexane = 1:2); mp 167–170
(Me), 25.4 (Me), 31.0 (C6), 69.3 (C7), 78.5 (C8), 104.9
(C3), 113.1 (C4a), 113.3 (C10), 116.8 (C5a), 129.2 (C7),
143.4 (C6), 154.2 (C10a), 156.7 (C9a), 161.6 (C2).
14. Nemoto, T.; Ohshima, T.; Shibasaki, M. Tetrahedron
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26
14
26
°
C; ½aꢀ +10.3 (c 1.0, CHCl
3
, 95% ee) (lit. ½aꢀ +10.8);
D
D
1
H NMR (300 MHz, CDCl
3
): d 1.36 (3H, s, Me), 1.39 (3H,
s, Me), 2.00 (1H, br s, OH), 2.83 (1H, dd, J = 5.7, 16.5 Hz,
C6–H), 3.10 (1H, dd, J = 5.7, 16.5 Hz, C6–H), 3.86 (1H,