An enantioselective total synthesis of (S)-(-)-licochalcone E: determination of the absolute configuration

Article abstract of DOI:10.1016/j.tet.2010.02.089

The absolute configuration of (-)-licochalcone E (1) was determined to be (S) via the first enantioselective total synthesis of the compound. The chirality in (S)-(-)-licochalcone E (1) was installed by asymmetric methylation of the Evans' oxazolidinone d

Full text of DOI:10.1016/j.tet.2010.02.089

Tetrahedron 66 (2010) 3165–3172
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Tetrahedron
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An enantioselective total synthesis of (S)-(ꢀ)-licochalcone E: determination of the
absolute configuration
,
Zhiguo Liu a, Goo Yoon b, Seung Hoon Cheon a
*
a College of Pharmacy and Research Institute of Drug Development, Chonnam National University, 300 Yongbong-Dong, Buk-Gu, Gwangju 500-757, Republic of Korea
b Korea Institute of Science and Technology, Gangneung Institute, Gangneung 210-340, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The absolute configuration of (ꢀ)-licochalcone E (1) was determined to be (S) via the first enantiose-
lective total synthesis of the compound. The chirality in (S)-(ꢀ)-licochalcone E (1) was installed by
asymmetric methylation of the Evans’ oxazolidinone derivatives.
Received 30 December 2009
Received in revised form 24 February 2010
Accepted 24 February 2010
Available online 1 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective synthesis
Licochalcone E
Asymmetric methylation
Chiral oxazolidinone
1. Introduction
protecting groups. The 2-allyl functionality of the 2-aryl-3-meth-
ylbut-3-ene 2 would be derived from carboxylic acid 3 through
Licochalcone E was isolated from the roots of Glycyrrhiza inflata
during cytotoxicity-guided fractionation using the HT1080 cell
line.1 Further studies revealed that it possessed diverse biological
activities, including the abilities to inhibit topoisomerase 1 and to
induce endothelial cell apoptosis by modulating NF-kB and the Bcl-
2 family.2 Recently, it was reported that licochalcone E (1) also
inhibited protein tyrosine phosphatase 1B.3 The structure of lico-
chalcone E was elucidated as (ꢀ)-(E)-3-[4-hydroxy-2-methoxy-
5-(3-methylbut-3-en-2-yl)phenyl]-1-(4-hydroxyphenyl)prop-2-en-
1-one (1) on the basis of spectral data, but its absolute
configuration has not been reported.1 Our interest in (ꢀ)-lico-
chalcone E (1) was to determine the absolute stereochemistry
and develop a highly versatile synthesis that might be suitable
for analogs preparation. Herein, we describe the first enantio-
selective total synthesis and the determination of the absolute
configuration of (S)-(ꢀ)-licochalcone E (1).
ketone formation followed by Wittig reaction. The chirality in
3 would be installed unambiguously by well established asym-
metric methylation of the Evans’ oxazolidinone 4, which would be
formed from aryl acetic acid 5.4 Compound 5, in turn, would arise
from 2,4-dihydroxybenzaldehyde by way of the bromide 6.
The synthesis of key intermediate
4 from 2,4-dihydroxy-
benzaldehyde (7) is illustrated in Scheme 2. Bromination of 7 fol-
lowed by selective MOM protection of 4-hydroxyl group provided
5-bromo-2-hydroxy-4-(methoxymethoxy)benzaldehyde (6), which
was protected with MeI/K2CO3, to furnish the aldehyde 9 in 71% yield
over three steps.5 NaBH4 reduction of the aldehyde 9 followed by TBS
protection of the resulting alcohol gave [5-bromo-2-methoxy-4-
(methoxymethoxy)benzyloxy](tert-butyl)dimethylsilane (11) in
quantitative yield from 9. With 11 in hand it was attempted to con-
vert the TBS-protected bromide 11 to aryl acetic ester, the esterified
product of the acid 5, using palladium-catalyzed Negishi–Refor-
matsky coupling with an appropriate stannane.7 Treatment of the
bromide 11 with PdCl2[P(o-tolyl)3]2 (5–10 mol % of 11), 1.2–2.0 equiv
of ethyl tributylstannylacetate and vacuum dried 1.2–2.0 equiv of
zinc bromide in DMF at 80–120 ꢁC did not provide the ethyl ester of
the acid 5. So 11 was treated with n-BuLi and DMF at ꢀ78 ꢁC to afford
the aldehyde 12 in 85% yield.6 Wittig reaction of the aldehyde 12
with methyltriphenylphosphoninum bromide in the presence of
n-BuLi afforded the arylethene 13, which was subjected to hydro-
boration with BH3, followed by oxidative workup to give the alcohol
14 in 71% overall yield from 12.8 The resultant primaryalcohol 14 was
oxidized using Dess–Martin periodinane in methylene chloride to
2. Results and discussion
Our overall synthetic strategy is outlined in Scheme 1. It was
envisaged that (S)-(ꢀ)-licochalcone E (1) would be constructed via
aldol condensation between the aldehyde 2 and properly protected
4-hydroxyacetophenone, followed by removal of both phenol
* Corresponding author. Tel.: þ82625302929; fax: þ82625302911.
E-mail address: shcheon@chonnam.ac.kr (S.H. Cheon).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.089

3166
Z. Liu et al. / Tetrahedron 66 (2010) 3165–3172
COOH
OMOM
OH
OMOM
HO
OHC
OCH3
TBSO
Br
OCH3
OCH3
O
(S)-(-)-Licochalcone E (1)
2
3
O
O
COOH
N
O
OMOM
OH
OMOM
TBSO
H3CO
OHC
OHC
TBSO
OCH3
OH
OH
OMOM
7
6
4
5
Scheme 1. Retrosynthesis of (S)-(ꢀ)-licochalcone E (1).
Br
Br
OH
OMOM
OH
Br2, CH3COOH
rt, 3 h, 83%
K2CO3, MOMCl
acetone, rt, 5 h
86%
OHC
OHC
OHC
OH
7
OH
OH
6
8
Br
Br
OMOM
OMOM
K2CO3, CH3I
TBSCl, imidazole
NaBH4, MeOH
0oC, 0.5 h
100%
acetone, rt, 16 h
100%
DMF, 0oC, 0.5 h
100%
OHC
OCH3
OH OCH3
9
10
Br
CHO
OMOM
OMOM
OMOM
n-BuLi, THF
Ph3PCH3Br, n-BuLi
DMF, -78-0oC, 3 h
85%
THF, rt, 4 h, 98%
TBSO
OCH3
11
TBSO
OCH3
12
TBSO
OCH3
13
OH
OMOM
CHO
1) BH3SMe2, THF
0oC-rt, 1 h
NaClO2, NaH2PO4
2-methyl-2-butene
t-BuOH, 0oC-rt
40 min, 100%
OMOM
Dess-Martin periodinane
DCM, 0oC, 3 h, 95%
2) H2O2, NaOH,
2 h, 72%
TBSO
OCH3
14
TBSO
15
OCH3
COOH
OMOM
O
O
1) Pivaloyl chloride, Et3N, THF
2)
N
O
O
O
HN
TBSO
H3CO
TBSO
OCH3
n-BuLi, -78oC-rt, 3 h, 83%
OMOM
5
4
Scheme 2. Synthesis of key intermediate 4 from 2,4-dihroxybenzaldehyde (7).
give the aldehyde 15, which was further oxidized using NaClO2,
NaH2PO4, tert-butanol, and 2-methyl-2-butene (Smith’s conditions)
to furnish the corresponding 2-aryl acetic acid 5 in 95% overall yield
in two steps.9
defined absolute stereochemistry with high ee in asymmetric
induction reaction.4 Fortunately, it turned out that the imide 4
afforded the same enantiomer as the natural licochalcone E after
subsequent reactions (vide infra).
2-Arylacetic acid 5 was reacted with pivaloyl chloride in the
presence of triethylamine to give mixed anhydride, which was
treated with the lithium anion of (4R,5S)-(þ)-4-methyl-5-phenyl-
2-oxazolidinone to afford the imide 4 in 83% yield over two steps.
(4R,5S)-(þ)-4-Methyl-5-phenyl-2-oxazolidinone was chosen as
a chiral auxiliary because it was proven to provide unambiguously
With the key intermediate 4 in hand, we introduced necessary
chirality to the molecule as shown in Scheme 3. The Evans’ oxa-
zolidinone derivative 4 was treated with NaHMDS and methyl io-
dide at ꢀ78 ꢁC to afford methylated imide 16 in 74% yield, which
was a single isomer by 300 MHz 1H NMR. Hydrolysis of the Evans’
oxazolidinone with LiOH and H2O2 provided acid 3 in 71% yield.10

Z. Liu et al. / Tetrahedron 66 (2010) 3165–3172
3167
O
O
O
O
N
O
N
O
NaHMDS, CH3I
-78oC-rt,4 h
74%
TBSO
H3CO
TBSO
H3CO
OMOM
OMOM
16
4
O
COOH
N(CH3)(OCH3)
OMOM
EDAC, HOBt, DCM
then CH3ONHCH3
OMOM
H2O2, LiOH
THF-H2O, 0oC-rt, 1 h
rt, 10 h, 81%
71%
TBSO
OCH3
O
TBSO
17
OCH3
3
OMOM
MeMgCl, THF
0oC, 3 h, 100%
Ph3PCH3Br, n-BuLi
THF, rt, 4 h, 81%
OMOM
TBAF, THF
0oC, 3 h, 95%
TBSO
OCH3
18
TBSO
OCH3
19
O
O
OMOM
Dess-Martin periodinane
DCM, 0oC, 3 h, 92%
OMOM
21
O
KOH, EtOH-H2O
rt, 48 h, 68%
OHC
HO
OCH3
20
OCH3
2
OMOM
OH
O
O
c-HCl, MeOH
rt, 5 h, 67%
HO
OCH3
OCH3
O
22
O
1
Scheme 3. Synthesis of (S)-(ꢀ)-licochalcone E (1) from 4.
2-Arylpropionic acid 3 was converted to 2-aryl-3-methylbut-3-ene
19 in three steps. Treatment of the chiral 2-arylpropionic acid 3
with EDAC, HOBt, followed by N,O-dimethylhydroxylamine hy-
drochloride in the presence of triethylamine gave Weinreb’s amide
17, which was reacted with methyl magnesium chloride to furnish
methyl ketone 18 in 81% overall yield from 3.11 This methyl ketone
18 underwent Wittig reaction with methyltriphenylphosphonium
bromide in the presence of n-BuLi to afford 2-aryl-3-methylbut-3-
ene 19, which was treated with TBAF to give the alcohol 20 in 77%
yield over two steps. Oxidation of alcohol 20 with Dess–Martin
periodinane provided the key aldehyde 2 in 92% yield. Aldol con-
densation between the aldehyde 2 and tetrahydropyran-protected
4-hydroxyacetophenone12 (21) in ethanolic KOH solution furnished
further proven its absolute configuration. Our work provided
flexible and highly versatile approaches to synthesize not only
(S)-(ꢀ)-licochalcone E (1) but also its analogs for biological
testing.
4. Experimental section
4.1. General
Solvents were distilled under positive pressure of dry argon
before use and dried by standard methods. Tetrahydrofuran
(THF) was distilled over sodium benzophenone ketyl radical,
triethylamine (Et3N) was distilled over calcium hydride and
stored over potassium hydroxide. (4R,5S)-(þ)-4-Methyl-5-phe-
nyl-2-oxazolidinone and (S)-(ꢀ)-4-benzyl-2-oxazolidinone were
purchased from Alfa Aesar and Sigma–Aldrich, respectively.
Unless otherwise noted, chemicals were obtained from local
suppliers and were used without further purification. All
reactions were performed under argon atmosphere and moni-
protected licochalcone
E (22), which was deprotected with
concd HCl in methanol gave (ꢀ)-licochalcone E (1) in 46% yield over
25
two steps.13 NMR, MS, IR, and optical rotation {[
a
]
D
ꢀ11.4 (c 1,
acetone)} data of synthetic licochalcone E (1) were fully consistent
with those for the natural (ꢀ)-licochalcone E.1
3. Conclusion
tored by thin-layer chromatography (250 m 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
In conclusion, we have synthesized the natural (S) enantiomer
of 1 through a stereochemically unambiguous route and have

3168
Z. Liu et al. / Tetrahedron 66 (2010) 3165–3172
spectrophotometer. NMR (1H, 13C) spectra were recorded on
Varian Unity Plus 300 spectrometer. Low resolution mass spectra
were obtained with a Shimadzu, JP/LCMS-2010 instrument. High
layers were washed with brine (100 mL) and dried over MgSO4,
filtered and concentrated under reduced pressure to give (5-bromo-
2-methoxy-4-(methoxymethoxy)phenyl)methanol (10) (4.23 g,
100%) as a white solid. Mp: 68–71 ꢁC. Rf¼0.23 (3:1 v/v hexanes/
resolution measurements were made with
a Synapt HDMS
(Waters, UK) instrument. Optical rotations were recorded in
a 1 dm cell at 25 ꢁC (JASCO, DiP-1000 digital polarimeter).
EtOAc). 1H NMR (CDCl3, 300 MHz):
d 7.43 (s, 1H, H6), 6.76 (s, 1H,
H3), 5.24 (s, 2H,ArOCH2OCH3), 4.59 (s, 2H, ArCH2OH), 3.84 (s, 3H,
ArOCH3), 3.53 (s, 3H, ArOCH2OCH3), 2.16 (s, 1H, OH). 13C NMR
4.1.1. 5-Bromo-2,4-dihydroxybenzaldehyde (8). Bromine (3.78 mL,
72.4 mmol) was added dropwise to a solution of 2,4-dihydroxy-
benzaldehyde (7) (10.0 g, 72.4 mmol) in acetic acid (70.0 mL). After
stirring for 3 h at room temperature, the resulting mixture was
poured into water (100 mL), then the precipitated product was
filtered and washed with water (100 mL), dried in vacuo, and the
crude solids were recrystallized from a hot solution of 50% aceto-
nitrile/toluene to yield 5-bromo-2,4-dihydroxybenzaldehyde
(13.09 g, 83%. Mp: 165–168 ꢁC).
(CDCl3, 75 MHz):
d 157.3, 154.0, 132.4, 124.4, 102.7, 100.1, 95.3, 60.5,
56.3, 55.6. IR (KBr, neat): 3290, 2947, 2912, 2870, 1604, 1578, 1502,
1467, 1408, 1371, 1291, 1215, 1158, 1084, 1040, 1011, 922, 835 cmꢀ1
.
LRMS (ESI): m/z 278 [MþH]þ. HRMS (ESI): calcd for C10H13O4BrNa
[MþNa]þ: 298.9895, found: 298.9907.
4.1.5. (5-Bromo-2-methoxy-4-(methoxymethoxy)benzyloxy)(tert-
butyl)dimethylsilane (11). To a solution of (5-bromo-2-methoxy-
4-(methoxymethoxy)phenyl)methanol (10) (4.20 g, 15.2 mmol) in
DMF (20 mL) was added imidazole (4.14 g, 60.8 mmol) at ice-bath
temperature followed by tert-butyldimethylsilyl chloride (TBSCl)
(4.12 g, 27.4 mmol) and the mixture was stirred at this temper-
ature for 30 min. The reaction mixture was quenched with
saturated aqueous NH4Cl (50 mL) and extracted with EtOAc
(3ꢂ50 mL). The combined organic layers were washed with
water (100 mL), brine (100 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (10:1, hexanes/EtOAc) to give
(5-bromo-2-methoxy-4-(methoxymethoxy)benzyloxy)(tert-butyl)-
dimethylsilane (11) (5.93 g, 100%) as a colorless oil. Rf¼0.59 (5:1
4.1.2. 5-Bromo-2-hydroxy-4-(methoxymethoxy)benzaldehyde (6). To
a mixture of 5-bromo-2,4-dihydroxybenzaldehyde (8) (7.07 g,
32.6 mmol), K2CO3 (13.6 g, 97.7 mmol) in anhydrous acetone
(100 mL) was added chloromethyl methyl ether (2.52 mL,
32.3 mmol) dropwise at room temperature. After 5 h, the resulting
mixture was filtered and the filtrate was concentrated under re-
duced pressure and the residue was then dissolved in EtOAc
(50 mL), further washed with water (50 mL) and brine (50 mL).
The organic layer was dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by chromato-
graphy on silica gel (hexanes/EtOAc¼10:1) to give 5-bromo-2-
hydroxy-4-(methoxymethoxy)benzaldehyde (6) (7.22 g, 86%) as
a white crystalline solid. Mp: 59–62 ꢁC. Rf¼0.66 (3:1 v/v hexanes/
v/v hexanes/EtOAc). 1H NMR (CDCl3, 300 MHz):
d 7.55 (s, 1H, H6),
6.70 (s,1H, H3), 5.22 (s, 2H, ArOCH2OCH3), 4.65 (d, 2H, J¼0.9 Hz, H1a),
3.79 (s,1H, ArOMe), 3.53 (s, 3H, ArOCH2OCH3), 0.95 [s, 9H, SiC(CH3)3].
EtOAc). 1H NMR (CDCl3, 300 MHz):
1H, H6), 6.74 (s, 1H, H3), 5.30 (s, 2H, ArOCH2OCH3), 3.51 (s, 3H,
ArOCH2OCH3). 13C NMR (CDCl3, 75 MHz):
193.8, 163.1, 160.2,
d
9.70 (s, 1H, ArCHO), 7.69 (s,
13C NMR (CDCl3, 75 MHz):
d 156.0, 153.2, 130.9, 125.2, 103.0,
99.9, 95.5, 59.4, 56.3, 55.4, 25.9, 25.6, 18.4, 17.9, ꢀ5.4. IR (KBr, neat):
2955, 2930, 2898, 2857, 1604, 1498, 1463, 1371, 1300, 1256, 1215,
1155, 1088, 1005, 837, 777 cmꢀ1. LRMS (ESI): m/z 393 [MþH]þ.
HRMS (ESI): calcd for C16H27O4BrSiNa [MþNa]þ: 413.0760, found:
413.0760.
d
137.4, 116.5, 103.4, 102.7, 94.8, 56.7. IR (KBr, neat): 3074, 3052,
2958, 2937, 2851, 1617, 1571, 1486, 1457, 1442, 1356, 1327, 1218,
1206, 1161, 1022, 966, 916, 832, 754, 742 cmꢀ1. LRMS (ESI): m/z 261
[MþH]þ. HRMS (ESI): calcd for C9H9O4Br: 260.9586, found:
260.9605.
4.1.6. 5-((tert-Butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxy-
methoxy)benzaldehyde (12). A 1.6 M solution of n-BuLi in hexane
(19.0 mL, 30.7 mmol) was added dropwise to a solution of (5-
bromo-2-methoxy-4-(methoxymethoxy)benzyloxy)(tert-butyl)di-
methylsilane (11) (6.10 g, 15.6 mmol) in anhydrous THF (60 mL) at
ꢀ78 ꢁC under argon. After 1 h, dry DMF (9.50 mL, 122 mmol) was
added dropwise. The reaction solution was then allowed to warm
up to room temperature and stirring was continued for 2 h. The
resulting solution was quenched with saturated aqueous NH4Cl
(50 mL) and extracted with EtOAc (3ꢂ50 mL). The combined or-
ganic layers were washed with water (100 mL), brine (100 mL),
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The residue was purified by chromatography on silica gel (10:1,
hexanes/EtOAc) to give 5-((tert-butyldimethylsilyloxy)methyl)-
4-methoxy-2-(methoxymethoxy)benzaldehyde (12) (5.26 g, 85%)
as a white solid. Mp: 66–69 ꢁC. Rf¼0.46 (4:1 v/v hexanes/EtOAc). 1H
4.1.3. 5-Bromo-2-methoxy-4-(methoxymethoxy)benzaldehyde (9). A
solution of 5-bromo-2-hydroxy-4-(methoxymethoxy)benzaldehyde
(6) (6.10 g, 23.4 mmol) in dry acetone (70 mL) was added K2CO3
(9.73 g, 70.1 mmol) portionwise, followed by MeI (1.65 mL,
25.7 mmol)atroomtemperature. After16 h, thereactionmixturewas
then filtered and the filtercake was washed with acetone (100 mL).
The filtrate was concentrated under reduced pressure and the residue
wasdissolved inEtOAc(50 mL), washed withwater(50 mL)andbrine
(50 mL). The organic layer was dried over MgSO4, and filtered and the
filtrate was concentrated in vacuo to give 5-bromo-2-methoxy-4-
(methoxymethoxy)benzaldehyde (9) (6.43 g, 100%) as a white crys-
talline solid. Mp: 70–73 ꢁC. Rf¼0.39 (3:1 v/v hexanes/EtOAc). 1H NMR
(CDCl3, 300 MHz):
H3), 5.33 (s, 2H, ArOCH2OCH3), 3.92 (s, 3H, ArOCH3), 3.54 (s,
3H, ArOCH2OCH3). 13C NMR (CDCl3, 75 MHz):
187.2, 162.2, 159.6,
d 10.26 (s, 1H, ArCHO), 8.01 (s, 1H, H6), 6.78 (s,1H,
d
NMR (CDCl3, 300 MHz): d 10.34 (s, 1H, ArCHO), 7.93 (s, 1H, H6), 6.67
132.8, 120.2, 104.1, 99.0, 95.0, 56.6, 55.9. IR (KBr, neat): 2968,
2945, 2866,1667,1601,1503,1470,1450,1420,1398,1323,1287,1204,
1164, 1104, 996, 943, 862, 815 cmꢀ1. LRMS (ESI): m/z 275 [MþH]þ.
HRMS (ESI): calcd for C10H11O4BrNa [MþNa]þ: 296.9738, found:
296.9742.
(s, 1H, H3), 5.29 (s, 2H, ArOCH2OCH3), 4.66 (d, 2H, J¼0.6 Hz, H1a),
3.88 (s, 3H, ArOMe), 3.53 (s, 3H, ArOCH2OCH3), 0.95 [s, 9H,
SiC(CH3)3]. 13C NMR (CDCl3, 75 MHz):
d 188.2, 162.4, 161.0, 127.5,
124.1, 118.7, 97.0, 94.9, 59.7, 56.4, 55.5, 25.9, 18.4, ꢀ5.4. IR (KBr,
neat): 2957, 2926, 2856, 1672, 1610, 1492, 1445, 1267, 1246, 1153,
1116, 1091, 1069, 855, 837, 778 cmꢀ1. LRMS (ESI): m/z 363 [MþNa]þ.
HRMS (ESI): calcd for C17H28O5SiNa [MþNa]þ: 363.1604, found:
363.1607.
4.1.4. (5-Bromo-2-methoxy-4-(methoxymethoxy)phenyl)methanol
(10). To a stirred solution of 5-bromo-2-methoxy-4-(methoxy-
methoxy)benzaldehyde (9) (4.20 g, 15.3 mmol) in methanol (30 mL)
was added NaBH4 (0.49 g, 15.3 mmol) slowly at ice-bath tempera-
ture. After stirring for 30 min, the mixture was diluted with water
(50 mL), extracted with EtOAc (3ꢂ50 mL). The combined organic
4.1.7. tert-Butyl(2-methoxy-4-(methoxymethoxy)-5-vinyl-
benzyloxy)dimethylsilane (13). To a suspension of Ph3PCH3Br (4.00 g,
11.2 mmol) in THF (50 mL) was added n-BuLi (1.6 M in hexane,

Z. Liu et al. / Tetrahedron 66 (2010) 3165–3172
3169
12.6 mL, 20.2 mmol) dropwise at room temperature and the mixture
was stirred for 15 min. A solution of 5-((tert-butyldimethylsilyl-
130.0, 123.3, 112.8, 97.7, 94.7, 60.0, 56.0, 55.4, 45.2, 26.0, 18.5, ꢀ5.3.
IR (KBr, neat): 2955, 2930, 2899, 2856, 1726, 1617, 1508, 1465,
1152,1117,1070,1023, 838, 777 cmꢀ1. LRMS (ESI): m/z 377 [MþNa]þ.
HRMS (ESI): calcd for C18H30O5SiNa [MþNa]þ: 377.1760,
found: 377.1760.
oxy)methyl)-4-methoxy-2-(methoxymethoxy)benzaldehyde
(12)
(3.80 g,11.2 mmol)inTHF(10 mL)wasaddeddropwisetothereaction
mixture. After stirring for additional 4 h, the reaction mixture was
quenched with saturated aqueous NH4Cl (30 mL) and extracted with
hexane (3ꢂ30 mL). The combined organic layers were dried over
anhydrousMgSO4, filtered, andconcentratedunderreducedpressure.
The residuewaspurified bychromatography (15:1, hexanes/EtOAc)to
afford tert-butyl(2-methoxy-4-(methoxymethoxy)-5-vinylbenzyl-
oxy)dimethylsilane (13) (3.70 g, 10.9 mmol, 98%) as a colorless oil.
4.1.10. 2-(5-((tert-Butyldimethylsilyloxy)methyl)-4-methoxy-2-
(methoxymethoxy)phenyl)acetic acid (5). To a solution of 2-(5-((tert-
butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxymethoxy)
phenyl)acetaldehyde (15) (400 mg, 1.13 mmol) in t-BuOH (23.0 mL)
was added 2-methyl-2-butene (6.50 mL) at 0 ꢁC followed by a solu-
tion of NaClO4 (746 mg, 8.25 mmol) and NaH2PO4$H2O (938 mg,
6.80 mmol) in H2O (8 mL) dropwise. After 10 min, the reaction
mixture was allowed to warm up to room temperature and stirred
vigorously for 30 min. The reaction mixture was diluted with satu-
rated aqueous NH4Cl (10 mL) and the aqueous layer was extracted
with EtOAc (3ꢂ10 mL). The combined organic layers were washed
with brine (30 mL) and dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (5:1, hexanes/EtOAc) to afford 2-
(5-((tert-butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxy-
methoxy)phenyl)acetic acid (5) (416 mg, 100%) as a colorless oil.
Rf¼0.63 (5:1 v/v hexanes/EtOAc).1H NMR (CDCl3, 300 MHz):
d 7.59 (s,
1H, H6), 7.00 (q, 1H, J¼17.7 Hz, H100), 6.63 (s, 1H, H3), 5.65 [dd, 1H,
J1¼1.5 Hz, J2¼17.7 Hz, H(200-
a)], 5.19 (s, 2H, ArOCH2OCH3), 5.14 [dd,1H,
b)], 4.69 (s, 2H, H1a), 3.80 (s, 3H, ArOMe),
J1¼1.5 Hz, J2¼11.1 Hz, H(200-
3.50 (s, 3H, ArOCH2OCH3), 0.96 [s, 9H, SiC(CH3)3]. 13C NMR (CDCl3,
75 MHz): d 156.7, 154.3, 131.0, 123.4, 119.5, 111.8, 98.1, 95.2, 59.9, 56.0,
55.2, 25.9, 18.4, ꢀ5.3. IR (KBr, neat): 3085, 2955, 2931, 2856, 1614,
1500, 1464, 1303, 1256, 1152, 1117, 1089, 1012, 840, 777 cmꢀ1. LRMS
(ESI):m/z 339 [MþH]þ. HRMS (ESI):calcd forC18H30O4SiNa [MþNa]þ:
361.1811, found: 361.1815.
4.1.8. 2-(5-((tert-Butyldimethylsilanyloxy)methyl)-4-methoxy-2-
(methoxymethoxy)phenyl)ethanol (14). To a solution of tert-butyl
(2-methoxy-4-(methoxymethoxy)-5-vinylbenzyloxy)dimethylsilane
(13) (2.20 g, 6.50 mmol) in dry THF (20 mL) was added BH3–SMe2
(2.0 M in diethyl ether, 13.1 mL, 6.57 mmol) dropwise at 0 ꢁC under
argon. The reaction solution was allowed to warm up to room
temperature and stirring was continued for 1 h before 2 N NaOH
(4 mL) and 30% H2O2 (2 mL) were added. The mixture was further
stirred for 2 h and diluted with saturated NH4Cl (34 mL), then
extracted with EtOAc (3ꢂ20 mL), and the combined organic layers
were washed with brine (50 mL) and dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel (10:1 to 5:1, hexanes/
EtOAc) to afford the 2-(5-((tert-butyldimethylsilyloxy)methyl)-4-
methoxy-2-(methoxymethoxy)phenyl)ethanol (14) (1.67 g, 72%) as
a colorless oil. Rf¼0.35 (3:1 v/v hexanes/EtOAc). 1H NMR (CDCl3,
Rf¼0.23 (3:1 v/v hexanes/EtOAc). 1H NMR (CDCl3, 300 MHz):
d 7.24
(s, 1H, H6), 6.68 (s, 1H, H3), 5.18 (s, 2H, ArOCH2OCH3), 4.67 (s, 2H,
H1a), 3.79 (s, 3H, ArOMe), 3.46 (s, 3H, ArOCH2OCH3), 3.63 (s, 2H,
ArCH2COOH), 0.95 [s, 9H, SiC(CH3)3]. 13C NMR (CDCl3, 75 MHz):
177.9,156.4,154.9,129.4,122.9,114.4, 97.8, 94.7, 59.8, 55.9, 55.3, 35.4,
29.7, 25.9, 18.6, ꢀ5.3. IR (KBr, neat): 2953, 2928, 2856, 1712, 1619,
1509, 1465, 1290, 1255, 1216, 1152, 1118, 1086, 1072, 1024, 837,
776 cmꢀ1. LRMS (ESI): m/z 393 [MþNa]þ. HRMS (ESI): calcd for
C18H30O6SiNa [MþNa]þ: 393.1709, found: 393.1709.
4.1.11. (4R,5S)-3-(2-(5-((tert-Butyldimethylsilyloxy)methyl)-4-methoxy-
2-(methoxymethoxy)phenyl)acetyl)-4-methyl-5-phenyloxazolidin-2-
one (4). To a solution of 2-(5-((tert-butyldimethylsilyloxy)methyl)-4-
methoxy-2-(methoxymethoxy)phenyl)aceticacid (5) (1.50 g, 4.05 mmol),
Et3N (0.65 mL, 4.60 mmol) in anhydrous THF (15.0 mL) at ꢀ78 ꢁC
was added pivaloyl chloride (0.68 mL, 5.5 mmol) dropwise under an
atmosphere of argon. The resulting mixture was stirred for 15 min at
ꢀ78 ꢁC and 1 h at 0 ꢁC, then recooled to ꢀ78 ꢁC. Meanwhile, n-BuLi
(1.6 M in diethyl ether, 3.19 mL, 5.10 mmol) was added dropwise to
300 MHz):
d 7.11 (s, 1H, H6), 6.57 (s, 1H, H3), 5.09 (s, 2H, ArO-
CH2OCH3), 4.58 (s, 2H, H1a), 3.71 (s, 2H, H200), 3.69 (s, 3H, ArOMe),
3.39 (s, 3H, ArOCH2OCH3), 2.77 (t, 2H, J¼6.6 Hz, H100), 1.64 (s, 1H
CH2OH), 0.84 [s, 9H, SiC(CH3)3]. 13C NMR (CDCl3, 75 MHz):
d
155.7,
a
solution of (4R,5S)-(þ)-4-methyl-5-phenyl-2-oxazolidinone
155.1, 129.3, 123.0, 118.7, 98.1, 94.9, 63.2, 59.9, 56.1, 55.4, 33.4, 26.0,
18.5, ꢀ5.3. IR (KBr, neat): 3464, 3357, 2955, 2931, 2856, 1617, 1507,
1464, 1291, 1256, 1216, 1152, 1116, 1069, 1023, 837, 777 cmꢀ1. LRMS
(ESI): m/z 379 [MþNa]þ. HRMS (ESI): calcd for C18H32O5SiNa
[MþNa]þ: 379.1917, found: 379.1920.
(0.90 g, 5.10 mmol) in anhydrous THF (10 mL) at ꢀ78 ꢁC under an
atmosphere of argon and the mixture was stirred for 40 min at
ꢀ78 ꢁC. The lithiated chiral auxiliary was then transferred into the
reaction flask containing the preformed mixed anhydride via
a cannula. After stirring for 15 min at ꢀ78 ꢁC, the reaction mixture
was allowed to warm up to room temperature for 2 h, then it was
quenched with saturated aqueous NH4Cl (30 mL), layers were sep-
arated and aqueous layer was extracted with EtOAc (3ꢂ30 mL). The
combined organic layers were washed with brine (50 mL) and dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (5:1, hexanes/EtOAc) to afford (4R,5S)-3-(2-(5-((tert-butyldi-
methylsilyloxy)methyl)-4-methoxy-2-(methoxymethoxy)phenyl)-
acetyl)-4-methyl-5-phenyloxazolidin-2-one (4) (1.88 g, 83%) as
a viscous oil. Rf¼0.34 (4:1 v/v hexanes/EtOAc). 1H NMR (CDCl3,
4.1.9. 2-(5-((tert-Butyldimethylsilyloxy)methyl)-4-methoxy-2-(me-
thoxymethoxy)phenyl)acetaldehyde (15). To a stirring solution of
2-(5-((tert-butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxy-
methoxy)phenyl)ethanol (14) (1.20 g, 3.37 mmol) in dry CH2Cl2
(40 mL) at 0 ꢁC was added Dess–Martin periodinane (2.97 g,
7.01 mmol) slowly. After 3 h, the mixture was taken up in water
(40 mL) and the aqueous layer was then extracted with Et2O
(3ꢂ50 mL). The combined organic layers were washed with brine
(100 mL) and dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. The residue was further purified
by chromatography on silica gel (10:1, hexanes/EtOAc) to give
2-(5-((tert-butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxy-
methoxy)phenyl)acetaldehyde (15) (1.14 g, 95%) as a colorless liquid.
Rf¼0.48 (3:1 v/v hexanes/EtOAc). 1H NMR (CDCl3, 300 MHz):
300 MHz):
d 7.26–7.40 (m, 5H, ArH), 7.20 (s, 1H, H6), 6.70 (s, 1H,
H3), 5.70 (d, 1H, J¼7.2 Hz, ArCH), 5.16 (d, 2H, J¼0.3 Hz, ArO-
CH2OCH3), 4.78 (dq, 1H, J¼7.2, 6.9 Hz, NCH), 4.68 (d, 2H, J¼0.6 Hz,
H1a), 4.24 (q, 2H, J¼17.4 Hz, H100), 3.80 (S, 3H, ArOMe), 3.46 (S, 3H,
ArOCH2OCH3), 0.93 [s, 9H, SiC(CH3)3]. 13C NMR (CDCl3, 75 MHz):
d 171.1, 156.2, 155.1, 153.2, 133.4, 129.3, 128.7, 128.6, 125.6, 122.9,
114.6, 97.9, 94.8, 78.9, 59.9, 55.9, 55.3, 54.9, 36.9, 26.0, 18.5, 14.5,
d
9.67 (t, 1H, J¼2.1 Hz, ArCH2CHO), 7.20 (s, 1H, H6), 6.71 (s, 1H, H3),
5.17 (s, 2H, ArOCH2OCH3), 4.68 (s, 2H, H1a), 3.81 (s, 3H, ArOMe), 3.61
(d, 2H, J¼2.1 Hz, ArCH2CHO), 3.46 (s, 3H, ArOCH2OCH3), 0.94
ꢀ5.3. IR (KBr, neat): 2954, 2930, 2897, 2855, 1782, 1706, 1618, 1508,
[s, 9H, SiC(CH3)3]. 13C NMR (CDCl3, 75 MHz):
d
200.5, 156.5, 155.2,
1463, 1362, 1249, 1217, 1197, 1119, 1089, 1069, 1023, 838, 769 cmꢀ1
.

3170
Z. Liu et al. / Tetrahedron 66 (2010) 3165–3172
LRMS (ESI): m/z 552 [MþNa]þ. HRMS (ESI): calcd for C28H39O7NSiNa
(17). To a solution of (R)-2-(5-((tert-butyldimethylsilyloxy)methyl)-
4-methoxy-2-(methoxymethoxy)phenyl)propanoic acid(3) (140 mg,
0.36 mmol) in dry CH2Cl2 (2.50 mL) were added EDCI (124 mg,
0.73 mmol), HOBt (60.0 mg, 0.45 mmol), Et3N (0.06 mL, 0.43 mmol),
20
[MþNa]þ: 552.2394, found: 552.2392. Optical rotation [
(c 1.0, CH3Cl).
a]
ꢀ10.4
D
4.1.12. (4R,5S)-3-((R)-2-(5-((tert-Butyldimethylsilyloxy)-methyl)-
4-methoxy-2-(methoxymethoxy)-phenyl)-propanoyl)-4-methyl-
and
N,O-dimethylhydroxylamine
hydrochloride
(70.0 mg,
0.72 mmol)andthemixturewasstirred atroom temperaturefor10 h.
The resulting mixture was diluted with saturated aqueous NH4Cl
solution (5.0 mL), and aqueous layer was extracted with EtOAc
(3ꢂ5.0 mL). The combined organic layers were washed with brine
(15 mL) and dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residuewaspurified bychromatography
on silica gel (6:1, hexanes/EtOAc) to give (R)-2-[5-(tert-butyldime-
thylsilanyloxymethyl)-4-methoxy-2-methoxymethoxyphenyl]-N-
methoxy-N-methylpropionamide (17) (125 mg, 81%) as a colorless
oil. Rf¼0.27 (3:1 v/v hexanes/EtOAc). 1H NMR (CDCl3, 300 MHz):
5-phenyloxazolidin-2-one (16). To
a
solution of (4R,5S)-3-
(2-(5-((tert-butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxy-
methoxy)phenyl)acetyl)-4-methyl-5-phenyloxazolidin-2-one (4)
(1.88 g, 3.55 mmol) in freshly distilled THF (20.0 mL) was added
NaHMDS (1.0 M in THF, 4.10 mL, 4.10 mmol) at ꢀ78 ꢁC under argon
and the mixture was stirred at ꢀ78 ꢁC for 1.2 h. A solution of MeI
(0.90 mL, 14.5 mmol) in THF (1 mL) was added to the reaction
mixture and the mixture was stirred for 4 h at ꢀ78 ꢁC and warmed
up to room temperature and further stirred for 2 h. The mixture
was then quenched with saturated aqueous NH4Cl (50 mL) and
extracted with EtOAc (3ꢂ50 mL). The combined organic layers
were washed with brine (100 mL) and dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (5:1,
hexanes/EtOAc) to give (4R,5S)-3-((R)-2-(5-((tert-butyldimethylsi-
lyloxy)methyl)-4-methoxy-2-(methoxymethoxy)phenyl)propanoyl)-
4-methyl-5-phenyloxazolidin-2-one (16) (1.42 g, 74%) as a viscous
oil. Rf¼0.46 (4:1 v/v hexanes/EtOAc). 1H NMR (CDCl3, 300 MHz):
d
7.29 (s, 1H, H6), 6.65 (s, 1H, H3), 5.20 (s, 2H, ArOCH2OCH3), 4.67 (s,
2H, H1a), 3.78 (s, 3H, ArOMe), 3.49 (s, 3H, NOCH3), 3.41 (s, 3H,
ArOCH2OCH3), 3.14 (s, 3H, NCH3),1.36 (d, 3H, J¼6.9 Hz, H400), 0.93 [s,
9H, SiC(CH3)3].13C NMR (CDCl3, 75 MHz):
d 155.7,153.8,126.8,123.2,
122.5, 97.7, 94.9, 60.8, 60.0, 55.9, 55.3, 35.1, 25.9,18.4,17.9, ꢀ5.3 cmꢀ1
.
IR (KBr, neat): 2957, 2930, 2856, 1728, 1670, 1508, 1465, 1289, 1120,
1078, 1004, 839, 778 cmꢀ1. LRMS (ESI): m/z 450 [MþNa]þ. HRMS
(ESI): calcd for C21H37O6NSiNa [MþNa]þ: 450.2288, found:
20
450.2285. Optical rotation [
a]
ꢀ50.2 (c 1.0, CH3Cl).
D
d
7.28–7.43 (m, 5H, ArH), 7.25 (s, 1H, H6), 6.68 (s, 1H, H3), 5.52 (d,
1H, J¼7.2 Hz, ArCH), 5.25 (dq, 1H, J¼6.9, 6.6 Hz, NCH), 5.22 (d, 2H,
J¼1.5 Hz, ArOCH2OCH3), 4.70 (q, 1H, J¼6.6 Hz, H100), 4.69 (d, 2H,
J¼0.9 Hz, H1a), 3.79 (s, 3H, ArOMe), 3.54 (s, 3H, ArOCH2OCH3), 1.45
(d, 3H, J¼6.9 Hz, H400), 0.95 [s, 9H, SiC(CH3)3]. 13C NMR (CDCl3,
4.1.15. (R)-3-(5-((tert-Butyldimethylsilyloxy)methyl)-4-methoxy-2-
(methoxymethoxy)phenyl)-butan-2-one (18). Under an atmosphere
of argon, a solution of (R)-2-(5-((tert-butyldimethylsilyloxy)methyl)-
4-methoxy-2-(methoxymethoxy)phenyl)-N-methoxy-N-methylpro-
panamide (17) (87.0 mg, 0.20 mmol) in anhydrous THF (3.0 mL) at
0 ꢁC was added dropwise MeMgCl (3 M in diethyl ether, 0.15 mL,
0.45 mmol). The reaction mixture was maintained at this tempera-
ture for 3 h, then quenched with saturated aqueous NH4Cl solution
(5 mL) and extracted with EtOAc (3ꢂ5 mL). The combined organic
layers were washed with brine (15 mL) and dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The resi-
due was purified by chromatography on silica gel (15:1, hexanes/
EtOAc) to afford (R)-3-(5-((tert-butyldimethylsilyloxy)methyl)-4-
methoxy-2-(methoxymethoxy)phenyl)butan-2-one (18) (78 mg,
100%) as a colorless oil. Rf¼0.62 (3:1 v/v hexanes/EtOAc). 1H NMR
75 MHz):
d 175.2, 155.8, 154.4, 152.3, 133.4, 128.9, 125.5, 125.4,
122.9, 121.3, 97.9, 95.1, 78.7, 59.9, 56.0, 55.4, 55.3, 37.7, 26.0, 18.4, 17.2,
14.5, ꢀ5.3. IR (KBr, neat): 2957, 2927, 2855, 1789, 1727, 1703, 1463,
1356, 1291, 1261, 1195, 1119, 1091, 836, 799 cmꢀ1. LRMS (ESI): m/z
566 [MþNa]þ. HRMS (ESI): calcd for C29H41O7NSiNa [MþNa]þ:
20
566.2550, found: 566.2552. Optical rotation [
a
]
ꢀ31.6 (c 1.0, CH3Cl).
D
4.1.13. (R)-2-(5-((tert-Butyldimethylsilyloxy)methyl)-4-methoxy-2-
(methoxymethoxy)phenyl)-propanoic acid (3). To a suspension of
(4R,5S)-3-((R)-2-(5-((tert-butyldimethylsilyloxy)methyl)-4-methoxy-
2-(methoxymethoxy)phenyl)propanoyl)-4-methyl-5-phenyloxazo-
lidin-2-one (16) (230 mg, 0.42 mmol) in THF/H2O (3.50 mL, v/v, 2:1)
at0 ꢁC wasaddedasolutionofLiOH$H2O(143 mg, 3.40 mmol)inH2O
(2.50 mL) dropwise, followed by a solution of 30% H2O2 (0.3 mL,
1.81 mmol). The mixture was allowed to warm up to room temper-
ature and further stirred for 4 h. After evaporation of most of the
solvent, the mixturewasextractedwithEt2O(3ꢂ10 mL). Theaqueous
layer was then acidified with 10% HCl to pH 2–3 and extracted with
EtOAc (3ꢂ10 mL). The combined organic layers were washed with
brine (30 mL) and dried over anhydrous MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified by flash
chromatography on silica gel (3:1, hexanes/EtOAc) to afford (R)-2-(5-
((tert-butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxymeth-
oxy)phenyl)propanoicacid(3)(115 mg, 71%)asacolorless oil. Rf¼0.16
(CDCl3, 300 MHz):
d 7.19 (s, 1H, H6), 6.68 (s, 1H, H3), 5.19 (s, 2H,
ArOCH2OCH3), 4.68 (d, 2H, J¼0.9 Hz, H1a), 3.94 (q,1H, J¼7.2 Hz, H100),
3.80 (s, 3H, ArOMe), 3.48 (s, 3H, ArOCH2OCH3), 1.56 (s, 3H, H300), 1.34
(d, 3H, J¼7.2 Hz, H400), 0.94 [s, 9H, SiC(CH3)3]. 13C NMR (CDCl3,
75 MHz): d 209.7,155.9,154.3,126.9,123.4,121.4, 97.7, 94.8, 59.9, 56.1,
55.3, 47.0, 27.9, 25.9, 18.4, 15.9, ꢀ5.3. IR (KBr, neat): 2954, 2931, 2897,
2856, 1715, 1615, 1505, 1464, 1290, 1256, 1216, 1152, 1119, 1087, 1011,
838, 777 cmꢀ1. LRMS (ESI): m/z 405 [MþNa]þ. HRMS (ESI): calcd for
C20H34O5SiNa [MþNa]þ: 405.2073, found: 405.2073. Optical rotation
20
[a]
ꢀ123.2 (c 1.0, CH3Cl).
D
4.1.16. (S)-tert-Butyl(2-methoxy-4-(methoxymethoxy)-5-(3-methyl-
but-3-en-2-yl)benzyloxy)dimethylsilane (19). To a suspension of
Ph3PCH3Br (180 mg, 0.56 mmol) in THF (3.0 mL) was added n-BuLi
(1.6 M inhexane, 0.34 mL, 0.55 mmol)dropwiseatroom temperature
and the mixture was stirred for 15 min. A solution of (R)-3-(5-((tert-
butyldimethylsilyloxy)methyl)-4-methoxy-2-(methoxymethoxy)ph-
enyl)butan-2-one (18) (95 mg, 0.25 mmol) in THF (0.5 mL) was
added dropwise to the reaction mixture. After stirring for addi-
tional 4 h, the reaction mixture was quenched with saturated
aqueous NH4Cl solution (5 mL) and extracted with hexane
(4ꢂ5 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (15:1, hex-
anes/EtOAc) to afford (S)-tert-butyl(2-methoxy-4-(methoxyme-
thoxy)-5-(3-methylbut-3-en-2-yl)benzyloxy)dimethylsilane (19)
(3:1 v/v hexanes/EtOAc).1H NMR (CDCl3, 300 MHz):
d 7.33 (s,1H, H6),
6.67 (s,1H, H3), 5.19 (s, 2H,ArOCH2OCH3), 4.68 (d, 2H, J¼1.5 Hz, H1a),
4.04 (q, 1H, J¼6.9 Hz, H100), 3.79 (s, 3H, ArOMe), 3.48 (s, 3H, ArO-
CH2OCH3),1.48 (d, 3H, J¼7.2 Hz, H400), 0.94 [s, 9H, SiC(CH3)3].13C NMR
(CDCl3, 75 MHz):
d 180.9, 155.9, 154.2, 126.5, 123.2, 120.7, 97.8, 94.9,
59.9, 55.9, 55.3, 38.7, 25.9,18.4,16.9, ꢀ5.3. IR (KBr, neat): 3448, 2954,
2931, 2856, 1707, 1618, 1508, 1459, 1292, 1254, 1152, 1119, 1086,1006,
838, 776 cmꢀ1. LRMS (ESI): m/z 407 [MþNa]þ. HRMS (ESI): calcd for
C19H32O6SiNa [MþNa]þ: 407.1866, found: 407.1867. Optical rotation
20
[a]
ꢀ15.0 (c 1.0, CH3Cl).
D
4.1.14. (R)-2-(5-((tert-Butyldimethylsilyloxy)methyl)-4-methoxy-2-
(methoxymethoxy)phenyl)-N-methoxy-N-methylpropanamide

Z. Liu et al. / Tetrahedron 66 (2010) 3165–3172
3171
(76.5 mg, 81%) as a colorless oil. Rf¼0.66 (5:1 v/v hexanes/EtOAc).
1H NMR (CDCl3, 300 MHz):
7.25 (s, 1H, H6), 6.63 (s, 1H, H3), 5.18
(28.0 mg, 0.51 mmol) in H2O (0.5 mL). The reaction mixture was
stirred at room temperature for 48 h and the resulting mixture was
diluted with H2O (5 mL) and extracted with EtOAc (3ꢂ5 mL). The
combined organic layers were washed with brine (15 mL) and 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 (E)-3-(2-methoxy-4-
(methoxymethoxy)-5-((S)-3-methylbut-3-en-2-yl)phenyl)-1-(4-(tetra-
hydro-2H-pyran-2-yloxy)phenyl)prop-2-en-1-one (22) (9.50 mg,
68%) as a yellow power. Mp: 73–77 ꢁC. Rf¼0.45 (3:1 v/v hexanes/
d
(d, 2H, J¼1.2 Hz, ArOCH2OCH3), 4.85 (s, 2H, H500), 4.69 (d, 2H,
J¼3.6 Hz, H1a), 4.28–4.29 (m, 1H, H100), 3.79 (s, 3H, ArOMe), 3.49 (s,
3H, ArOCH2OCH3), 1.63 (s, 3H, H300), 1.29 (d, 3H, J¼7.2 Hz, H400), 0.91
[s, 9H, SiC(CH3)3]. 13C NMR (CDCl3, 75 MHz):
d 154.9, 154.3, 149.3,
125.9, 125.7, 123.0, 109.4, 97.9, 95.1, 60.0, 55.9, 55.3, 37.9, 25.9, 22.2,
19.6, ꢀ5.3. IR (KBr, neat): 3084, 2956, 2929, 2856, 1615, 1504, 1464,
1291, 1254, 1151, 1117, 1083, 1061, 1025, 1011, 838, 776 cmꢀ1. LRMS
(ESI): m/z 381 [MþH]þ. HRMS (ESI): calcd for C21H36O4SiNa
20
[MþNa]þ: 403.2281, found: 403.2282. Optical rotation [
(c 1.0, CH3Cl).
a
]
ꢀ40.7
EtOAc). 1H NMR (CDCl3, 300 MHz):
d
8.01 (dd, 3H, J¼8.7 Hz,
D
J¼15.9 Hz, H20, H60, H1a), 7.53 (d, 1H, J¼15.9 Hz, H1
b), 7.38 (s, 1H,
H6), 7.12 (d, 2H, J¼9.0 Hz, H3050), 6.71 (s, 1H, H3), 5.53 (t, 1H,
J¼3 Hz, THP), 5.25 (s, 2H, ArOCH2OCH3), 4.88 (d, 2H, J¼8.7 Hz,
H500), 3.90 (s, 3H, ArOMe), 3.57–3.88 (m, 3H, THP H100), 3.50 (s, 3H,
ArOCH2OCH3), 1.68–1.92 (m, 6H, THP), 1.57 (S, 3H, H300), 1.33 (d, 3H,
4.1.17. (S)-2-Methoxy-4-(methoxymethoxy)-5-(3-methylbut-3-en-2-
yl)phenylmethanol (20). A solution of (S)-tert-butyl(2-methoxy-4-
(methoxymethoxy)-5-(3-methylbut-3-en-2-yl)benzyloxy)dimethyl-
silane (19) (80.0 mg, 0.21 mmol) in THF (3.50 mL) was treated with
tetra-n-butylammonium fluoride (165 mg, 0.63 mmol) at 0 ꢁC. After
stirring for 3 h at 0 ꢁC, the resulting mixture was diluted with satu-
rated aqueous NH4Cl solution (5 mL), and extracted with EtOAc
(3ꢂ5 mL). The combined organic layers were washed with brine
(15 mL) and dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was subjected to flash chro-
matography on silica gel (5:1, hexanes/EtOAc) to give (S)-2-methoxy-
4-(methoxymethoxy)-5-(3-methylbut-3-en-2-yl)phenylmethanol
(20) (53.1 mg, 95%) as a colorless oil. Rf¼0.21 (3:1 v/v hexanes/
J¼7.2 Hz, H400). 13C NMR (CDCl3, 75 MHz):
d 189.9, 160.5, 158.5,
157.6, 148.8, 140.1, 132.3, 130.5, 128.8, 126.5, 120.7, 117.5, 115.9,
115.7, 109.9, 97.9, 96.0, 94.3, 62.0, 56.1, 55.7, 37.9, 30.1, 25.1, 22.2,
19.5, 18.5. IR (KBr, neat): 2959, 2917, 2849, 1769, 1599, 1501, 1464,
1451, 1281, 1219, 1192, 1164, 1119, 1006 cmꢀ1. LRMS (ESI): m/z 489
[MþNa]þ. HRMS (ESI): calcd for C28H34O6Na [MþNa]þ: 489.2253,
20
found: 489.2259. Optical rotation [
a]
ꢀ34.9 (c 1.0, CH3Cl).
D
4.1.20. (S)-Licochalcone E (1). To a solution of (E)-3-(2-methoxy-4-
(methoxymethoxy)-5-((S)-3-methylbut-3-en-2-yl)-phenyl)-1-(4-
(tetrahydro-2H-pyran-2-yloxy)phenyl)prop-2-en-1-one (22) (5.00 mg,
0.01 mmol) in dry MeOH (1.5 mL) was added 10 drops of concen-
trated HCl. The reaction mixture was stirred at room temperature
for 5 h, then quenched with saturated aqueous NH4Cl solution
(5 mL) and extracted with EtOAc (3ꢂ5 mL). The combined organic
layers were washed with brine (15 mL) and dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (3:1, hexanes/
EtOAc) to afford (S)-licochalcone E (1) (2.90 mg, 67%) as a yellow
power. Mp: 76–80 ꢁC. Rf¼0.28 (1:1 v/v hexanes/EtOAc). 1H NMR
EtOAc).1H NMR (CDCl3, 300 MHz):
d 7.00 (s,1H, H6), 6.69 (s,1H, H3),
5.19 (d, 2H, J¼0.6 Hz, ArOCH2OCH3), 4.84 (d,1H, J¼4.2 Hz, H500), 4.60
(d, 2H, J¼4.2 Hz, H1a), 3.85 (s, 3H, ArOMe), 3.49 (s, 3H, ArO-
CH2OCH3), 3.76 (q, 1H, J¼7.2 Hz H100), 1.63 (s, 3H, H300), 1.28 (d, 3H,
J¼6.9 Hz, H400). 13C NMR (CDCl3, 75 MHz):
d 156.6,155.2,149.1,127.9,
125.9,122.3,109.5, 98.3, 94.8, 62.0, 55.9, 55.4, 37.8, 22.3,19.6. IR (KBr,
neat): 3512, 2961, 2929, 2873,1727,1504,1465,1289,1193,1151,1116,
1079, 1060, 1023 cmꢀ1. LRMS (ESI): m/z 289 [MþNa]þ. HRMS (ESI):
calcd for C15H22O4Na [MþNa]þ: 289.1416, found: 289.1416. Optical
20
rotation [
a]
ꢀ84.4 (c 1.0, CH3Cl).
D
(CDCl3, 300 MHz):
d
8.01 (d, 1H, J¼15.6 Hz, H-
b
), 7.97 (d, 2H,
4.1.18. (S)-2-Methoxy-4-(methoxymethoxy)-5-(3-methylbut-3-en-2-
yl)benzaldehyde (2). To a stirring solution of (S)-(2-methoxy-4-
(methoxymethoxy)-5-(3-methylbut-3-en-2-yl)phenylmethanol (20)
(18.0 mg, 0.07 mmol) in dry CH2Cl2 (1.5 mL) at 0 ꢁC was added Dess–
Martin periodinane (80.0 mg, 0.20 mmol) slowly. After 3 h, the
mixture was taken up in water (5.0 mL) and the aqueous layer was
extracted with Et2O (4ꢂ5 mL). The combined organic layers were
washed with brine (20 mL) and dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The residue was purified by chromato-
graphy on silica gel (8:1, hexanes/EtOAc) to give (S)-2-methoxy-4-
J¼9.0 Hz, H-20,60), 7.62 (d, 1H, J¼15.6 Hz, H-
a), 7.52 (s, 1H, H6), 6.93
(d, 2H, J¼9.0 Hz, H-3050), 6.61 (s, 1H, H3), 4.89 (d, 2H, J¼7.2 Hz, H-
500), 3.88 (s, 3H, ArOMe), 3.79 (m, 1H, H-100), 1.67 (s, 3H, H-300), 1.34
(d, 3H, J¼7.2 Hz, H-400). 13C NMR (CDCl3, 75 MHz):
d 188.5, 162.4,
159.6,159.3,149.9,139.9,131.8,131.6,129.4,125.0,119.6,116.6,110.2,
99.9, 56.0, 38.7, 22.4, 19.7. IR (KBr, neat): 3440, 1716, 1645, 1603,
1509, 1448, 1288, 1261, 1216, 1168, 1121, 1036 cmꢀ1. LRMS (ESI): m/z
339 [MþH]þ. HRMS (ESI): calcd for C21H23O4 MþH]þ: 339.1596,
20
found: 339.1593. Optical rotation [
a
]
ꢀ11.4 (c 1.0, acetone).14
D
(methoxymethoxy)-5-(3-methylbut-3-en-2-yl)benzaldehyde
(2)
Acknowledgements
(15.6 mg, 92%) as a colorless liquid. Rf¼0.47 (3:1 hexanes/EtOAc). 1H
NMR (CDCl3, 300 MHz): d 10.31 (s,1H, ArCHO), 7.65 (s,1H, H6), 6.69 (s,
This work was supported by National Research Foundation of
Korea Grant funded by the Korean Government 2009-0075257. We
thank the Korea Basic Science Institute (KBSI), Gwangju Center, for
performing the NMR and HRMS experiments.
1H, H3), 5.28 (d, 2H, J¼2.7 Hz, ArOCH2OCH3), 4.84 (d, 2H, J¼9.9 Hz,
H500), 3.91 (s, 3H, ArOMe), 3.74 (q, 1H, J¼7.5 Hz, H100), 3.49 (s, 3H,
ArOCH2OCH3), 1.62 (s, 3H, H300), 1.31 (d, 3H, J¼7.2 Hz, H400). 13C NMR
(CDCl3, 75 MHz): d 188.6, 162.2, 161.1, 148.3, 127.8, 126.9, 119.0, 110.2,
97.2, 94.1, 56.3, 55.7, 38.1, 21.9, 19.2. IR (KBr, neat): 2964, 2927, 2854,
1676,1606,1493,1459,1450,1270,1152,1119,1001 cmꢀ1. LRMS (ESI):
Supplementary data
m/z 265 [MþH]þ. HRMS (ESI): calcd for C15H20O4Na [MþNa]þ:
20
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.02.089.
287.1259, found: 287.1265. Optical rotation [
a
]
ꢀ57.4 (c 1.0, CH3Cl).
D
4.1.19. (E)-3-(2-Methoxy-4-(methoxymethoxy)-5-((S)-3-methylbut-
3-en-2-yl)phenyl)-1-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)prop-
References and notes
2-en-1-one (22). To
methoxy)-5-(3-methylbut-3-en-2-yl)-benzaldehyde (2) (8.00 mg,
0.03 mmol) and 1-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-
a solution of (S)-2-methoxy-4-(methoxy-
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ethanone (21) (14.0 mg, 0.06 mmol) in EtOH and H2O (1.2 mL, v/v
2:1) at room temperature was added dropwise a solution of KOH
3. Yoon, G.; Lee, W.; Kim, S.; Cheon, S. H. Bioorg. Med. Chem. Lett. 2009, 19, 5155.

3172
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(b) Mohapatra, D. K.; Rahaman, H.; Pal, R.; Gurjar, M. K. Synlett 2008, 1801.
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13. Enantiomeric excess of the synthetic (S)-(ꢀ)-licochalcone E (1) can be readily
determined by HPLC on a Chiracel OJ column detecting at 254 nm (0.1% formic
acid in hexane/0.1% formic acid in isopropanol¼90:10; (S) enantiomer 41.9 min;
(R) enantiomer 44.1 min) and was found to be 96% ee by integration.
14. Spectral data of isolated (S)-(ꢀ)-licochalcone E. Amorphous powder; [ D ꢀ11.9
a
]
(c 0.1, MeOH); 1H NMR (acetone-d6, 300 MHz)
d
1.33 (3H, d, J¼7.2 Hz, H-400), 1.
67 (3H, s, H-500), 3.82 (3H, s, OMe), 3.87 (1H, m, H-100), 4.87 (1H, br s, H-300a), 4.
90 (1H, br s, H-300b), 6.59 (1H, s, H-3), 6.89 (2H, d, J¼8.7 Hz, H-30, 50), 7.43 (1H, s,
H-6), 7.57 (1H, d, J¼15.5 Hz, H-
a
), 7.93 (2H, d, J¼8.7 Hz, H-20,60), 8.00 (1H, d,
J¼15.5 Hz, H-
b d
). 13C NMR (acetone-d6, 125 MHz) : 187.5 (C]O), 162.9 (C-40),
159.7 (C-4), 158.8 (C-2), 149.2 (C-200), 139.0 (C-
128.3 (C-6), 124.3 (C-5), 118.1 (C-
), 115.5 (C-30, C-50), 114.9 (C-1), 109.1 (C-300),
99.1 (C-3), 55.0 (OMe), 37.7 (C-100), 21.5 (C-500), 18.8 (C-400).
b
), 130.6 (C-20, C-60), 130.0 (C-10),
a