First total synthesis of (±)-sepicanin A

Article abstract of DOI:10.1016/j.cclet.2011.11.015

A facile approach for the first total synthesis of naturally occurring geranylated flavanoids sepicanin A has been obtained with total yield 16% starting from 2,4,6-trihydroxyacetophenone after four steps. The key step was the protic acids (HCl or p-TsOH)

Full text of DOI:10.1016/j.cclet.2011.11.015

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 127–129
www.elsevier.com/locate/cclet
First total synthesis of (ꢀ)-sepicanin A
*
Jin Hui Yang , Wen Qian Huang, Jun Shan Luo, Dong Dong Guo,
Yu Heng Zhang, Hong Jun Li
State Key Laboratory Cultivation Base of Natural Gas Conversion, Ningxia University, Yinchuan 750021, China
Received 6 September 2011
Available online 21 December 2011
Abstract
A facile approach for the first total synthesis of naturally occurring geranylated flavanoids sepicanin A has been obtained with
total yield 16% starting from 2,4,6-trihydroxyacetophenone after four steps. The key step was the protic acids (HCl or p-TsOH)-
catalyzed benzopyrone formation in a protic polar solvent by deprotection and cyclization of chalcone in one step.
#
2011 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Sepicanin A; Flavanone; Geranylated flavonoids; Total synthesis
Geranylflavonoids are a unique class of naturally products existed in various traditional medicinal plants, exhibiting
a wide range of interesting physiological properties such as hypotensive [1], antifungal [2], antibacterial [3,4], and
antitumor [5]. It was reported that prenylated flavanones and geranylflavanone showed a remarkably greater
bioactivities than the normal flavanones [6]. So this wide range of biological properties has stimulated interest in the
synthesis of naturally occurring geranylated flavonoids.
In continuation of our ongoing program on the studies of geranylated flavanoids in our laboratory [7–9], herein we
report a facile and efficient approach (Scheme 1) based on the protic acids (HCl or p-TsOH)-mediated benzopyrone
formation by cyclization chalcone in a protic polar solvent, as illustrated in the first total synthesis of the naturally
occurring C-6 geranylated flavanoids, (ꢀ)-sepicanin A (1).
Sepicanin A (Fig. 1) had been isolated from Artocarpus sepicanus Diels leaves and displayed a significant selective
antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) with IC50 and MIC values of 1.4
and 2.9 mmol/L, respectively [11]. What is more, we found sepicanin A shown activity against s. aureus with MIC
values of 6.25 mg/mL through antimicrobial testing. As far as we know, the total synthesis of sepicanin A has not been
report yet. So the development of an efficient synthetic method to sepicanin A would not only have theoretical
importance, but also have the potential medical prospect.
0
4
,6-Bis[(methoxy)methoxy]-2-hydroxy-3-(1 -geranyl)acetophenone 4 was prepared from 2,4,6-trihydroxy-
acetophenone 2 by the geranylation according to Huang’s report [10] in 72% yield and selective
bismethoxymethylation in 77% yield. Compound 6 prepared from compound 5 by standard methoxymethylation
(
chloromethyl methyl ether: MOMCl, potassium carbonate) in 90% yield. Compound 4 was condensed with
*
Corresponding author.
E-mail address: yang_jh@nxu.edu.cn (J.H. Yang).
1001-8417/$ – see front matter # 2011 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2011.11.015

128
J.H. Yang et al. / Chinese Chemical Letters 23 (2012) 127–129
OH
HO
OH
O
HO
G
OH
O
a
OH
OH
OH
CHO
5
2
3
c
b
OMOM
MOMO
G
OMOM
O
+
OMOM
OH
CHO
6
4
d
OH
MOMO
OMOM
OMOM
HO
O
e
G
OH
OH
G
OH
O
OMOM
f
OH
O
7
1
OMOM
G
HO
G
OH
O
MOMO
O
O
OMOM
OH
OH
OH
9
8
Scheme 1. Conditions and reagents: (a) geranyl bromine, anhydrous K
reflux, 77%; (c) CH OCH Cl, anhydrous K CO , acetone, reflux, 90%; (d) KOH, H
L HCl, MeOH, reflux, 1 h, 32%; (f) p-TsOHꢂH O (4 equiv.), MeOH, 48 h, 23%.
2
CO
3
, acetone, reflux, 72%; (b) CH
3 2 2 3
OCH Cl, anhydrous K CO , acetone,
3
2
2
3
2
O–EtOH (v:v = 2:3), under nitrogen, 0 8C ꢁ r.t, 90%; (e) 3 mol/
2
compound 6 in potassium hydroxide and hydrous ethanolic solution for 24 h to form the desired chalcone 7 in 90%
yield. Direct cyclization chalcone 7 will result to C-8 geranylated flavanoids 8. In order to obtain C-6 geranylated
flavanoids, (ꢀ)-sepicanin A (1) will be synthesized from chalcone 7 by a two-step sequence: (1)
demethoxymethylation; (2) cyclization. Demethoxymethylation of chalcone 7 by a treatment with 3 mol/L HCl
in methanol for 1 h did not give corresponding chalcone 9 but gave cyclization product, (ꢀ)-sepicanin A (1) in 32%
yield. Treatment of compound 7 with p-toluenesulfonic acid monohydrate in methanol also gave (ꢀ)-sepicanin A (1)
in 23% yield. The synthetic (ꢀ)-sepicanin A has identical spectral data [12] with those of natural 1 [11]. It is worthy to
note that flavanones—sepicanin Awas gained by one step from chalcone 7. In traditionally, it must be synthesized by
two steps, one step is deprotection, other step is cyclization of chalcone.
HO
OH
HO
G
O
G=
OH
O
1
Sepicanin A
Fig. 1. The structure of sepicanin A.

J.H. Yang et al. / Chinese Chemical Letters 23 (2012) 127–129
129
In summary, this paper described a concise synthetic route, and the overall yield for the entire four-step synthesis is
6%.
1
Acknowledgments
This work was financially supported by the National Natural Science Foundation (No. 20962016) and Ningxia
Natural Science Foundation (No. NZ1006) and Program for New Century Excellent Talents in University (No. NCET-
0
9-0860).
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[
[
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ꢃ1
12] Spectral data of (ꢀ)-sepicanin A: yellow powder, IR (KBr, cm ) n: 3237, 2911, 1697, 1639, 1600, 1452, 1374, 1265, 1156, 1088, 1046, 976,
1
35, 756; H NMR (400 MHz, acetone-d
8
3
1
6
): d 1.15, 1.52, 1.64 (s, 9H, 3ꢄ CH
3 2
), 1.89–1.93 (m, 4H, CH ), 2.58 (dd, 1H, J = 3.0, 17.2 Hz, H3b),
0
0
.03 (dd, 1H, J = 13.0, 17.2 Hz, H3a), 3.13 (d, 2H, J = 7.2 Hz, 1 -2H), 4.96 (t, 1H, J = 6.8 Hz, CH) 5.13 (t, 1H, J = 6.8 Hz, CH), 5.56 (dd,
0
0
0
H, J = 3.0, 13.0 Hz, 2-CH), 5.90 (s, 1H, 8-H), 6.30 (dd, 1H, J = 2.0, 8.2 Hz, 5 -H), 6.33 (d, 1H, J = 2.0 Hz, 3 -H), 7.18 (d, 1H, J = 8.2 Hz, 6 -
+
H), 12.38 (s, 1H, –OH); EIMS m/z [M] : 424 (32), 219 (100), 69 (96), 165 (86), 283 (83), 301 (47), 187 (39), 177 (31).