Stereoselective total synthesis of (+)-licochalcone e

Article abstract of DOI:10.1007/s12272-011-0805-9

The synthesis of (+)-licochalcone E (1) was accomplished for the first time in 13 steps from aryl bromide (6) with 8% overall yield. Palladium-catalyzed Negishi-Reformatsky coupling reaction of compound 6 with ethyl 2-(tributylstannyl)acetate provided the aryl acetic ester (5), which was converted to aryl acetamide (4) via mixed anhydride formation. Chiral auxiliarymediated methylation of the (S)-4-benzyl-2-oxazolidinone-derived aryl acetamide (4) provided the key asymmetric benzylic methyl group in compound 1.

Full text of DOI:10.1007/s12272-011-0805-9

Arch Pharm Res Vol 34, No 8, 1269-1276, 2011
DOI 10.1007/s12272-011-0805-9
Stereoselective Total Synthesis of (+)-Licochalcone E
Zhiguo Liu1, Zengtao Wang1, Goo Yoon2, and Seung Hoon Cheon1
1College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757,
2
Korea and College of Pharmacy, Mokpo National University, Muan 534-729, Korea
(Received February 8, 2011/Revised March 20, 2011/Accepted March 28, 2011)
The synthesis of (+)-licochalcone E (
aryl bromide ( ) with 8% overall yield. Palladium-catalyzed Negishi-Reformatsky coupling
reaction of compound with ethyl 2-(tributylstannyl)acetate provided the aryl acetic ester ( ),
which was converted to aryl acetamide ( ) via mixed anhydride formation. Chiral auxiliary-
mediated methylation of the ( )-4-benzyl-2-oxazolidinone-derived aryl acetamide ( ) provided
the key asymmetric benzylic methyl group in compound
1) was accomplished for the first time in 13 steps from
6
6
5
4
S
4
1
.
Key words: (+)-Licochalcone E, Negishi-Reformatsky reaction, Retrochalcone
mer, (+)-licochalcone E (
can be synthesized in a divergent fashion from a late-
stage intermediate derived from the arylacetate (
Although the racemic mixture and the natural (
1), since the natural product
Selected by Editors, See page 1219
INTRODUCTION
5).
−)-
licochalcone E have been synthesized before (Na et al.,
Licorice is the roots and stolons of certain Glycyrrhiza 2009; Yoon et al., 2009b; Liu et al., 2010), synthesis of
species such as G. inflata and G. uralensis. Licorice is (+)-licochalcone E ( ) has never been reported. The
a popular food additive used worldwide as a sweetener synthetic route described here gives access to (+)-
in tobaccos, chewing gums, and candies, but it is also licochalcone E ( ) and its derivatives in a more concise
1
1
one of the most widely used medicinal herbs with anti- and high-yielding fashion and this will contribute to
tumorigenic, antimicrobial, antiulcer, and antioxidant the ongoing search for their molecular target. Herein,
activities (Nomura and Fukai, 1998). Recently, (−)- we describe the first enantioselective total synthesis of
licochalcone E was isolated from the roots of G. inflata (+)-licochalcone E (
1).
during cytotoxicity-guided fractionation using the
HT1080 cell line (Yoon et al., 2005). In addition to
cytotoxicity, it possessed diverse biological activities,
including the abilities to inhibit topoisomerase 1 (Yoon et
MATERIALS AND METHODS
Solvents were distilled under positive pressure of
al., 2007), to inhibit protein tyrosine phosphatase 1B dry argon before use and dried by standard methods.
(Yoon et al., 2009a), and to induce endothelial cell Tetrahydrofuran (THF) was distilled over sodium ben-
apoptosis by modulating NF-
(Chang et al., 2007). It was also reported that (
licochalcone E had vasorelaxing effects (Yoon et al., sium hydroxide. (
κ
B and the Bcl-2 family zophenone ketyl radical, and triethylamine (Et3N) was
)- distilled over calcium hydride and stored over potas-
)-( )-4-Benzyl-2-oxazolidinone was
−
S
−
2010). We chose to synthesize the unnatural enantio- purchased from Sigma-Aldrich. Unless otherwise noted,
chemicals were obtained from local suppliers and were
used without further purification. All reactions were
Correspondence to: Goo Yoon, College of Pharmacy, Mokpo
performed under argon atmosphere and monitored by
thin-layer chromatography (250 micron silica gel 60
F254 glass plates). Visualization was performed by
ultraviolet light and/or by staining with 3% ethanol
solution of phosphomolybdic acid. Infrared data were
obtained on a JASCO, JP/FT-IR 300E infrared spec-
National University, Muan 534-729, Korea
Tel: 82-61-450-2682
E-mail: gyoon@mokpo.ac.kr
Seung Hoon Cheon, College of Pharmacy, Chonnam National
University, Gwangju 500-757, Korea
Tel: 82-62-530-2929, Fax: 82-62-530-2911
E-mail: shcheon@chonnam.ac.kr
1269

1270
Z. Liu et al.
trophotometer. NMR (1H, 13C) spectra were recorded centrated under reduced pressure. The crude residue
on Varian Unity Plus 300 spectrometer. Low resolution was further purified by flash chromatography (3:1,
mass spectra were obtained with a Shimadzu, JP/ hexanes-EtOAc) to give (5-(tert-butyldimethylsilanyl-
LCMS-2010 instrument. High resolution measurements oxymethyl)-4-methoxy-2-methoxymethoxyphenyl)ace-
were made with a Synapt HDMS (Waters) instru- tic acid (102 mg, 0.28 mmol, 99%) as a colorless oil. R
f
1
ment. Optical rotations were recorded in a 1 dm cell at = 0.23 (3:1 v/v hexanes-EtOAc). H-NMR (CDCl3, 300
25oC (JASCO, DiP-1000 digital polarimeter).
MHz): δ 7.24 (s, 1H, H6), 6.68 (s, 1H, H3), 5.18 (s, 2H,
ArOCH2OCH3), 4.67 (s, 2H, ArCH2OTBS), 3.79 (s, 3H,
ArOCH3), 3.46 (s, 3H, ArOCH2OCH3), 3.63 (s, 2H,
ArCH2COOH), 0.95 [s, 9H, SiC(CH3)3]. 13C-NMR (CDCl3,
Ethyl (5-(tert-butyldimethylsilanyloxymethyl)-
4-methoxy-2-methoxymethoxyphenyl)-acetate
(5)
75 MHz):
δ 177.9, 156.4, 154.9, 129.4, 122.9, 114.4,
Zinc bromide (1.56 g, 6.92 mmol) in a dry flask was 97.8, 94.7, 59.8, 55.9, 55.3, 35.4, 29.7, 25.9, 18.6, −5.3.
heated at 140oC for 1 h under high vacuum. Then a IR (KBr, neat): 2953, 2928, 2856, 1712, 1619, 1509,
mixture of (5-bromo-2-methoxy-4-methoxymethoxy- 1465, 1290, 1255, 1216, 1152, 1118, 1086, 1072, 1024,
benzyloxy)-tert-butyldimethylsilane (
6
) (1.93 g, 4.94 837, 776 cm−1. LRMS (ESI): m/z 393 [M+Na]+. HRMS
mmol),
α
-(tributylstannyl)acetate (2.61 g, 6.92 mmol), (ESI): calcd for C18H30O6SiNa [M+Na]+: 393.1709,
and PdCl2(o-tol3P)2 (310 mg, 0.395 mmol) in dry DMF found: 393.1709.
(10 mL) was added to the flask and heated at 80oC for
To a solution of (5-(tert-butyldimethylsilanyloxy-
14 h under argon. The black reaction mixture was methyl)-4-methoxy-2-methoxymethoxyphenyl)acetic
diluted with water (10 mL) and extracted with Et2O (3 acid (860 mg, 2.40 mmol), and Et3N (0.38 mL, 2.64
×
10 mL). The combined organic layers were washed mmol) in anhydrous THF (10 mL) at −
78oC was added
with brine, dried over anhydrous MgSO4, filtered, and pivaloyl chloride (0.4 mL, 3.12 mmol) dropwise under
concentrated under reduced pressure. The crude resi- an atmosphere of argon. The resulting mixture was
due was further purified by flash chromatography on stirred for 15 min at
silica gel (15:1, hexanes-EtOAc) to give (1.41 g, 3.58 to
78oC. Meanwhile, in a different flask,
mmol, 72%) as a pale yellow oil. R = 0.43 (3:1 v/v mL of 1.6 M in diethyl ether, 2.9 mmol) was added
hexanes-EtOAc). 1H-NMR (CDCl3, 300 MHz):
7.23 (s, dropwise to a solution of ( )-( )-4-benzyl-2-oxazolidi-
1H, H6), 6.67 (s, 1H, H3), 5.16 (s, 2H, ArOCH2OCH3), none (518 mg, 2.92 mmol) in anhydrous THF (10 mL)
4.68 (d, 2H, = 3.9 Hz, ArCH2OTBS), 4.14 (q, 2H, at
78oC under an atmosphere of argon and the
= 7.2 Hz, OCH2CH3), 3.79 (s, 1H, ArOMe), 3.58 (s, mixture was stirred for 40 min at
78oC, it was then
2H, ArCH2COOEt), 3.49 (s, 3H, ArOCH2OCH3), 1.24 transferred into the reaction flask containing the
(t, 3H, = 7.2 Hz, OCH2CH3), 0.94 [(s, 9H, SiC(CH3)3]. preformed mixed anhydride via a cannula. After stir-
13C-NMR (CDCl3, 75 MHz):
172.1, 156.1, 155.0, 129.3, ring the reaction mixture for 15 min, it was allowed to
122.9, 115.2, 97.9, 94.8, 60.5, 59.9, 55.9, 55.3, 35.6, warm up to room temperature for 2 h then quenched
25.9, 18.4, 14.2, 5.3. IR (KBr, neat): 2955, 2931, 2903, with saturated aqueous NH4Cl (30 mL) and extracted
−
78oC, 1 h at 0oC, then recooled
-BuLi (1.8
5
−
n
f
δ
S −
J
J
−
−
J
δ
−
2855, 1737, 1618, 1509, 1465, 1254, 1215, 1191, 1153, with EtOAc (3 × 30 mL). The combined organic layers
1116, 1091, 1073, 1021, 996, 838, 776 cm−1. LRMS were washed with brine (100 mL), dried over anhy-
(ESI): m/z 421 [M+Na]+. HRMS (ESI): calcd for drous MgSO4, filtered, and concentrated under re-
C20H34O6SiNa [M+Na]+: 421.2101, found: 421.2101.
duced pressure. The residue was purified by flash
chromatography on silica gel (4:1, hexanes-EtOAc) to
afford
0.38 (3:1 v/v hexanes-EtOAc). H-NMR (CDCl3, 300
MHz): 7.20-7.36 (m, 5H, ArH), 7.22 (s, 1H, H6), 6.72
= 1.5 Hz, ArOCH2OCH3), 4.69
(s, 2H, ArCH2OTBS), 4.66-4.73 (m, 1H, NCH), 4.13-
) (110 mg, 0.28 mmol) in EtOH (3 mL) was added 4.35 (m, 4H, ArCH2CON, NCHCH2O), 3.81 (s, 3H,
1 N NaOH dropwise. The solution was heated to 40oC ArOCH3), 3.47 (s, 3H, ArOCH2OCH3), 3.28 (dd, 1H,
and stirred for 16 h, the reaction solution was allowed = 3.3, 13.2 Hz, ArCH), 2.82 (dd, 1H, = 9.3, 13.2 Hz,
to cool to room temperature and concentrate under ArCH), 0.94 [s, 9H, SiC(CH3)3]. 13C-NMR (CDCl3, 75
reduced pressure. The residue was then acidified with MHz): 171.1, 156.2, 155.1, 153.2, 133.4, 129.3, 128.7,
5% HCl to pH 3~4 and extracted with EtOAc (3 128.6, 125.6, 122.9, 114.6, 97.9, 94.8, 78.9, 59.9, 55.9,
mL). The combined organic layers were washed with 55.3, 54.9, 36.9, 26.0, 18.5, 14.5, 5.3. IR (KBr, neat):
brine, dried over anhydrous MgSO4, filtered, and con- 2954, 2930, 2897, 2855, 1782, 1706, 1618, 1508, 1463,
4 (1.01 g, 1.95 mmol, 81%) as a viscous oil. Rf =
(S)-4-Benzyl-3-(2-(5-((tert-butyldimethylsilyloxy)
methyl)-4-methoxy-2-(methoxy-methoxy)phenyl)
acetyl)oxazolidin-2-one (4)
1
δ
A solution of ethyl (5-(tert-butyldimethylsilanyloxy- (s, 1H, H3), 5.18 (d, 2H,
methyl)-4-methoxy-2-methoxymethoxyphenyl)acetate
J
(5
J
J
δ
×
5
−

Stereoselective Total Synthesis of (+)-Licochalcone E
1271
1362, 1249, 1217, 1197, 1119, 1089, 1069, 1023, 838, H2O2 (0.6 mL, 3.6 mmol). The mixture was allowed to
769 cm−1. LRMS (ESI): m/z 552 [M+Na]+. HRMS warm up to room temperature and stirred for an
(ESI): calcd for C28H39O7NSiNa [M+Na]+: 552.2397, additional 4 h. After evaporation of most of the solvent,
found: 552.2394. Optical rotation [α 20
1.0, CHCl3).
]
D = +60.7 (
c
=
the mixture was extracted with Et2O (3 × 15 mL). The
aqueous layer was then acidified with 10% HCl to pH
2~3 and extracted with EtOAc (3 × 15 mL). The com-
bined organic layers were washed with brine (50 mL),
dried over anhydrous MgSO4, filtered, concentrated
under reduced pressure. The residue was purified
(S)-4-Benzyl-3-((S)-2-(5-((tert-butyldimethylsilyl-
oxy)methyl)-4-methoxy-2-(methoxy-methoxy)
phenyl)propanoyl)oxazolidin-2-one (7)
To a solution of (
methylsilyloxy)methyl)-4-methoxy-2-(methoxymethoxy) EtOAc) to afford
phenyl)acetyl)oxazolidin-2-one ( ) (0.88 g, 1.66 mmol) = 0.16 (3:1 v/v hexanes-EtOAc). H-NMR (CDCl3, 300
in freshly distilled THF (10 mL) was added NaHMDS MHz): 7.33 (s, 1H, H6), 6.67 (s, 1H, H3), 5.19 (s, 2H,
(1.90 mL of 1.0 M in THF, 1.90 mmol) at = 1.5 Hz, ArCH2OTBS),
78oC under ArOCH2OCH3), 4.68 (d, 2H,
argon and the mixture was stirred for 1.2 h. A solu- 4.04 (q, 1H, = 6.9 Hz, ArCH(CH3)), 3.79 (s, 3H,
tion of MeI (0.41 mL, 6.64 mmol) in THF (1 mL) was ArOMe), 3.48 (s, 3H, ArOCH2OCH3), 1.48 (d, 3H,
added dropwise to the reaction mixture and stirring 7.2 Hz, ArCH(CH3)), 0.94 [s, 9H, SiC(CH3)3]. 13C-NMR
was continued for 4 h at 180.9, 155.9, 154.2, 126.5, 123.2,
78oC. The reaction mixture (CDCl3, 75 MHz):
was allowed to warm up to room temperature and 120.7, 97.8, 94.9, 59.9, 55.9, 55.3, 38.7, 25.9, 18.4, 16.9,
stirred for an additional 2 h. It was then quenched 5.3. IR (KBr, neat): 3448, 2954, 2931, 2856, 1707,
S)-4-benzyl-3-(2-(5-((tert-butyldi- by flash chromatography on silica gel (3:1, hexanes-
3
(230 mg, 71%) as a colorless oil. R
f
1
4
δ
−
J
J
J
=
−
δ
−
with saturated aqueous NH4Cl (50 mL) and extracted 1618, 1508, 1459, 1292, 1254, 1152, 1119, 1086, 1006,
with EtOAc (3 × 50 mL). The combined organic layers 838, 776 cm−1. LRMS (ESI): m/z 407 [M+Na]+. HRMS
were washed with brine (100 mL), dried over anhy- (ESI): calcd for C19H32O6SiNa [M+Na]+: 407.1866,
drous MgSO4, filtered, and concentrated under re- found: 407.1874. Optical rotation [
duced pressure. The residue was purified by flash CHCl3).
chromatography on silica gel (5:1, hexanes-EtOAc) to
α] c = 1.0,
20 = +13.7 (
D
give
0.39 (3:1 v/v hexanes-EtOAc). H-NMR (CDCl3, 300
MHz): 7.24-7.40 (m, 5H, ArH), 7.26 (s, 1H, H6), 6.69 (s,
1H, H3), 5.21 (d, 2H, = 3.9 Hz, ArOCH2OCH3), 4.72 (s,
2H, ArCH2OTBS), 4.64-4.73 (m, 1H, NCH), 4.08-4.18 methyl)-4-methoxy-2-(methoxymethoxy)phenyl)pro-
(m, 2H, NCHCH2O), 3.82 (s, 3H, ArOCH3), 3.53 (s, 3H, panoic acid ( ) (210 mg, 0.54 mmol) in dry CH2Cl2 (4
ArOCH2OCH3), 3.39 (dd, 1H, = 3.3, 13.2 Hz, ArCH), mL) was added EDCI (186 mg, 1.1 mmol), HOBt (90
2.82 (dd, 1H, = 9.9, 13.2 Hz, ArCH), 1.53 (d, 3H, mg, 0.68 mmol), Et3N (0.09 mL, 0.65 mmol), and
6.9 Hz, ArCH(CH3)), 0.95 [s, 9H, SiC(CH3)3]. 13C-NMR dimethylhydroxylamine hydrochloride (105 mg, 0.11
(CDCl3, 75 MHz): 175.2, 155.8, 154.4, 152.3, 133.4, mmol) and the mixture was stirred at room temper-
128.9, 125.5, 125.4, 122.9, 121.3, 97.9, 95.1, 78.7, 59.9, ature for 10 h. The resulting mixture was diluted with
56.0, 55.4, 55.3, 37.7, 26.0, 18.4, 17.2, 14.5, 5.3. IR saturated aqueous NH4Cl solution (8 mL), and aque-
7 (0.68 g, 1.25 mmol, 74%) as a viscous oil. Rf =
(
S
)-2-(5-((tert-Butyldimethylsilyloxy)methyl)-4-
methoxy-2-(methoxymethoxy)phenyl)- -meth-
oxy- -methylpropanamide (8)
To a solution of ( )-2-(5-((tert-butyldimethylsilyloxy)
1
N
δ
N
J
S
3
J
J
J
=
N,O-
δ
−
(KBr, neat): 2957, 2927, 2855, 1789, 1727, 1703, 1463, ous layer was extracted with EtOAc (3 × 8 mL). The
1356, 1291, 1261, 1195, 1119, 1091, 836, 799 cm−1. combined organic layers were washed with brine (25
LRMS (ESI): m/z 566 [M+ Na]+. HRMS (ESI): calcd for mL), dried over anhydrous MgSO4, filtered, and con-
C29H41O7NSiNa [M+Na]+: 566.2550, found: 566.2550. centrated under reduced pressure. The residue was
Optical rotation [
α
]
20 = +93.8 (
c
= 1.0, CHCl3).
purified by chromatography on silica gel (6:1, hexanes-
EtOAc) to give (188 mg, 81%) as a colorless oil. R
0.27 (3:1 v/v hexanes-EtOAc). H-NMR (CDCl3, 300
MHz): 7.29 (s, 1H, H6), 6.65 (s, 1H, H3), 5.20 (s, 2H,
ArOCH2OCH3), 4.67 (s, 2H, ArCH2OTBS), 3.78 (s, 3H,
ArOMe), 3.49 (s, 3H, NOCH3), 3.41 (s, 3H, ArOCH2OCH3),
D
8
f =
1
(S)-2-(5-((tert-Butyldimethylsilyloxy)methyl)-4-
δ
methoxy-2-(methoxymethoxy)phenyl)-propanoic
acid (3)
To a suspension of (
butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxy-
methoxy)phenyl)propanoyl)-oxazolidin-2-one (
) (460 0.93 [s, 9H, SiC(CH3)3]. 13C-NMR (CDCl3, 75 MHz):
mg, 0.84 mmol) in THF-H2O (7 mL, v/v, 2:1) at 0oC 155.7, 153.8, 126.8, 123.2, 122.5, 97.7, 94.9, 60.8, 60.0,
was added a solution of LiOH H2O (286 mg, 6.8 mmol) 55.9, 55.3, 35.1, 25.9, 18.4, 17.9, 5.3. IR (KBr, neat):
in H2O (5 mL) dropwise, followed by a solution of 30% 2957, 2930, 2856, 1728, 1670, 1508, 1465, 1289, 1120,
S)-4-benzyl-3-((S)-2-(5-((tert-
3.14 (s, 3H, NCH3), 1.36 (d, 3H,
J = 6.9 Hz, ArCH(CH3)),
7
δ
·
−

1272
Z. Liu et al.
1078, 1004, 839, 778 cm−1. LRMS (ESI): m/z 450 under reduced pressure. The residue was purified by
[M+Na]+. HRMS (ESI): calcd for C21H37O6NSiNa chromatography on silica gel (15:1, hexanes-EtOAc) to
[M+Na]+: 450.2288, found: 450.2292. Optical rotation afford 10 (153 mg, 81%) as a colorless oil. R
f
= 0.66
(5:1 v/v hexanes-EtOAc). H-NMR (CDCl3, 300 MHz):
7.25 (s, 1H, H6), 6.63 (s, 1H, H3), 5.18 (d, 2H, = 1.2
Hz, ArOCH2OCH3), 4.85 (s, 2H, C(=CH2)CH3), 4.69 (d,
2H, = 3.6 Hz, ArCH2OTBS), 4.28-4.29 (m, 1H, ArCH
(CH3)), 3.79 (s, 3H, ArOCH3), 3.49 (s, 3H, ArOCH2OCH3),
)-2- 1.63 (s, 3H, C(=CH2)CH3), 1.29 (d, 3H, = 7.2 Hz,
(5-((tert-butyldimethylsilyloxy)methyl)-4-methoxy-2- ArCH(CH3)), 0.91 [s, 9H, SiC(CH3)3]. 13C-NMR (CDCl3,
(methoxymethoxy)phenyl)- -methoxy- -methylpro- 75 MHz): 154.9, 154.3, 149.3, 125.9, 125.7, 123.0,
panamide ( ) (174 mg, 0.4 mmol) in anhydrous THF (6 109.4, 97.9, 95.1, 60.0, 55.9, 55.3, 37.9, 25.9, 22.2, 19.6,
mL) at 0oC was added dropwise to a solution of
5.3. IR (KBr, neat): 3084, 2956, 2929, 2856, 1615,
[α]D c = 1.0, CHCl3).
20 = +62.0 (
1
δ
J
(S)-3-(5-((tert-Butyldimethylsilyloxy)methyl)-4-
methoxy-2-(methoxymethoxy)phenyl)-butan-2-
one (9)
J
Under an atmosphere of argon, a solution of (
S
J
N
N
δ
8
−
MeMgCl (3 M in diethyl ether, 0.3 mL, 0.9 mmol). The 1504, 1464, 1291, 1254, 1151, 1117, 1083, 1061, 1025,
reaction mixture was maintained at this temperature 1011, 838, 776 cm−1. LRMS (ESI): m/z 381 [M+H]+.
for 3 h, then quenched with saturated aqueous NH4Cl HRMS (ESI): calcd for C21H36O4SiNa [M+Na]+: 403.2281,
solution (10 mL) and extracted with EtOAc (3 × 10 found: 403.2280. Optical rotation [α]D
20 = +39.3 (c = 1.0,
mL). The combined organic layers were washed with CHCl3).
brine (30 mL), dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The resi-
due was purified by chromatography on silica gel
(
R
)-(2-Methoxy-4-(methoxymethoxy)-5-(3-methyl-
but-3-en-2-yl)phenylmethanol (11)
A solution of ( )-tert-butyl(2-methoxy-4-(methoxy-
= 0.62 (3:1 v/v hexanes-EtOAc). H- methoxy)-5-(3-methylbut-3-en-2-yl)benzyloxy)dimethyl-
NMR (CDCl3, 300 MHz): 7.19 (s, 1H, H6), 6.68 (s, silane (10) (120 mg, 0.32 mmol) in THF (6 mL) was
1H, H3), 5.19 (s, 2H, ArOCH2OCH3), 4.68 (d, 2H, = 0.9 treated with tetra-n-butylammonium fluoride (250
Hz, ArCH2OTBS), 3.94 (q, 1H,
= 7.2 Hz, ArCH(CH3)), mg, 0.95 mmol) at 0oC. After stirring for 3 h at 0oC,
3.80 (s, 3H, ArOCH3), 3.48 (s, 3H, ArOCH2OCH3), 1.56 the resulting mixture was diluted with saturated
(s, 3H, COCH3), 1.34 (d, 3H, = 7.2 Hz, ArCH(CH3)), aqueous NH4Cl solution (10 mL), and extracted with
0.94 [s, 9H, SiC(CH3)3]. 13C-NMR (CDCl3, 75 MHz):
EtOAc (3 × 10 mL). The combined organic layers were
209.7, 155.9, 154.3, 126.9, 123.4, 121.4, 97.7, 94.8, washed with brine (25 mL), dried over anhydrous
59.9, 56.1, 55.3, 47.0, 27.9, 25.9, 18.4, 15.9, 5.3. IR MgSO4, filtered, and concentrated under reduced pres-
(15:1, hexanes-EtOAc) to afford
colorless oil. R
9
(156 mg, 100%) as a
R
1
f
δ
J
J
J
δ
−
(KBr, neat): 2954, 2931, 2897, 2856, 1715, 1615, 1505, sure. The residue was subjected to flash chromatog-
1464, 1290, 1256, 1216, 1152, 1119, 1087, 1011, 777 raphy on silica gel (5:1, hexanes-EtOAc) to give 11
cm−1. LRMS (ESI): m/z 405 [M+Na]+. HRMS (ESI): (107 mg, 95%) as a colorless oil. R
f = 0.21 (3:1 v/v
1
calcd for C20H34O5SiNa [M+Na]+: 405.2073, found: hexanes-EtOAc). H-NMR (CDCl3, 300 MHz):
δ
7.00
= 0.6 Hz,
= 4.2 Hz, C(=CH2)CH3),
= 4.2 Hz, ArCH2OTBS), 3.85 (s, 3H,
ArOCH3), 3.49 (s, 3H, ArOCH2OCH3), 3.76 (q, 1H,
7.2 Hz, ArCH(CH3)), 1.63 (s, 3H, C(=CH2)CH3), 1.28
(d, 3H,
= 6.9 Hz, ArCH(CH3)). 13C-NMR (CDCl3, 75
156.6, 155.2, 149.1, 127.9, 125.9, 122.3, 109.5,
-BuLi (1.6 M in hexane, 98.3, 94.8, 62.0, 55.9, 55.4, 37.8, 22.3, 19.6. IR (KBr,
20
405.2073. Optical rotation [
CHCl3).
α
]
= +117.8 (
c
= 1.0, (s, 1H, H6), 6.69 (s, 1H, H3), 5.19 (d, 2H,
ArOCH2OCH3), 4.84 (d, 2H,
4.60 (d, 2H,
J
D
J
J
J
=
(R)-tert-Butyl(2-methoxy-4-(methoxymethoxy)-
5-(3-methylbut-3-en-2-yl)benzyloxy)-dimethyl-
silane (10)
J
δ
To a suspension of Ph3PCH3Br (360 mg, 1.12 mmol) MHz):
in THF (6 mL) was added
n
0.68 mL, 1.1 mmol) dropwise at room temperature neat): 3512, 2961, 2929, 2873, 1727, 1504, 1465, 1289,
and the mixture was stirred for 15 min. A solution of 1193, 1151, 1116, 1079, 1060, 1023 cm−1. LRMS (ESI):
(
S
)-3-(5-((tert-butyldimethylsilyloxy)methyl)-4-methoxy-
m/z 289 [M+Na]+. HRMS (ESI): calcd for C15H22O4Na
2-(methoxymethoxy)phenyl)butan-2-one (
9
) (190 mg, [M+Na]+: 289.1416, found: 289.1415. Optical rotation
0.5 mmol) in THF (1 mL) was added dropwise to the
reaction mixture. After stirring for additional 4 h, the
reaction mixture was quenched with saturated aque-
ous NH4Cl solution (10 mL) and extracted with hexane
(4 × 10 mL). The combined organic layers were dried
[α]D c = 1.0, CHCl3).
20 = +58.0 (
(R
)-2-Methoxy-4-(methoxymethoxy)-5-(3-methyl-
but-3-en-2-yl)benzaldehyde (2)
To a stirring solution of ( )-(2-methoxy-4-(methoxy-
R
over anhydrous MgSO4, filtered, and concentrated methoxy)-5-(3-methylbut-3-en-2-yl)phenylmethanol (11
)

Stereoselective Total Synthesis of (+)-Licochalcone E
1273
(36 mg, 0.14 mmol) in dry CH2Cl2 (3 mL) at 0oC was 109.9, 97.9, 96.0, 94.3, 62.0, 56.1, 55.7, 37.9, 30.1, 25.1,
added Dess-Martin periodinane (160 mg, 0.4 mmol) 22.2, 19.5, 18.5. IR (KBr, neat): 2959, 2917, 2849, 1769,
slowly. After 3 h, the mixture was taken up in water 1599, 1501, 1464, 1451, 1281, 1219, 1192, 1164, 1119,
(10 mL) and the aqueous layer was extracted with 1006 cm−1. LRMS (ESI): m/z 489 [M+Na]+. HRMS
Et2O (4 × 10 mL). The combined organic layers were (ESI): calcd for C28H34O6Na [M+Na]+: 489.2253, found:
20
washed with brine (30 mL), dried over anhydrous 489.2249. Optical rotation [α D
]
= +42.8 (
c
= 1.0,
MgSO4, filtered, and concentrated in vacuo. The resi- CHCl3).
due was purified by chromatography on silica gel (8:1,
hexanes-EtOAc) to give
liquid. R
= 0.47 (3:1 hexanes-EtOAc). 1H-NMR (CDCl3,
300 MHz): 10.31 (s, 1H, ArCHO), 7.65 (s, 1H, H6), oxy)-5-((
6.69 (s,1H, H3), 5.28 (d, 2H, = 2.7 Hz, ArOCH2OCH3), hydro-2
4.84 (d, 2H, = 9.9 Hz, C(=CH2)CH3), 3.91 (s, 3H, (10 mg, 0.02 mmol) in dry MeOH (3 mL) was added 10
ArOCH3), 3.74 (q, 1H, = 7.5 Hz, ArCH(CH3)), 3.49 (s, drops of concentrated HCl. The reaction mixture was
3H, ArOCH2OCH3), 1.62 (s, 3H, C(=CH2)CH3), 1.31 (d, stirred at room temperature for 5 h, then quenched
3H,
= 7.2 Hz, ArCH(CH3)). 13C-NMR (CDCl3, 75 with saturated aqueous NH4Cl solution (10 mL) and
MHz): 188.6, 162.2, 161.1, 148.3, 127.8, 126.9, 119.0, extracted with EtOAc (3 × 10 mL). The combined organic
2 (32 mg, 92%) as a colorless
(R
)-Licochalcone E (1)
To a solution of ( )-3-(2-methoxy-4-(methoxymeth-
)-3-methylbut-3-en-2-yl)-phenyl)-1-(4-(tetra-
-pyran-2-yloxy)phenyl)prop-2-en-1-one (13
f
E
δ
R
H
J
)
J
J
J
δ
110.2, 97.2, 94.1, 56.3, 55.7, 38.1, 21.9, 19.2. IR (KBr, layers were washed with brine (20 mL), dried over
neat): 2964, 2927, 2854, 1676, 1606, 1493, 1459, 1450, anhydrous MgSO4, filtered, and concentrated under
1270, 1152, 1119, 1001 cm−1. LRMS (ESI): m/z 265 reduced pressure. The residue was purified by chroma-
[M+H]+. HRMS (ESI): calcd for C15H20O4Na [M+Na]+: tography on silica gel (3:1, hexanes-EtOAc) to afford
20
287.1259, found: 287.1260. Optical rotation [
α]
=
(
R
)-licochalcone E (
m.p. 76-80oC. R
= 0.28 (1:1 v/v hexanes-EtOAc). H-
NMR (CDCl3, 300 MHz): 8.01 (d, 1H, = 15.6 Hz,
), 7.97 (d, 2H, = 9.0 Hz, H-2', H-6'), 7.62 (d, 1H,
= 15.6 Hz, H- ), 7.52 (s, 1H, H6), 6.93 (d, 2H,
Hz, H-3’, H-5’), 6.61 (s, 1H, H3), 4.89 (d, 2H,
)-2-methoxy-4-(methoxymethoxy)- C(=CH2)CH3), 3.88 (s, 3H, ArOCH3), 3.79 (m, 1H, ArCH
5-(3-methylbut-3-en-2-yl)-benzaldehyde ( ) (16 mg, 0.06 (CH3)), 1.67 (s, 3H, C(=CH2)CH3), 1.34 (d, 3H, = 7.2
mmol) and 1-(4-(tetrahydro-2 188.5,
-pyran-2-yloxy)phenyl) Hz, ArCH(CH3)). 13C-NMR (CDCl3, 75 MHz):
1) (5.8 mg, 67%) as a yellow power.
D
1
+58.2 ( = 1.0, CHCl3).
c
f
δ
J
H
β
J
J
(E
)-3-(2-Methoxy-4-(methoxymethoxy)-5-((
methylbut-3-en-2-yl)phenyl)-1-(4-(tetrahydro-
-pyran-2-yloxy)phenyl)prop-2-en-1-one (13)
To a solution of (
R)-3-
α
J
= 9.0
J
= 7.2 Hz,
2H
R
2
J
δ
H
ethanone (12) (28 mg, 0.12 mmol) in EtOH and H2O 162.4, 159.6, 159.3, 149.9, 139.9, 131.8, 131.6, 129.4,
(2.4 mL, v/v 2:1) at room temperature was added drop- 125.0, 119.6, 116.6, 110.2, 99.9, 56.0, 38.7, 22.4, 19.7.
wise a solution of KOH (56 mg, 1 mmol) in H2O (1 IR (KBr, neat): 3440, 1716, 1645, 1603, 1509, 1448,
mL). The reaction mixture was stirred at room tem- 1288, 1261, 1216, 1168, 1121, 1036 cm−1. LRMS (ESI):
perature for 48 h and the resulting mixture was m/z 339 [M+H]+. HRMS (ESI): calcd for C21H22O4Na
diluted with H2O (10 mL) and extracted with EtOAc [M+Na]+: 361.1416, found: 361.1421. Optical rotation
(3 × 10 mL). The combined organic layers were washed
with brine (30 mL), dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure.
The residue was further purified by chromatography
on silica gel (5:1, hexanes-EtOAc) to afford 13 (19 mg,
[α]D c = 0.3, acetone).
20 = +13.6 (
RESULTS AND DISCUSSION
As shown in Scheme 1, Claisen-Schmidt condensa-
68%) as a yellow power. m.p. 76-78oC. R
f
= 0.45 (3:1 v/ tion of the aldehyde
v hexanes-EtOAc). H-NMR (CDCl3, 300MHz): 8.01 phenone would provide (+)-licochalcone E (
(dd, 3H, = 8.7, 15.9 Hz, H2’, H6’, H ), 7.53 (d, 1H, deprotection. Fully functionalized aldehyde could be
= 15.9 Hz, H ), 7.38 (s, 1H, H6), 7.12 (d, 2H, = 9.0 prepared by oxidation of the corresponding benzylic
Hz, H-3’, H-5’), 6.71 (s, 1H, H3), 5.53 (t, 1H, = 3 Hz, alcohol. Conversion of the carboxylic acid in to iso-
THP), 5.25 (s, 2H, ArOCH2OCH3), 4.88 (d, 2H, = 8.7 propenyl group in could be done by Weinreb’s amide
Hz, C(=CH2)CH3), 3.90 (s, 3H, ArOCH3), 3.57-3.88 (m, formation then the methyl Grignard reaction followed
3H, THP, ArCH(CH3)), 3.50 (s, 3H, ArOCH2OCH3), by the Wittig reaction. The chiral methyl group in
1.68-1.92 (m, 6H, THP), 1.57 (s, 3H, C(=CH2)CH3), could be introduced by the well-established asymmetric
1.33 (d, 3H, derived from Evans’
= 7.2 Hz, ArCH(CH3)). 13C-NMR (CDCl3, alkylation of the aryl acetamide
75 MHz): 189.9, 160.5, 158.5, 157.6, 148.8, 140.1, )-4-benzyl-2-oxazolidinone. And the aryl acetamide
132.3, 130.5, 128.8, 126.5, 120.7, 117.5, 115.9, 115.7, would come from aryl acetate (Ghosh and Gong,
2
with protected 4-hydroxyaceto-
1
δ
1
) after
J
β
J
2
α
J
J
3
J
2
3
J
4
δ
(S
4
5

1274
Z. Liu et al.
Scheme 1. Retrosynthesis of (+)-licochalcone E (1)
2004). Compound
5, in turn, would be formed from the
known aryl bromide
6, applying the palladium-cat-
alyzed Negishi-Reformatsky coupling reaction with
ethyl 2-(tributylstannyl)acetate. Negishi reported the
improvement of palladium-catalyzed Reformatsky
arylation using organotin analog of Reformatsky
reagent in the presence of zinc bromide and catalytic
amount of dichlorobis(tri-
(Kosugi et al., 1985; Heckrodt and Mulzer, 2003).
Actual synthesis of is depicted in Scheme 2. Pal-
ladium-catalyzed Negishi-Reformatsky coupling of [5-
bromo-2-methoxy-4-(methoxymethoxy)benzyloxy](tert
butyl)dimethylsilane, with ethyl 2-(tributylstannyl)
acetate in the presence of dry ZnBr2 and DMF at 80oC
afforded 72% yield of aryl acetate . The aryl acetate
was hydrolyzed with 1
-NaOH in ethanol at 40oC to
give aryl acetic acid, which was subsequently convert- in 81% yield, which was reacted with methyl magne-
ed to the aryl acetamide
via the mixed anhydride. sium chloride in THF at 0oC to furnish the methyl
Thus, treatment of the arylacetic acid with pivaloyl ketone in quantitative yield. This methyl ketone
chloride in the presence of triethylamine gave the underwent the Wittig reaction with methyltriphenyl-
mixed anhydride, which was treated with the lithium phosphonium bromide in the presence of -BuLi in
anion of ( )-4-benzyl-2-oxazolidinone to afford the aryl THF at ambient temperature to afford ( )-2-aryl-3-
acetamide in 81% overall yield over 3 steps. methyl-3-butene 10 in 81% yield, which was treated
)-4-Benzyl-2-oxazolidinone-derived compound
with TBAF at 0oC for three hours to give the alcohol
was treated with NaHMDS and methyl iodide at 78 11 in 95% yield.
oC to afford methylated aryl acetamide
in 74% yield Oxidation of the benzylalcohol 11 with Dess-Martin
as shown in Scheme 3. Hydrolysis of the Evans’ periodinane provided the key benzaldehyde in 92%
oxazolidinone in with LiOH and H2O2 in THF-H2O yield. Claisen-Schmidt condensation between the
provided ( )-2-arylpropionic acid in 71% yield (Qin aldehyde and tetrahydropyran-protected 4-hydroxy-
et al., 2007). The acid was converted to ( )-2-aryl-3- acetophenone 12 in ethanolic KOH solution furnished
methyl-3-butene 10 in 3 steps. Treatment of the ( )-2- protected (+)-licochalcone E (13), which was depro-
arylpropionic acid with EDAC, HOBt, followed by tected with -HCl in methanol at room temperature
-dimethylhydroxylamine hydrochloride in the for five hours to give (+)-licochalcone E ( ) in 46%
presence of triethylamine gave the Weinreb’s amide overall yield in 2 steps. NMR, MS, and IR data of (+)-
o-tolylphosphine)palladium
4
-
6
Scheme 2. Synthesis of key intermediate
4 from 6
5
5
N
4
9
9
n
S
R
4
(S
4
−
7
2
7
S
3
2
3
R
S
3
c
N,O
1
8

Stereoselective Total Synthesis of (+)-Licochalcone E
1275
Scheme 3. Synthesis of (+)-licochalcone E (1) from 4
licochalcone E (
the natural ( )-licochalcone E except optical rotation. tion.
(+)-Licochalcone E (
+13.6o (
= 0.3, acetone) while that of natural (
licochalcone was reported as [ ]D =
10.0o (
tone) (Yoon et al., 2005). Thus, we have synthesized
the enantiomer of natural (
stereochemically unambiguous route in 13 steps with Government 2010-0016417. We thank the Korea
8% overall yield. Basic Science Institute (KBSI), Gwangju branch, for
We have accomplished for the first time the syn- performing the NMR and HRMS experiments.
thesis of (+)-licochalcone E ( ) in 13 steps from aryl
bromide ( ) with 8% overall yield. The highlight of
this concise asymmetric synthesis of is Palladium-
1) were fully consistent with those for synthesize other licochalcones for biological evalua-
−
25
1
) has optical rotation of [α D
]
=
)-
c
−
ACKNOWLEDGEMENTS
α
−
c = 0.2, ace-
This work was supported by National Research
−)-licochalcone E through a Foundation of Korea Grant funded by the Korean
1
6
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