Synthesis of 4-hydroxyderricin and related derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.09.015

Naturally occurring chalcones, namely 4-hydroxyderricin (1), xanthoangelol H (2), deoxyxanthoangelol H (3), and deoxydihydroxanthoangelol H (4), were first synthesized and evaluated for antibacterial activities.

Full text of DOI:10.1016/j.tetlet.2008.09.015

Tetrahedron Letters 49 (2008) 6639–6641
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Tetrahedron Letters
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Synthesis of 4-hydroxyderricin and related derivatives
Kazuhiro Sugamoto *, Chiaki Kurogi, Yoh-ichi Matsushita, Takanao Matsui
Faculty of Engineering, University of Miyazaki, Gakuen-Kibanadai, Miyzaki 889-2192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Naturally occurring chalcones, namely 4-hydroxyderricin (1), xanthoangelol H (2), deoxyxanthoangelol H
(3), and deoxydihydroxanthoangelol H (4), were first synthesized and evaluated for antibacterial
activities.
Received 29 August 2008
Revised 3 September 2008
Accepted 5 September 2008
Available online 7 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
4-Hydroxyderricin (1) was isolated from Lonchocarpus neurosc-
apha1 and Angelica keiskei2 (Fig. 1). Xanthoangelol H (2),3 deoxy-
xanthoangelol H (3),4 and deoxydihydroxanthoangelol H (4)4
were isolated from Angelica keiskei. Compound 1 exhibited various
biological activities, such as antibacterial activity against gram-
positive pathogenic bacteria,5 antitumor promoting activity in
mouse skin carcinogenesis using DMBA and TPA,6 phenylephrine-
induced vasoconstriction in vivo,7 hypotensive and lipid regulatory
actions in hypertensive rats,8 antitumor and antimetastatic activi-
ties,9 and inhibitory effect on induction of EBV-EA by TPS in Raji
cells.10 Compounds 1 and 2 exhibited cytotoxicity against neuro-
flastoma cells.11 Compound 3 exhibited inhibitory effect on induc-
tion of EBV-EA by TPS in Raji cells.4 Compound 1 is one of the major
components of Angelica keiskei, on the other hand, 2–4 are minor
components. For example, 1 (13.5 g) and 2 (30 mg) were isolated
from air-dried roots (19.5 kg),3 and 3 (17 mg) and 4 (3 mg) were
isolated from stem exudates (300 g).4 It is difficult to isolate 2–4
from Angelica keiskei. Therefore, few reports have been published
on the biological activities of 2–4.4,10,11 To our knowledge, no work
has been done on total synthesis of 1–4. It seems to be important
to develop synthetic routes of these chalcones for elucidation of
the relationship between their structures and promising activities.
Herein, we report the synthesis of these chalcones 1–4 and evalu-
ation of their antibacterial activity.
4-Hydroxyderricin (1) would be prepared by Claisen–Schmidt
condensation of the key intermediate 5 with 4-methoxymethoxy-
benzaldehyde (6) (Scheme 1). Compound 5 could be converted
from accessible 20-hydroxy-40-methoxyacetophenone (7). Xantho-
angelol H (2), deoxyxanthoangelol H (3), and deoxydihydroxantho-
angelol H (4) also would be prepared via 5.
Treatment of 7 with prenyl chloride in the presence of K2CO3
gave prenyloxyacetophenone (10) in 91% yield (Scheme 2). The
rearrangement of 10 was first attempted in the presence of solid
OH
O
OH
O
OHC
+
1
OMOM MeO
MeO
6
5
7
HO
O
O
2
6 +
MeO
8
O
O
3, 4
6 +
MeO
HO
OH
O
O
O
9
MeO
MeO
OH MeO
OH
OH
Scheme 1.
1
2
O
O
O
O
OH
MeO
O
O
prenyl chloride (2 equiv),
K CO (3 equiv)
3
OH
O
4
2
3
Figure 1.
acetone, reflux, 24 h
Y: 91%
MeO
MeO
10
7
* Corresponding author. Tel.: +81 985 58 7390; fax: +81 985 58 7323.
E-mail address: sugamoto@cc.miyazaki-u.ac.jp (K. Sugamoto).
Scheme 2.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.015

6640
K. Sugamoto et al. / Tetrahedron Letters 49 (2008) 6639–6641
Table 1
product 13 in 46% yield. 4-Hydroxyderricin (1) was synthesized
Rearrangement of 10 in the presence of solid acid catalyst
by deprotection of 13 using p-toluenesulfonic acid monohydrate
at 30 °C in high yield. Compound 1 was prepared in 41% yield over
4 steps from 7 via 14. Physical and spectral data of synthetic 1 were
consistent with those reported for natural 1.1
The epoxidation of 5 with m-CPBA proceeded at room temper-
ature to afford the epoxide as an intermediate, which was immedi-
ately converted into the chroman 8 (Scheme 4). Condensation of 8
with 6 gave chalcone 15 in 76% yield. Xanthoangelol H (2) was syn-
thesized by deprotection of 15 using p-toluenesulfonic acid mono-
hydrate under reflux in good yield. Physical and spectral data of
synthetic 2 were consistent with those reported for natural 2.3
Treatment of 5 in the presence of montmorillonite K10 at 50 °C
provided the chroman 9 in high yield (Scheme 5).15
Condensation of 9 with 6 gave the chalcone 16 in 95% yield.
Deoxyxanthoangelol H (3) was synthesized by deprotection of 16
under similar conditions described above in good yield.
Hydrogenation of 16 in the presence of Pd/C catalyst gave 17 in
94% yield (Scheme 6). Deoxydihydroxanthoangelol H (4) was syn-
thesized by deprotection of 17 under similar conditions described
above in good yield. Physical and spectral data of synthetic 3 and 4
were consistent with those reported for natural 32 and 4.4
Antibacterial activities of synthesized chalcones 1–4 were
investigated against both Gram-negative (Escherichia coli, Proteus
OH
O
OH O
OH
O
+
MeO
MeO
+
MeO
5
O
O
11
12
MeO
OH
O
O
O
10
+
MeO
+
MeO
7
9
Entry Conditions
Yield (%)
5
11 12
9
7
1
2
Montomorillonite K10 (1 wt equiv), CH2Cl2, 0 °C,
0.5 h
53 25
27 32
7
0
0
4
FlorisilÒ (10 wt equiv), toluene, reflux, 2 h
8
10
acid catalyst in a procedure similar to that described in the previ-
ous reports (Table 1).12,13 The treatment of 10 in the presence of
montmorillonite K10 in CH2Cl2 at 0 °C gave desired compound 5
in 53% yield, along with 11 (25%), 12 (7%), and 7 (4%). The rear-
rangement of 10 using FlorisilÒ in toluene at 110 °C gave 5 as well,
but only provided 5 in 27% yield, along with 11 (32%), 7 (8%), and
chroman 9 (10%).
Table 2 shows the Claisen–Schmidt condensation of 5 with 6
under several conditions. The yield of chalcone 13 was low in all
cases. The low yield is presumably caused by secondary cyclization
of 20-hydroxychalcone to flavanone as reported in the literature.14
In contrast, condensation of 10 with 6 in the presence of 3 M NaOH
afforded the chalcone 14 in good yield (Scheme 3). The rearrange-
ment of 14 using montmorillonite K10 at 0 °C gave the desired
OH
O
OH O
a
O
MeO
b
MeO
5
HO
O
O
MeO
8
(Y: 81% from 5)
HO
O
O
Table 2
c
Claisen–Schmidt condensation of 5 with 6
Y: 76%
MeO
HO
OMOM
OH
OH
O
OH O
15
OHC
O
O
d
MeO
OMOM MeO
OMOM
+
6
13
5
Y: 94%
Entry
Conditions
Yield of 13 (%)
MeO
2
1
2
3
3 M KOH, EtOH, rt, 24 h
50% KOH, EtOH, rt, 35 h
Ba(OH)2ꢀ8H2O (2.5 equiv), EtOH, 50 °C, 1 h
38
33
23
Scheme 4. Reagents and conditions: (a) m-CPMA (1.2 equiv), CH2CH2, rt, 0.5 h; (b)
montmorillonite K10 (1 wt equiv), CH2CH2, rt, 1 h; (d) 6 (1.2 equiv), 3 M NaOH,
EtOH, rt, 20 h; (d) p-TsOH–H2O (1 equiv), MeOH, reflux, 2 h.
OH
O
O
O
a
O
O
O
O
a
Y: 96%
MeO
MeO
Y: 98%
5
9
MeO
MeO
O
OMOM
10
14
O
O
O
b
OH
Y: 95%
b
MeO
OMOM
Y: 46%
MeO
OMOM
16
13
OH
O
O
c
c
Y: 89%
Y: 99%
MeO
OH
MeO
OH
1
3
Scheme 3. Reagents and conditions: (a) 6 (1.2 equiv), 3 M NaOH, EtOH, rt, 12 h; (b)
montmorillonite K10 (1 wt equiv), CH2CH2, 0 °C, 1.5 h; (c) p-TsOH–H2O (1 equiv),
MeOH, 30 °C, 24 h.
Scheme 5. Reagents and conditions: (a) montmorillonite K10 (1 wt equiv), Tolu-
ene, 50 °C, under N2, 40 h; (b) 6 (1.2 equiv), 3 M NaOH, EtOH, rt, 20 h; (c) p-TsOH–
H2O (1 equiv), MeOH, reflux, 2 h.

K. Sugamoto et al. / Tetrahedron Letters 49 (2008) 6639–6641
6641
activity against R. salanacearum, B. subtilis, and S. epidermidis.
Inamori et al. reported that compound 1 have no effect against
Gram-negative bacteria.5 It is interesting to note that compound
1 exhibited strong antibacterial activity against R. salanacearum.
On the other hand, the other chalcones 2–4 showed no activity.
These results suggested that 20-hydroxy and/or 30-prenyl groups
were important for antibacterial activity.
In conclusion, the described method allowed for the synthesis
of 1 in 4 steps with 41% overall yield from commercially available
7. Compound 2 was prepared in 28% yield at 6 steps, 3 in 39% yield
at 5 steps, and 4 in 38% yield at 6 steps from 7 via the key interme-
diate 5.
O
O
MeO
OMOM
16
O
O
O
a
Y: 94%
17
MeO
MeO
OMOM
OH
O
b
Y: 93%
4
References and notes
Scheme 6. Reagents and conditions: (a) Pd/C (0.1 wt equiv), under H2, (1 atm),
EtOH, rt, 0.5 h; (b) p-TsOH–H2O (1 equiv), MeOH, reflux, 1 h.
1. Delle Monache, G.; de Mèllo, J. F.; Delle Monache, F.; Marini Bettolo, G. B.;
Gonçaleves de Lima, O.; Coélhode de Barros, J. S. Gazz. Chim. Ital. 1975, 104,
861–865.
2. Kozawa, M.; Morita, N.; Baba, K.; Hata, K. Yakugaku Zasshi 1978, 98, 210–214.
3. Nakata, K.; Taniguchi, M.; Baba, K. Nat. Med. 1999, 53, 329–332.
4. Akihisa, T.; Tokuda, H.; Hasegawa, D.; Ukiya, M.; Kimura, Y.; Enjo, F.; Suzuki, T.;
Nishino, H. J. Nat. Prod. 2006, 69, 38–42.
5. Inamori, Y.; Baba, K.; Tsujibo, H.; Taniguchi, M.; Nakata, K.; Kozawa, M. Chem.
Pharm. Bull. 1991, 39, 1604–1605.
6. Okuyama, T.; Takata, M.; Takayasu, J.; Hasegawa, T.; Tokuda, H.; Nishino, A.;
Nishino, H. Planta Med. 1991, 57, 242–246.
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133–137.
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Lett. 2004, 45, 79–81.
Table 3
Antibacterial effect of compounds 1–4
Entry Type
Bacterium
MIC (
l
g/ml)
1
2
3
4 Chloramphenicol
1
2
3
3
4
Gram-
Escherichia
negative coli
Proteus
negative mirabilis
Rastonia
negative salanacearum
>256 >256 >256 >256 16
>256 >256 >256 >256 02
Gram-
Gram-
2
>256 >256 >256 02
<1 >256 >256 >256 03
>256 >256 >256 01
Gram-
positive
Gram-
Bacillus subtilis
Staphylococcus
positive epidermidis
1
13. Talamás, F. X.; Smith, D. B.; Cervantes, A.; Franco, F.; Cutler, S. T.; Loughhead, D.
G., ; Morgans, D. J., Jr.; Weikert, R. J. Tetrahedron Lett. 1997, 38, 4725–4728.
14. Formentín, P.; García, H.; Leyva, A. J. Mol. Catal. A: Chem. 2004, 214, 137–
142.
15. Dauben, W. G.; Corgen, J. M.; Behar, V. Tetrahedron Lett. 1990, 31, 3241–
3244.
mirabilis, Rastonia salanacearum) and Gram-positive bacteria (Bacil-
lus subtilis, Staphylococcus epidermidis). The MIC values are summa-
rized in Table 3. 4-Hydroxyderricin (1) showed strong antibacterial