Synthesis and Absolute Configuration of Two Natural Phenolic Homobenzyl Esters

Article abstract of DOI:10.1002/cjoc.201500315

Two recently identified natural phenolic homobenzyl esters, isolated from Phragmipedium calurum (an orchid) and Eupatorium fortunei TURCZ (a perennial herb in the Asteraceae family), respectively, were synthesized in enantiopure forms. By comparison of the optical rotations for the synthetic and the natural samples, the absolute configurations for the natural products were reliably assigned. The synthesis also enables establishment of the absolute configuration of a closely related natural homobenzyl alcohol and provided for the first time complete physical and spectroscopic data for two other natural homobenzyl esters. Two recently isolated natural phenolic homobenzyl esters were synthesized in enantiopure forms. The absolute configurations for these natural products were thus reliably assigned. En route to the total synthesis of the first target, complete physical and spectroscopic data for two other related natural products were made available for the first time. Configuration assignment of a third natural product was also achieved.

Full text of DOI:10.1002/cjoc.201500315

FULL PAPER
DOI: 10.1002/cjoc.201500315
Synthesis and Absolute Configuration of Two Natural
Phenolic Homobenzyl Esters
Murong Xu,a,b Shijun Zhu,b Zejun Xu,b Yikang Wu*,b and Po Gao*,a
a School of Chemistry and Material Sciences, Heilongjiang University, Harbin, Heilongjiang 150080, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Two recently identified natural phenolic homobenzyl esters, isolated from Phragmipedium calurum (an orchid)
and Eupatorium fortunei TURCZ (a perennial herb in the Asteraceae family), respectively, were synthesized in en-
antiopure forms. By comparison of the optical rotations for the synthetic and the natural samples, the absolute con-
figurations for the natural products were reliably assigned. The synthesis also enables establishment of the absolute
configuration of a closely related natural homobenzyl alcohol and provided for the first time complete physical and
spectroscopic data for two other natural homobenzyl esters.
Keywords esters, alkylation, natural products, stereochemistry, phenols
Introduction
configurations remain unknown. To confirm the as-
signed structures and to acquire the still missing infor-
mation about the stereochemistry of these natural prod-
ucts, we performed the enantioselective syntheses de-
scribed below.
The subjects of this synthetic study, compounds 1
and 2 (Figure 1), were identified and characterized very
recently by Guo et al.[1] and Starks et al.,[2] respectively.
Compound 1 was isolated[1] from Eupatorium fortunei
TURCZ, a perennial herb in the family Asteraceae
widely distributed in China and has been used as a Chi-
nese folk medicine for the treatment of dissipating
dampness, diaphoresis relieving superficies, and reliev-
ing summer-heat. Compound 2 was isolated[2] from the
orchid Phragmipedium calurum, which showed anti-
tumor activity (non-small lung adenocarcinoma A549)
in the preliminary screening.
Results and Discussion
The synthesis of 1 is shown in Scheme 1. Taking in-
to consideration several factors including the commer-
cial availability, experimental feasibility and overall cost,
we chose the strategy developed by Snieckus[3] to gain
the carbogenic framework of the target 1. Thus, using
the inexpensive 2,5-dimethylphenol (6) as the starting
material, acylation[4] with diethylcarbamyl chloride (7)
gave 8. Selective deprotonation of the methyl group in
vicinity of the amido group with lithium diisopropyla-
mide (LDA) induced an intramolecular migration of the
carbonyl group as reported by Snieckus, with addition
of t-butyl-dimethylsilyl chloride (TBSCl) to prevent the
reverse reaction caused by the resulting phenoxide. It
was noticed in this work that use of a 5-fold excess of
LDA could effectively raise the overall yield of 10,
probably due to effective suppression of the quenching
of the intermediate carbanion by the moisture introduced
with the addition of hygroscopic TBSCl.
O
OH
O
O
O
OH
HO
1
2
O
O
OH
OH
O
O
O
OH
3
4
5
The undesired amido functionality in 9 was then
converted into lactone 10[5] by treatment with trifluro-
acetic acid (TFA) as reported[3] in the literature. The lac-
tone ring was subsequently cleaved via hydrolysis, with
the newly freed phenol OH protected with methoxy-
Figure 1 The planar structures for 1, 2, and three other natural
products studied in this work (cf. text).
While the planar structures for 1 and 2 were assigned
on the basis of spectroscopic analyses, their absolute
*
E-mail: yikangwu@sioc.ac.cn
Received March 24, 2015; accepted April 17, 2015; published online June 2, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500315 or from the author.
Chin. J. Chem. 2015, 33, 729—738
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Xu et al.
FULL PAPER
methyl chloride (MOMCl). The resulting mixture of 12
and its MOM ester was then exposed to refluxing
NaOH/EtOH to afford pure 12 after careful neutraliza-
tion. The free carboxylic acid group was connected to
the known[6] chiral auxiliary oxazolidinone 13 under the
EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride)/DMAP (4-dimethylaminopyridine) con-
ditions. An Evans[7] asymmetric methylation was then
performed using NaN(SiMe3)2 (NaHMDS) as the base
and MeI as the methylating agent, which delivered the
desired enantiomer 15 in 88% isolated yield. It is note-
worthy that use of LiHMDS under the otherwise the
same conditions led to 15 in only 20%－30%.
conditions. However, the desired 19 was obtained in
only 20% yield; the undesired (E) isomer turned out to
be the main product (80%). Addition of HOBt (1-hy-
droxybenzotriazole) or using DCC (dicyclohexylcarbo-
diimide)/DMAP conditions with different addition se-
quences and different amounts of DMAP at different
temperatures led to essentially the same results. The
inversion of the C－C double bond appeared uncontrol-
lable. Fortunately, finally the Yamaguchi conditions
worked reasonably well, giving ester 19 in 64% isolated
yield.
It should be noted that the double bond inversion
problem not only occurred in the acylation but also at
the removal of the MOM group. For instance, under the
NaI/TMSCl[9] conditions, the resulting 1 was heavily
contaminated by the inseparable (E) isomer. However, if
the cleavage of the MOM protecting group was carried
out under the TFA/THF conditions, the isomerization of
the double bond could be efficiently suppressed and
pure (R)-(Z)-1 could be acquired in 72% isolated yield.
Scheme 1 Synthesis of (R)-1
OH
CONEt2
NEt2
O
DMAP
toluene
OTBS
1) LDA/THF
O
−78 °C
6
99%
2) TBSCl
O
The synthetic (R)-(Z)-1 showed the 1H NMR and 13
C
9
8
Me2N
Cl
NMR in full consistency with those reported for the
natural 1. The optical rotations were also consistent with
each other. Therefore, the absolute configuration for the
natural 1 must be (R).
94%
from 8
7
1) EtOH/H2SO4
TFA/toluene
2) NaH/MOMCl
THF/reflux
3) NaOH/EtOH
CO2H
OH
O
O
CO2H
NaOH
EtOH
OMOM
11
59% from
O
89%
Scheme 2 Conversion of 16 into (R)-3 and (R)-4
AcOH/EDCI
12
EDCI
DMAP
CH2Cl2
11
OMOM
OMOM
O
10
OH
HN
Bn
O
DMAP/CH2Cl2
93%
O
O
Bn
62%
O
13
20
O
N
O
16
1) NaHMDS
THF/−78 °C
NaI/TMSCl
CH2Cl2-MeCN
O
O
91%
MeOH
HCl
91%
OMOM
3'
−
°
N
O
2) CH3I/ 40 C
88% from 14
OH
O
[α]D26 −2.8 (c 0.5, CHCl3)
Bn
OMOM
OH
14
15
O
CO2H
OH
NaBH4/THF-H2O 91%
(R)-4
[α]D28 −7.0 (c 0.85, CHCl3)
92%
(R)-3
ee
17
COCl
Cl
(R)
OH
Cl
Because of their closely related structures, three
other natural products, i.e., 3, 4 and 5, were also synthe-
sized. To this end, acylation of 16 with acetic acid in-
stead of angelic acid (Scheme 2) gave acetate 20 in 93%
yield, which on removal of the MOM protecting group
in 20 under the NaI/TMSCl[9] conditions afforded the
end product (R)-4.
Et3N/toluene
16
64% from
OMOM
Cl
16
18
O
O
O
(R)
MOMO
O
TFA/CH2Cl2
72%
(Z)
HO
Alternatively, in an effort to gain access to (R)-3,[10]
19
alcohol 16 was subjected to the often employed TFA/
[11]
Synth. [α]D28 −17.2 (c 0.55, MeOH)
Nat. [α]D28 −11.6 (c 0.55, MeOH)
CH2Cl2
conditions. However, instead of the well-
(R)-1
expected (R)-3, the totally unexpected 3' was formed.
Fortunately, the desired transformation eventually could
be achieved smoothly under the aq. HCl/MeOH[12] con-
ditions, providing diol (R)-3 in 91% yield.
It should be noted that neither of the originally re-
ported 3[13a,13b] and 4[13b] was fully characterized because
of the small quantities of the samples. It is therefore
The chiral auxiliary was cleaved under the NaBH4/
THF-H2O[8] conditions. The alcohol 16, determined to
be of 99% ee by chiral HPLC analysis, was acylated
with angelic acid (17) to afford the desired ester 19. The
transformation first attempted under the EDCI/DMAP
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Chin. J. Chem. 2015, 33, 729—738

Synthesis and Absolute Configuration of Two Natural Phenolic Homobenzyl Esters
impossible to establish the absolute configurations for
those compounds. However, the complete sets of physi-
cal and spectroscopic data acquired in this work may
provide reliable references of comparison for future
studies.
which on treatment with p-TsCl in the presence of
n-Bu2SnO furnished tosylate 28.
The aromatic moiety of the target was then installed
via the intermediate epoxide derived from 28 with the
Grignard reagent derived in situ from the commercially
available bromide 29. The resulting alcohol 30 was ac-
etylated with Ac2O to furnish acetate 31, which on
treatment[15] with BBr3 delivered the end product (R)-2.
Apart from the first report, there have been several
other ones on the isolation of 3 (or its antipode) from
other natural sources. One[13c] of them came with com-
1
plete H and 13C NMR (fully consistent with those for
Scheme 4 Synthesis of (R)-2
the synthetic 3, cf. the Supporting Information) and op-
tical rotation data. By comparison of the signs for the
natural and synthetic 3, the absolute configuration of the
natural 3 can be assigned as (S).
H
OH
(R)
.
O
CuBr SMe2
OBn
THF
(R)
25
Like compound 4, acetate 5 was also isolated[13b] in
very small quantity. Only the GC-MS data were col-
lected. Therefore, a synthesis of 5, which would provide
OBn
27
99%
MgBr
1) H2/Pd-C/EtOAc
90%
2) p-TsCl/Et3N/n-Bu2SnO
1
26
the so far missing H NMR and 13C NMR data, ap-
1) NaH/THF/rt
peared to be warranted.
OH
(R)
(R)
2) Mg/29/THF
MeO
Scheme 3 Elaboration of 11 into (R)-5
80% from 28
OH
OTs
30
1) EtOH/H2SO4
2) Cs2CO3/DMF
CO2H
O
OMe
O
CO2H
OH
28
Br
HN
Bn
O
-BuBr/KI
i
80 °C/72 h
3) NaOH/EtOH
71% f rom 11
13
MeO
OMe
11
21
29
CH2Cl2
72%
EDCI
DMAP
O
O
1) NaHMDS
O
O
(R)
(R)
Bn
THF/−78 °C
2) CH3I/−40°C
88% f rom 22
O
MeO
O
BBr3/CH2Cl2
N
O
HO
O
N
O
O
rt/12 h
99%
Bn
31
O
(R)-2
OMe
OH
O
nat. [α]D25 −223 (c 0.10, CHCl3); synth. [α]D26 −4.14 (c 0.80, CHCl3)
23
22
26
[α]D −20.9 (c 0.3, CHCl3)
NaBH4/THF-H2O
The spectroscopic data for the synthetic (R)-2 were
in full consistence with those reported for the natural 2,
while the optical rotation[16] had the same sign as that
for the natural 2. Therefore, the natural 2 must be an (R)
isomer.
91%
O
O
OH
O
Ac2O/DMAP
Et3N/CH2Cl2
O
93%
24
(R)-5
Conclusions
The synthesis of compound 5 is outlined in Scheme
3. Starting with the acid 11 via esterification, alkylation
and hydrolysis afforded acid 21. Connection of this acid
with the chiral auxiliary 13 under the same conditions
for conversion of 12 into 14 delivered 22 in 72% yield.
The stereogenic center was then installed by the Evans
asymmetric methylation. The resulting 23 was exposed
to the NaBH4/THF/H2O conditions to remove the chiral
auxiliary, affording alcohol 24 in 91% yield. Finally, an
acetylation of the homobenzyl alcohol furnished (R)-5.
The synthesis of target 2 was first attempted as
shown in Scheme 4. The commercially available (R)-25
was treated with n-hexyl Grignard reagent in the pres-
ence of CuBr•SMe2 leading to 27 in 99% yield.[14] Re-
moval of the benzyl protecting group by catalytic hy-
drogenolysis over Pd－C afforded the intermediate diol,
In summary, the absolute configurations of two re-
cently identified natural homobenzyl esters (1 and 2)
along with a natural homobenzyl alcohol (3) were estab-
lished through enantioselective synthesis. The adequate
amount of synthetic (R)-2 allowed for acquisition of a
more reliable optical rotation data. En route to the target
molecules, complete physical and spectroscopic data for
another two closely related natural products (4 and 5),
long-known yet still under-characterized, were also
made available for the first time.
Experimental
The NMR spectra were recorded on either an
Agilent 500/54 NMR spectrometer (operating at 500
1
MHz for H) or a Bruker Avance 400 (operating at 400
Chin. J. Chem. 2015, 33, 729—738
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Xu et al.
FULL PAPER
MHz for 1H) NMR spectrometer. IR spectra were meas-
ured on a Nicolet 380 Infrared spectrophotometer.
ESI-MS data were acquired on a Shimadzu LCMS-
2010EV mass spectrometer. HRMS data were obtained
with a Bruker APEXIII 7.0 Tesla FT-MS spectrometer.
Optical rotations were measured on a Jasco P-1030 po-
larimeter. Melting points were uncorrected (measured on
a hot stage melting point apparatus equipped with a mi-
croscope). CH2Cl2 was dried with activated 4 Å MS
(molecular sieves). Dry THF was obtained by distilla-
tion over Ph2CO/Na under argon prior to use. All
chemicals were reagent grade and used as purchased.
Column chromatography was performed on silica gel
(300－400 mesh) under slightly positive pressure. PE＝
petroleum ether (b.p. 60－90 ℃).
CF3CO2H (2.1 mL). The mixture was refluxed for 1.5 h.
The solvent was removed by rotary evaporation. The
residue was purified by column chromatography (6∶1,
PE/EtOAc) on silica gel to give the known[5] lactone 10
as a red-brown solid (maybe recrystalized to remove the
color but not really necessary here, 1.255 g, 8.47 mmol,
94%): m.p. 78－80 ℃ (lit.[3] m.p. 73－74.5 ℃; lit.[5a]
1
m.p. 68－70 ℃; lit.[5b] m.p. 73 ℃); H NMR (500
MHz, CDCl3) δ: 7.14 (d, J＝7.6 Hz, 1H), 6.93 (d, J＝
7.7 Hz, 1H), 6.90 (s, 1H), 3.67 (s, 2H), 2.37 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ: 174.7, 154.9, 139.4, 124.8,
124.3, 120.0, 111.4, 32.9, 21.7; FT-IR (film) v: 2924,
1804, 1630, 1595, 1501, 1427, 1391, 1326, 1280, 1259,
1223, 1200, 1151, 1128, 1056, 946, 860, 835, 807, 760,
683, 668, 590, 567, 547, 427 cm–1. EI-MS m/z (%): 148
(90), 51 (11), 65 (14), 91 (100), 92 (67), 120 (57), 121
(18), 149 (11).
Acylation of 6 with 7 to afford 8
A solution of phenol 6 (4.00 g, 32.74 mmol), DMAP
(8.00 g, 65.48 mmol) and diethylcarbamoyl chloride 7
(8.3 mL, 65.48 mmol) in dry toluene (164 mL) was
stirred at refluxing temperature for 7 h (TLC showed
completion of the reaction). The heating bath was re-
moved. The mixture was partitioned between water and
EtOAc. The organic layer was washed with water and
brine before being dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and column
chromatography (5∶1, PE∶EtOAc) on silica gel gave
8 as a colorless oil (7.20 g, 32.56 mmol, 99%). 1H NMR
(500 MHz, CDCl3) δ: 7.07 (d, J＝7.6 Hz, 1H), 6.90 (d,
J＝7.7 Hz, 1H), 6.88 (s, 1H), 3.46－3.38 (m, 4H), 2.30
(s, 3H), 2.17 (s, 3H), 1.26 (t, J＝6.3 Hz, 3H), 1.20 (t,
J＝6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 154.2,
149.9, 136.7, 130.7, 127.3, 126.2, 122.9, 42.3, 42.0,
21.0, 16.0, 14.4, 13.6; FT-IR (film) v: 2974, 2931, 1717,
1509, 1473, 1457, 1421, 1405, 1379, 1274, 1246, 1223,
1158, 1117, 1097, 996, 962, 806, 757 cm–1. ESI-MS m/z:
222.5 ([M＋H]+). ESI-HRMS calcd for C13H20NO2 ([M
＋H]＋): 222.1483, found 222.1489.
Hydrolysis of lactone 10 to afford acid 11
A solution of 10 (200 mg, 1.35 mmol) in EtOH (6.8
mL) and aq. NaOH (1 N, 1.4 mL) was stirred at ambient
temperature for 3 h. Water was added, followed by
EtOAc. The phases were separated. The aqueous layer
was acidified to pH 1 with HCl (1 N) and extracted with
EtOAc. The organic layer was concentrated on a rotary
evaporator to dryness to give a yellowish solid (200 mg,
1
1.2 mmol, 89%): m.p. 121－123 ℃; H NMR (500
MHz, CDCl3) δ: 7.00 (d, J＝7.5 Hz, 1H), 6.71 (d, J＝
10.7 Hz, 1H), 6.69 (s, 1H), 3.63 (s, 2H), 2.27 (s, 3H);
13C NMR (125 MHz, CDCl3) δ: 178.8, 154.3, 139.7,
131.1, 122.1, 117.8, 117.2, 36.7, 21.2; FT-IR (KBr) v:
3312, 2922, 1698, 1626, 1588, 1525, 1432, 1336, 1238,
1197, 1179, 1155, 1115, 957, 915, 866, 798, 726, 677,
459 cm–1. ESI-MS (negative) m/z: 165.0 ([M–H]–).
ESI-HRMS (negative) calcd for C9H9O3 ([M–H]–):
165.0554, found 165.0557.
Conversion of 11 into 12
Concentrated H2SO4 (4 drops from a pipette) was
added to a solution of 11 (190 mg, 1.14 mmol) in EtOH
(99.5%, 2 mL). The mixture was refluxed for 4 h. After
being cooled down to ambient temperature, the mixture
was diluted with water and extracted with EtOAc. The
organic layer was washed with water and brine before
being dried over anhydrous Na2SO4. Removal of the
solvent on a rotary evaporator left a yellowish oil (205.2
mg, 1.06 mmol, 93% from 11), which was dissolved in
dry THF (1.8 mL) and added to a mixture of NaH (60%,
in mineral oil, 48 mg, 1.2 mmol) in dry THF (2 mL).
The resulting mixture was stirred at ambient temperature
for 15 min. With cooling (0 ℃ bath), MOMCl (90 μL,
2.08 mmol) was added. The mixture was then stirred at
0 ℃ for 5 min and then at ambient temperature for 30
min. Aq. NaOH (2 N) was added to quench the reaction.
The mixture was extracted with EtOAc. The organic
layer was dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatog-
raphy (4∶1, PE/EtOAc) on silica gel afforded a pale
Conversion of 8 into 10[3]
n-BuLi (2.5 mol/L, in hexanes, 18.1 mL, 45.2 mmol)
was added to a solution of i-Pr2NH (8.0 mL, 45.2 mmol)
in dry THF (30 mL) stirred at –20 ℃ under N2 (bal-
loon). After completion of the addition, the mixture was
stirred for 30 min before the bath temperature was low-
ered to –78 ℃. At that temperature stirring was contin-
ued for another 30 min. A solution of 8 (2.00 g, 9.04
mmol) in dry THF (37 mL) was introduced very slowly
so that the inner temperature did not exceed –72 ℃.
After completion of the addition, the mixture was stirred
at –78 ℃ for 1 h. TBSCl (1.63 g, 10.8 mmol) was then
added. The mixture was stirred at –20 ℃ for 30 min
and at 0 ℃ for 1 h. Aq. saturated NH4Cl was added to
quench the reaction. The mixture was extracted with
EtOAc. The organic layer was washed with water and
brine before being dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation left an oily
residue, which was dissolved in toluene (23 mL) and
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Chin. J. Chem. 2015, 33, 729—738

Synthesis and Absolute Configuration of Two Natural Phenolic Homobenzyl Esters
yellow oil (the intermediate ethyl ester, 179 mg, 0.75
mmol, 66% from 11), which was dissolved in EtOH (2
mL) and aq. NaOH (2 N, 0.4 mL). The mixture was
stirred at reflux temperature for 1.5 h. The mixture was
allowed to cool down to ambient temperature before
being diluted with water and washed with EtOAc. The
aqueous layer was then acidified with HCl (1 N) to pH 1
and extracted with EtOAc. The organic layer was con-
centrated to dryness on a rotary evaporator to give acid
12 as a white solid (42.8 mg, 0.68 mmol, 60% overall
from 11): m.p. 41－43 ℃; 1H NMR (500 MHz, CDCl3)
δ: 7.06 (d, J＝7.6 Hz, 1H), 6.92 (s, 1H), 6.78 (d, J＝7.5
Hz, 1H), 5.16 (s, 2H), 3.63 (s, 2H), 3.44 (s, 3H), 2.32 (s,
3H); 13C NMR (125 MHz, CDCl3) δ: 178.3, 155.1,
139.1, 130.9, 122.6, 120.1, 114.9, 94.4, 56.1, 35.7, 21.6;
FT-IR (film) v: 2923, 1718, 1616, 1585, 1510, 1400,
1283, 1260, 1210, 1154, 1122, 1079, 1016, 940, 922,
803, 669 cm–1. ESI-MS m/z: 233.1 ([M＋Na]＋). ESI-
HRMS calcd for C13H20NO2 ([M＋Na]＋): 233.0779,
found 233.0784.
was added. The mixture was extracted with EtOAc. The
organic layer was washed with water and brine and
dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (4∶
1, PE/EtOAc) on silica gel afforded 15 as a colorless oil
28
(91 mg, 0.24 mmol, 88% from 14): [α]D –98.1 (c 0.5,
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.35－7.21 (m,
5H), 7.11 (d, J＝7.8 Hz, 1H), 6.88 (s, 1H), 6.80 (d, J＝
10.8 Hz, 1H), 5.29 (q, J＝7 Hz , 1H), 5.17 (dd, J＝15.8,
6.6 Hz, 2H), 4.66－4.61 (m, 1H), 4.14 (dd, J＝9.0, 2.7
Hz, 1H), 4.11 (dd, J＝9.0, 7.3 Hz, 1H), 3.48 (s, 3H),
3.33 (dd, J＝13.3, 3.2 Hz, 1H), 2.79 (dd, J＝13.3, 9.7
Hz, 1H), 2.31 (s, 3H), 1.51 (d, J＝7 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ: 175.7, 154.4, 152.9, 138.4, 135.6,
129.6, 129.1, 127.4, 127.2, 126.8, 122.6, 114.9, 94.7,
66.1, 56.3, 56.0, 38.2, 37.7, 21.6, 17.1; FT-IR (film) v:
2924, 1782, 1699, 1613, 1507, 1454, 1378, 1358, 1288,
1210, 1153, 1125, 1078, 1012, 924, 762, 748, 702, 668,
594, 536, 509, 427, 404 cm–1. ESI-MS m/z: 406.3 ([M＋
Na]＋). ESI-HRMS calcd for C22H25NNaO5 ([M＋Na]＋):
406.1626, found 406.1625.
Condensation of acid 12 with chiral auxiliary 13 to
give 14
Reductive cleavage of the chiral auxiliary in 15 to
afford alcohol 16
A solution of acid 12 (31.5 mg, 0.15 mmol), chiral
auxilary 13 (40 mg, 0.025 mmol), DMAP (28 mg, 0.025
mmol) and EDCI (58 mg, 0.3 mmol) in dry CH2Cl2 (1
mL) was stirred at ambient temperature for 2 h. Aq. HCl
(1 N) was added to quench the reaction. The mixture
was extracted with EtOAc. The organic layer was
washed with water and brine and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (4∶1, PE/EtOAc) 2－3
times (to remove the purple impurities) on silica gel
gave 14 as an almost colorless oil (34 mg, 0.092 mmol,
61%): [α]D28 –82.2 (c 0.25, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 7.34－7.20 (m, 5H), 7.06 (d, J＝7.6 Hz, 1H),
6.96 (s, 1H), 6.82 (d, J＝8.2 Hz, 1H), 5.18 (dd, J＝6.7,
10.8 Hz , 2H), 4.69－4.67 (m, 1H), 4.31 (d, J＝17.7 Hz,
1H), 4.24 (dd, J＝8.7, 8.7 Hz, 1H), 4.20 (dd, J＝9.1, 3
Hz, 1H), 4.19 (d, J＝18.1 Hz, 1H), 3.46 (s, 3H), 3.29
(dd, J＝13.4, 3.1 Hz, 1H), 2.81 (dd, J＝13.4, 9.4 Hz,
1H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 171.3,
155.3, 153.8, 139.0, 135.5, 131.1, 129.6, 129.1, 127.5,
122.6, 120.3, 115.0, 94.5, 66.4, 56.2, 55.5, 38.0, 37.4,
21.7; FT-IR (film) v: 2922, 1781, 1701, 1616, 1511,
1454, 1390, 1365, 1298, 1248, 1211, 1153, 1121, 1077,
NaBH4 (44.5 mg, 1.17 mmol) was added small por-
tions to a solution of 15 (90 mg, 0.235 mmol) in THF
(1.9 mL) and H2O (0.5 mL) stirred at ambient tempera-
ture. After completion of the addition, the mixture was
stirred at the same temperature for 10 h (when TLC
showed completion of the reaction). Aq. saturated
NH4Cl was added to quench the reaction. The mixture
was extracted with EtOAc. The organic layer was
washed with water and brine and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (4∶1, PE/EtOAc) on sil-
ica gel afforded 15 as a colorless oil (45 mg, 0.21 mmol,
91%): [α]D28 –0.35 (c 1.00, CHCl3). 1H NMR (500 MHz,
CDCl3) δ: 7.09 (d, J＝7.7 Hz, 1H), 6.92 (s, 1H), 6.82 (d,
J＝7.8 Hz, 1H), 5.19 (dd, J＝8.2, 6.8 Hz, 1H), 3.73 (dd,
J＝10.5, 7 Hz, 1H), 3.68 (dd, J＝10.5, 6.2 Hz, 1H), 3.49
(s, 3H), 3.44－3.37 (m, 1H), 2.32 (s, 3H), 1.25 (d, J＝
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 155.1,
137.6, 129.5, 127.3, 122.9, 115.2, 94.7, 68.0, 56.3, 35.2,
21.4, 17.0; FT-IR (film) v: 3398, 2958, 2925, 1613, 1578,
1507, 1451, 1398, 1250, 1209, 1153, 1133, 1075, 1015,
925, 812, 594 cm–1. ESI-MS m/z: 233.2 ([M＋Na]＋).
＋
1012, 922, 761, 703, 508, 427, 719, 404 cm–1. ESI-MS
ESI-HRMS calcd for C12H18NaO3 ([M ＋ Na] ):
＋
m/z: 392.3 ([M ＋ Na] ). ESI-HRMS calcd for
233.1146, found 233.1148.
C21H23NNaO5 ([M＋Na]＋): 392.1478, found 392.1468.
Acylation of 16 to afford 19
Asymmetric methylation of 14 to afford 15
2,4,6-Trichlorobenzoyl chloride 18 (30 μL, 0.189
mmol) was added to a solution of angelic acid 17 (18.9
mg, 0.189 mmol) and Et3N (14 μL, 0.189 mmol) in dry
toluene (120 μL). The mixture was stirred at ambient
temperature for 2 h. A solution of alcohol 16 (20 mg,
0.095 mmol) in toluene (0.15 mL) was added. The mix-
ture was stirred in a 70 ℃ bath for 6 h (when TLC
showed completion of the reaction). The heating bath
NaHMDS (1.0 mol/L, in THF, 0.33 mL, 0.33 mmol)
was added to a solution of 14 (100 mg, 0.27 mmol) in
dry THF (2.7 mL) stirred at –78 ℃ under argon (bal-
loon). After completion of the addition, the mixture was
stirred at the same temperature for 1 h. MeI (50 μL, 0.81
mmol) was added. Stirring was continued at –78 ℃ for
10 min, then at –40 ℃ for 1 h. Aq. saturated NH4Cl
Chin. J. Chem. 2015, 33, 729—738
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
733

Xu et al.
FULL PAPER
was removed. The mixture was diluted with EtOAc.
Solids were filtered. The filtrate was concentrated on a
rotary evaporator to give a residue, which was purified
by column chromatography (8∶1, PE/EtOAc) on silica
gel to afford ester 19 as a colorless oil (17.7 mg, 0.06
3H); 13C NMR (125 MHz, CDCl3) δ: 171.3, 154.9,
137.6, 128.9, 127.3, 122.6, 115.0, 94.6, 68.7, 56.2, 32.1,
21.5, 21.1, 17.3; FT-IR (film) v: 2965, 1733, 1614, 1578,
1508, 1452, 1387, 1371, 1234, 1155, 1077, 1014, 926,
812 cm–1. ESI-MS m/z: 275.3 ([M＋Na]＋). ESI-HRMS
calcd for C14H20NaO4 ([M＋Na]＋): 275.1254, found
275.1254.
28
1
mmol, 64%): [α]D –12.8 (c 1.00, CHCl3); H NMR
(500 MHz, CDCl3) δ: 7.09 (d, J＝7.7 Hz, 1H), 6.91 (s,
1H), 6.79 (d, J＝7.8 Hz, 1H), 6.04－5.99 (m, 1H), 5.19
(dd, J＝10.7, 6.7 Hz, 2H), 4.31 (dd, J＝10.7, 6.1 Hz,
1H), 4.20 (dd, J＝10.7, 7.5 Hz, 1H), 3.59－3.52 (m, 1H),
3.49 (s, 3H), 2.31 (s, 3H), 1.92－1.90 (dq, J＝7.3, 1.6
Hz, 3H), 1.85－1.84 (m, 3H), 1.31 (d, J＝7 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ: 168.3, 154.9, 137.7,
137.6, 129.0, 128.2, 127.5, 122.6, 114.9, 94.6, 68.4, 56.2,
32.2, 21.5, 20.8, 17.5, 15.8; FT-IR (film) v: 2958, 1715,
1613, 1579, 1508, 1455, 1389, 1351, 1254, 1231, 1209,
1078, 1043, 1014, 926, 848, 811, 595, 431, 416 cm–1.
ESI-MS m/z: 351.3 ([M＋Na]＋). ESI-HRMS calcd for
C17H24NaO4 ([M＋Na]＋): 315.1567, found 315.1568.
Removal of the MOM in 20 to furnish (R)-4
A solution of 20 (20 mg, 0.08 mmol), NaI (11.9 mg,
0.08 mmol) and TMSCl (10 μL, 0.12 mmol) in dry
CH3CN (210 μL) was stirred at ambient temperature for
15 min (when TLC showed completion of the reaction).
Aq. saturated Na2S2O3 was added. The mixture was ex-
tracted with EtOAc. The organic layer was concentrated
to dryness on a rotary evaporator. The residue was puri-
fied by column chromatography (4∶1, PE/EtOAc) on
silica gel to furnish (R)-4 as a colorless oil (16.4 mg,
0.08 mmol, 99%): [α]D28 –7.0 (c 0.85, CHCl3); 1H NMR
(500 MHz, CDCl3) δ: 7.03 (d, J＝7.8 Hz, 1H), 6.72 (d,
J＝7.8 Hz, 1H), 6.65 (s, 1H), 5.88 (br. s, 1H), 4.27 (dd,
J＝10.9, 5.5 Hz, 1H), 3.98 (dd, J＝10.9, 7.8 Hz, 1H),
3.39－3.32 (m, 1H), 2.27 (s, 3H), 2.07 (s, 3H), 1.33 (d,
J＝7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 172.1,
153.9, 138.0, 127.1, 125.4, 121.6, 116.8, 69.8, 32.3, 21.2,
21.1, 16.6; FT-IR (film) v: 3402, 2968, 1736, 1686, 1676,
1654, 1618, 1586, 1460, 1421, 1390, 1372, 1266, 1028,
947, 807 cm–1. ESI-MS m/z: 231.1 ([M ＋ Na] ＋ ).
Removal of the MOM in 19 to afford (R)-1
A solution of 19 (10 mg, 0.034 mmol) in CH2Cl2 (1.8
mL) and CF3CO2H (10 μL) was stirred at ambient tem-
perature overnight. The mixture was concentrated to
dryness on a rotary evaporator. The residue was purified
by column chromatography (6∶1, PE/EtOAc) on silica
gel to give (R)-1 as a colorless oil (6.1 mg, 0.025 mmol,
72%): [α]D28 –17.2 (c 0.55, MeOH); 1H NMR (500 MHz,
CDCl3) δ: 7.05 (d, J＝7.8 Hz, 1H), 6.72 (d, J＝7.8 Hz,
1H), 6.68 (s, 1H), 6.14－6.08 (m, 1H), 4.38 (dd, J＝11,
4.7 Hz, 1H), 3.96 (dd, J＝11, 8.2 Hz, 1H), 3.37 (d quint,
J＝4.8, 7.5 Hz, 1H), 2.28 (s, 3H), 1.98 (dq, J＝7.3, 1.5
Hz, 3H), 1.90－1.89 (m, 3H), 1.37 (d, J＝6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ: 169.0, 154.1, 139.2,
138.0, 127.7, 127.0, 125.1, 121.5, 116.9, 69.7, 32.4, 21.1,
20.7, 16.6, 16.0; FT-IR (film) v: 3415, 2963, 2925, 1691,
1644, 1619, 1587, 1520, 1457, 1421, 1391, 1378, 1351,
1291, 1235, 1162, 1085, 1043, 980, 947, 851, 806, 669,
594 cm–1. ESI-MS m/z: 271.3 ([M＋Na]＋). ESI-HRMS
calcd for C15H20NaO3 ([M＋Na]＋): 271.1306, found
271.1305.
＋
ESI-HRMS calcd for C12H16NaO3 ([M ＋ Na] ):
231.0988, found 231.0992.
Removal of the MOM in 16 to afford (R)-3
A solution of 16 (26 mg, 0.124 mmol) in MeOH (12
mL) and HCl (10 N, 0.5 mL) was stirred at ambient
temperature overnight. Water was added (2 mL). The
mixture was extracted with EtOAc (5 mL×3). The or-
ganic layer was concentrated on a rotary evaporator. The
residue was purified by column chromatography (2∶1
PE/EtOAc) on silica gel to give (R)-3 as a colorless oil
(19.6 mg, 0.118 mmol, 95%): [α]D26 –2.8 (c 0.5, CHCl3),
26
26
[α]D –4.8 (c 0.25, CHCl3), [α]D –6.4 (c 0.13, CHCl3)
(lit.[13c] [α]D ＋21.2 (c 0.25, MeOH), but 3 turned out to
be almost insoluble in MeOH); of 92% ee as shown by
HPLC analysis on a Chiralcel IC column (4.6 mm×250
mm, particle size 5 μm) eluting with 95∶5 n-hexane/
i-PrOH at a flow rate of 0.7 mL/min with the UV
Acetylation of 16 to afford 20
A solution of 16 (21 mg, 0.1 mmol), CH3CO2H (1
μL, 0.12 mmol), DMAP (6.1 mg, 0.05 mmol) and EDCI
(28.8 mg, 0.15 mmol) in dry CH2Cl2 (1 mL) was stirred
at ambient temperature for 2 h (when TLC showed
completion of the reaction). Aq. saturated NH4Cl was
added. The mixture was extracted with EtOAc. The or-
ganic layer was concentrated to dryness on a rotary
evaporator. The residue was purified by column chro-
matography (4∶1, PE/EtOAc) on silica gel to furnish
acetate 20 as a colorless oil (23.4 mg, 0.093 mmol,
93%): [α]D28 –15.6 (c 0.01, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 7.07 (d, J＝7.8 Hz, 1H), 6.91 (s, 1H), 6.80 (d,
J＝8.3 Hz, 1H), 5.19 (s, 2H), 4.22 (dd, J＝10.6, 6.2 Hz,
1H), 4.13 (dd, J＝10.6, 7.5 Hz, 1H), 3.52－3.50 (m, 1H),
3.49 (s, 3H), 2.31 (s, 3H), 2.01 (s, 3H), 1.27 (d, J＝7 Hz,
1
detector set to 214 nm; H NMR (500 MHz, CDCl3) δ:
7.00 (d, J＝8.2 Hz, 1H), 6.72 (s, 1H), 6.71 (d, J＝4.7 Hz,
1H), 3.93 (dd, J＝9.7, 3.7 Hz ,1H), 3.71 (dd, J＝9.7, 7.9
Hz, 1H), 3.23－3.18 (m, 1H), 2.28 (s, 3H), 1.30 (d, J＝
7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 154.8,
138.0, 127.8, 127.7, 121.6, 118.0, 69.7, 36.7, 21.1, 15.9;
FT-IR (film) v: 3344, 2962, 2923, 2877, 1619, 1576,
1508, 1452, 1422, 1380, 1288, 1263, 1127, 1013, 946,
861, 808 cm–1. ESI-MS m/z: 167.1 ([M ＋ H] ＋ ).
ESI-HRMS calcd for C10H15O2 ([M＋H]＋): 167.1067,
found 167.1066.
734
www.cjc.wiley-vch.de
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 729—738

Synthesis and Absolute Configuration of Two Natural Phenolic Homobenzyl Esters
Conversion of 11 into 21
66.4, 55.7, 38.1, 37.2, 29.8, 28.5, 21.8, 19.4; FT-IR (film)
v: 2957, 2921, 2872, 1781, 1703, 1614, 1584, 1510,
1469, 1454, 1391, 1365, 1287, 1247, 1200, 1124, 1105,
1035, 988, 762, 703 cm–1. ESI-MS m/z: 404.3 ([M＋
Na]＋). ESI-HRMS calcd for C23H27NaO4 ([M＋Na]＋):
404.1837, found 404.1832.
A solution of acid 11 (110 mg，0.67 mmol) and conc.
H2SO4 (4 drops from a pipette) in EtOH (2 mL) was
refluxed for 4 h. Water was added. The mixture was ex-
tracted with EtOAc. The organic layer was washed with
brine and dried over anhydrous Na2SO4. The solvent
was removed on a rotary evaporator. The yellowish oily
residue (crude ethyl ester, 120 mg, 0.62 mmol, 93%)
was dissolved in dry DMF (1.4 mL). Cs2CO3 (303 mg,
0.93 mmol) and KI (154 mg, 0.93 mmol) were then
added. The mixture was stirred at ambient temperature
under argon (balloon) for 1 h. 1-Bromo-2-methyl-
propane (1.8 mL, 1.55 mmol) was then introduced. The
mixture was stirred under argon in an 80 ℃ bath for 72
h. The heating bath was removed. The solids were fil-
tered off. The filtrate was partitioned between aq. NaOH
(2 N, 2 mL). The mixture was extracted with EtOAc (5
mL×3). The combined organic layers were washed
with brine and dried over anhydrous Na2SO4. The sol-
vent was removed on a rotary evaporator. The residue
was purified by column chromatography (8∶1
PE/EtOAc) on silica gel to give the intermediate ethyl
ester-phenol ether (120 mg, 0.48 mmol, 72% from 11),
which was dissolved in EtOH (2.4 mL) and aq. NaOH
(2 N, 0.5 mL) and stirred at reflux temperature for 1 h.
The heat bath was removed. Water (2 mL) was added,
followed by EtOAc (5 mL). The mixture was washed
with EtOAc (5 mL×3). The aqueous layer was acidified
with HCl (1 N) to pH 1 and extracted with EtOAc (15
mL×3). The combined organic layers were concen-
trated to dryness on a rotary evaporator to afford 21 as a
yellowish solid (106 mg, 0.48 mmol, 71% overall from
Asymmetric methylation of 22 to afford 23
This was done using the same procedure given above
for the conversion of 14 into 15 (except using 22 to re-
place 14). Yield: 51% (chromatography eluting with 4∶
1, PE/EtOAc). Data for 23 (a colorless oil): [α]D27 –86.0
(c 0.68, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.34－
7.21 (m, 5H), 7.14 (d, J＝7.7 Hz, 1H), 6.76 (d, J＝7.7
Hz, 1H), 6.64 (s, 1H), 5.25 (q, J＝7.1 Hz, 1H), 4.66－
4.62 (m, 1H), 4.16 (dd, J＝9.1, 2.5 Hz, 1H), 4.11 (dd,
J＝8.5, 8.5 Hz, 1H), 3.74 (dd, J＝8.7, 6.2 Hz, 1H), 3.67
(dd, J＝8.7, 6.4 Hz, 1H), 3.32 (dd, J＝13.3, 3.1 Hz, 1H),
2.77 (dd, J＝13.3, 9.9 Hz, 1H), 2.32 (s, 3H), 2.07－1.99
(m, 1H), 1.55 (d, J＝7.1 Hz, 3H), 1.01 (d, J＝6.9 Hz,
3H), 1.00 (d, J＝6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ: 176.0, 156.2, 152.9, 138.2, 135.7, 129.6,
129.1, 127.4, 127.2, 125.9, 121.0, 112.0, 74.3, 66.1, 55.9,
38.2, 37.7, 28.7, 21.6, 19.43, 19.40, 16.3; FT-IR (film) v:
2960, 2872, 1781, 1698, 1611, 1582, 1506, 1454, 1416,
1380, 1358, 1288, 1260, 1237, 1209, 1130, 1104, 1036,
965, 817, 762, 744, 702 cm–1. ESI-MS m/z: 418.4 ([M＋
Na]＋). ESI-HRMS calcd for C24H29NaO4 ([M＋Na]＋):
418.1995, found 418.1989.
Reductive cleavage of the chiral auxiliary in 23 to
afford alcohol 24
1
This was done using the same procedure given above
for the reductive cleavage of the chiral auxiliary in 15 to
afford alcohol 16 (except using 23 to replace 15). Yield:
91% (7.1 mg, chromatography eluting with 4∶1
PE/EtOAc). Data for 24 (a colorless oil): [α]D26 –5.6 (c
11): m.p. 64－66 ℃; H NMR (500 MHz, CDCl3) δ:
7.06 (d, J＝7.5 Hz, 1H), 6.72 (d, J＝7.6 Hz, 1H), 6.68 (s,
1H), 3.73 (d, J＝6.3 Hz, 2H), 3.63 (s, 2H), 2.33 (s, 3H),
2.10－2.04 (m, 1H), 1.01 (d, J＝6.7 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ: 178.4, 156.9, 139.0, 130.8, 121.0,
120.0, 112.2, 74.4, 35.9, 28.5, 21.7, 19.4; FT-IR (film) v:
2959, 2924, 2873, 1710, 1615, 1585, 1509, 1469, 1415,
1286, 1267, 1158, 1125, 1037, 947, 800 cm–1. ESI-MS
m/z: 245.2 ([M＋Na]＋). ESI-HRMS calcd for C13H18Na-
O3 ([M＋Na]＋): 245.1153, found 245.1148.
1
0.3, CHCl3); H NMR (500 MHz, CDCl3) δ: 7.07 (d,
J＝7.7 Hz, 1H), 6.75 (d, J＝7.6 Hz, 1H), 6.68 (s, 1H),
3.76－3.68 (m, 4H), 3.44－3.37 (m, 1H), 2.32 (s, 3H),
2.15－2.07 (m, 1H), 1.52 (br, s, 1H), 1.26 (d, J＝7 Hz,
3H), 1.05 (d, J＝6.7 Hz, 3H), 1.04 (d, J＝6.7 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ: 156.9, 137.4, 128.8,
127.4, 121.2, 112.5, 74.5, 68.0, 35.5, 28.6, 21.6, 19.60,
19.59, 16.8; FT-IR (film) v: 2960, 2921, 2873, 1611,
1505, 1470, 1414, 1393, 1287, 1260, 1164, 1137, 1039,
1017, 809, 772 cm–1. ESI-MS m/z: 223.1 ([M＋H]＋).
ESI-HRMS calcd for C14H23O2 ([M＋H]＋): 223.1693,
found 223.1698.
Condensation of 21 with 13 to furnish 22
This was done using the same procedure given above
for the condensation of acid 12 with chiral auxiliary 13
to give 14 (except using acid 21 to replace acid 11).
Yield: 72% (83 mg, chromatography eluting with 8∶1
PE/EtOAc). Data for 22 (a yellowish oil): [α]D25 –31.6 (c
0.6, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.34－7.20
(m, 5H), 7.05 (d, J＝7.2 Hz, 1H), 6.74 (d, J＝7.4 Hz,
1H), 6.70 (s, 1H), 4.67－4.63 (m, 1H), 4.28－4.18 (m,
4H), 3.75 (dd, J＝9, 6.7 Hz, 1H), 3.71 (dd, J＝8.8, 7 Hz,
1H), 3.34 (dd, J＝13.2, 2.9 Hz, 1H), 2.74 (dd, J＝13.3,
9.9 Hz, 1H), 2.34 (s, 3H), 2.07－2.02 (m, 1H), 1.00 (d,
J＝6.7 Hz, 3H), 0.98 (d, J＝6.7 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ: 171.6, 157.0, 153.8, 138.8, 135.6,
131.0, 129.6, 129.1, 127.4, 121.1, 119.8, 112.3, 74.3,
Acetylation of 24 to afford (R)-5
A solution of alcohol 24 (7 mg, 0.03 mmol), Ac2O (3
μL, 0.036 mmol), DMAP (1 mg, 0.006 mmol) and Et3N
(6 μL, 0.045 mmol) in dry CH2Cl2 (0.3 mL) was stirred
at ambient temperature for 2 h. Water was added (1 mL).
The mixture was extracted with EtOAc (5 mL×3). The
combined organic layers were washed with brine and
dried over anhydrous Na2SO4. The solvent was removed
Chin. J. Chem. 2015, 33, 729—738
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
735

Xu et al.
FULL PAPER
on a rotary evaporator. The residue was purified by
column chromatography (2∶1, PE/EtOAc) on silica gel
to give (R)-5 as a colorless oil (7.8 mg, 0.03 mmol,
To the solution were added n-Bu2SnO (116 mg, 0.6
mmol), DMAP (73 mg, 0.6 mmol), Et3N (0.9 mL, 6.6
mmol) and p-TsCl (1.26 g, 6.6 mmol). The mixture was
stirred at ambient temperature for 3 h. Et2O (20 mL) was
added. The solids were filtered off. The filtrate was
concentrated on a rotary evaporator. The residue was
chromatographed (4∶1, PE/EtOAc) on silica gel to give
a white solid (the intermediate primary tosylate, 1.86 g,
99%): [α]D26 –20.9 (c 0.3, CHCl3); H NMR (400 MHz,
1
CDCl3) δ: 7.05 (d, J＝7.7 Hz, 1H), 6.72 (d, J＝7.3 Hz,
1H), 6.66 (s, 1H), 4.23 (dd, J＝10.6, 6.0 Hz,1H), 4.14
(dd, J＝10.5, 7.5 Hz, 1H), 3.72 (d, J＝6.4 Hz, 2H),
3.52－3.47 (m, 1H), 2.32 (s, 3H), 2.13－2.08 (m, 1H),
2.02 (s, 3H), 1.27 (d, J＝7 Hz, 3H), 1.04 (d, J＝6.7 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ: 171.4, 156.7,
137.5, 128.3, 127.3, 121.0, 112.3, 74.4, 68.7, 32.2, 28.6,
21.6, 21.2, 19.59, 19.57, 17.2; FT-IR (film) v: 2962,
2874, 1741, 1613, 1581, 1507, 1469, 1415, 1388, 1369,
1287, 1233, 1166, 1039, 809, 669 cm–1. ESI-MS m/z:
287.3 ([M＋Na]＋). ESI-HRMS calcd for C16H25O3
([M＋H]＋): 265.1798, found 265.1798.
25
5.9 mmol, 99%): ｍ.p. 32－33 ℃. [α]D ＋2.47 (c
1
2.55, EtOH); H NMR (500 MHz, CDCl3) δ: 7.80 (d,
J＝8.3 Hz, 2H), 7.35 (d, J＝8.2 Hz, 2H), 4.03 (dd, J＝
10, 3.0 Hz, 1H), 3.89 (dd, J＝10, 7 Hz, 1H), 3.84－3.80
(m, 1H), 2.45 (s, 3H), 2.29 (br. s, 1H), 1.43－1.39 (m,
2H), 1.30－1.24 (m, 10H), 0.87 (t, J＝6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ: 145.1, 132.8, 130.0, 128.0,
74.1, 69.5, 32.8, 31.8, 29.5, 29.2, 25.3, 22.7, 21.7, 14.1;
FT-IR (film) v: 3535, 2927, 2856, 1598, 1496, 1458,
1360, 1308, 1189, 1176, 1097, 1020, 968, 814, 667, 555
cm–1. ESI-MS m/z: 337.2 ([M＋Na]＋ ). ESI-HRMS
calcd for C16H26NaO4S ([M＋Na]＋): 337.1452, found
337.1444.
Conversion of epoxide 25 into alcohol 27
n-Hexyl bromide (2.1 mL, 15 mmol) added slowly
(first only a small part to induce the reaction, with the
main part added after the yellow-brown color faded) to a
suspension of Mg turnings (828 mg, 34.5 mmol) and a
small grain of solid I2 in dry THF (15 mL) stirred at am-
bient temperature under argon (balloon). The mixture
was then heated in a 60 ℃ bath for 2 h to give a
dark-grey yet clear solution. This Grignard reagent (af-
ter being cooled down to ambient temperature) was then
added to a mixture of CuBr•Me2S (65 mg, 0.32 mmol)
in dry THF (25 mL) stirred at –78 ℃ under argon
(balloon). The mixture was stirred at the same tempera-
ture for 30 min. A solution of epoxide 25 (1.00 g, 6.1
mmol) in dry THF (5 mL) was added slowly. The mix-
ture was stirred at –78 ℃ for 1 h (TLC showed com-
pletion of the reaction). Aq. sat. NH4Cl (15 mL) was
added. The mixture was extracted with EtOAc (15 mL
×3). The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatog-
raphy (8∶1, PE/EtOAc) on silica gel gave alcohol 27 as
Conversion of 28 into 30
NaH (60%, 20 mg, 0.8 mmol) and a magnetic stir-
ring bar were placed in a three-neck flask. One of the
necks was equipped with a condenser while another
sealed with an uninflated balloon containing CuBr•Me2S
(which was needed in the next step, vide infra). PE (pe-
troleum ether) was added through the third neck. The
mixture was stirred for a few minutes. The liquid/emul-
sion phase was removed with a pipette and another por-
tion of PE was added. The process was repeated three
times. And then using dry THF to replace PE to repeat
the washing two times. The flask was sealed with a
rubber septum and cooled in an ice-water bath under
argon (balloon). Dry THF (1 mL) was added, followed
by a solution of tosylate 28 (100 mg, 0.32 mmol) in dry
THF (1 mL). The mixture was stirred at ambient tem-
perature overnight (when TLC showed completion of
the reaction).
24
a colorless oil (1.51 g, 6.0 mmol, 99% from 25): [α]D
–6.1 (c 1.00, CHCl3) (lit.[14] [α]D –3.6 (c 1.03, CHCl3));
1H NMR (500 MHz, CDCl3) δ: 7.36－7.26 (m, 5H),
4.54 (s, 2H), 3.82－3.77 (m, 1H), 3.49 (dd, J＝9.4, 3.1
Hz, 1H), 3.31 (dd, J＝9.4, 7.9 Hz, 1H), 2.42 (br. s, 1H),
1.48－1.39 (m, 2H), 1.31－1.27 (m, 10H), 0.87 (t, J＝
6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 138.1,
128.5, 127.83, 127.81, 74.8, 73.4, 70.5, 33.3, 31.9, 29.7,
29.3, 25.6, 22.8, 14.2.
A solution of 1-bromo-3,5-dimethoxy-benzene 29
(1.08 g, 5mmol) in dry THF (3 mL) was added slowly
(first only a small part to induce the reaction, with the
main part added after the brown-yellow color faded) to a
suspension of Mg turnings (276 mg, 11.5 mmol) and a
small grain of solid I2 in dry THF (2 mL) stirred at am-
bient temperature under argon (balloon). The mixture
was then heated in a 60 ℃ bath for 2 h to give a dark-
grey yet clear solution. A portion of this Grignard re-
agent (cooled to ambient temperature, 3.2 mL, ca. 3.2
mmol) was then added to the above mentioned reaction
mixture (containing the epoxide prepared from 28)
stirred under argon (balloon) in a –78 ℃ bath (ace-
tone-dry ice). CuBr•Me2S (placed in an uninflated bal-
loon sealed onto a side neck of the three-neck flask for
the above mentioned epoxidation from the beginning,
132 mg, 0.64 mmol) was then added. The mixture was
stirred at –78 ℃ for 5 h (TLC showed completion of
Conversion of alcohol 27 into tosylate 28
A mixture of 27 (1.51 g, 6.0 mmol) and 10% Pd-C
(150 mg) in anhydrous EtOH (99.5%, 60 mL) was
stirred at 40 ℃ (bath) under H2 (1 atm) atmosphere for
4 h (TLC showed completion of the reaction). The sol-
ids were filtered off. The filtrate and washings were
combined and concentrated on a rotary evaporator to
afford the intermediate diol as a white solid (960 mg,
99% from 27), which was dissolved in CH3CN (27 mL).
736
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Chin. J. Chem. 2015, 33, 729—738

Synthesis and Absolute Configuration of Two Natural Phenolic Homobenzyl Esters
the reaction). Aq. sat. NH4Cl (5 mL) was added. The
mixture was extracted with EtOAc (15 mL×3). The
combined organic layers were washed with brine and
dried over anhydrous Na2SO4. The combined organic
layers were washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (8∶1, PE/EtOAc) on sil-
ica gel gave alcohol 30 as a colorless oil (48 mg, 0.17
extracted with EtOAc (5 mL×3). The combined organic
layers were washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (2 ∶ 1, PE/EtOAc) on
silica gel gave (R)-2 as a yellowish oil (17.4 mg, 0.059
26
26
mmol, 99%): [α]D –4.14 (c 0.80, CHCl3), [α]D –9.4
25
(c 0.10, CHCl3) (lit.[2] [α]D –223 (c 0.10, CHCl3),
measured on 0.34 mg of the natural sample); H NMR
1
25
mmol, 53% overall from 28): [α]D –6.36 (c 1.00,
(500 MHz, CD3OD) δ: 6.15 (d, J＝2.1 Hz, 2H), 6.12 (t,
J＝2.1 Hz, 1H), 5.02－4.97 (m, 1H), 2.69 (dd, J＝13.5,
7.0 Hz, 1H), 2.63 (dd, J＝13.6, 6.1 Hz, 1H), 1.99 (s,
3H), 1.54－1.51 (m, 2H), 1.29－1.27 (m, 10H), 0.89 (t,
J＝7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ: 172.7,
159.4, 141.3, 108.9, 101.7, 76.4, 41.6, 34.6, 32.9, 30.4,
30.3, 26.5, 23.7, 21.1, 14.4; FT-IR (film) v: 3381, 2926,
2856, 1736, 1706, 1602, 1456, 1378, 1269, 1148, 1026,
999, 841, 705, 669, 609 cm–1. ESI-MS (negative) m/z:
293.3 ([M–H]–). ESI-HRMS calcd for C17H25O4 ([M –
H]–): 293.1751, found 293.1758.
CHCl3), 98% ee as determined by HPLC on a Chiralcel
OD-H column (4.6 mm×250 mm, particle size 5 μm)
eluting with 80∶20 n-hexane/i-PrOH at a flow rate of
1
0.7 mL/min with the UV detector set to 214 nm; H
NMR (500 MHz, CDCl3) δ: 6.37 (d, J＝2.1 Hz, 2H),
6.34 (t, J＝2.1 Hz, 1H), 3.84－3.80 (m, 1H), 3.78 (s,
6H), 2.77 (dd, J＝13.4, 3.9 Hz, 1H), 2.57 (dd, J＝13.4,
8.6 Hz, 1H), 1.61 (br. s, 1H), 1.53－1.51 (m, 2H), 1.30
－1.28 (m, 10H), 0.88 (t, J＝6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ: 161.1, 141.1, 107.5, 98.6, 72.7,
55.4, 44.6, 37.0, 32.0, 29.8, 29.4, 25.9, 22.8, 14.2; FT-IR
(film) v: 3448, 3998, 2927, 2854, 1596, 1462, 1429,
1343, 1323, 1293, 1205, 1150, 1068, 925, 829, 700, 456
cm–1. ESI-MS m/z: 281.4 ([M＋H]＋). ESI-HRMS calcd
for C17H29O3 ([M＋H]＋): 281.2110, found 281.2111.
Acknowledgement
This work was supported by the National Natural
Science Foundation of China (21172247, 21032002)
and the Chinese Academy of Sciences.
Acetylation of 30 to afford acetate 31
References
A solution of 30 (20 mg, 0.07 mmol), Ac2O (7 μL,
0.084 mmol), DMAP (2 mg, 0.014 mmol) and Et3N (12
μL, 0.11 mmol) in dry CH2Cl2 (0.7 mL) was stirred at
ambient temperature for 1.5 h. Water was added. The
mixture was extracted with EtOAc (5 mL×3). The
combined organic layers were washed with brine and
dried over anhydrous Na2SO4. The combined organic
layers were washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (10∶1, PE/EtOAc) on
silica gel gave acetate 31 as a colorless oil (22.3 mg,
0.069 mmol, 99%): [α]D –4.14 (c 0.80, CHCl3); H
NMR (400 MHz, CDCl3) δ: 6.35 (d, J＝2 Hz, 2H), 6.33
(t, J＝2.1 Hz, 1H), 5.09－5.03 (m, 1H), 3.77 (s, 6H),
2.82 (dd, J＝13.7, 6.8 Hz, 1H), 2.72 (dd, J＝13.7, 6.3
Hz, 1H), 2.01 (s, 3H), 1.54－1.50 (m, 2H), 1.29－1.25
(m, 10H), 0.87 (t, J＝7 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ: 170.8, 160.8, 140.1, 107.6, 98.6, 74.8, 55.4,
41.0, 33.7, 31.9, 29.6, 29.3, 25.5, 22.8, 21.4, 14.2; FT-IR
(film) v: 2930, 2857, 1737, 1608, 1597, 1464, 1430,
1374, 1326, 1292, 1240, 1206, 1152, 1069, 1023, 939,
831, 772, 703, 608 cm–1. ESI-MS m/z: 323.4 ([M＋H]＋).
ESI-HRMS calcd for C19H31O4 ([M＋H]＋): 323.2216,
found 323.2217.
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26
1
[6] For a practical access to such chiral auxiliaries, see: Wu, Y.-K.; Shen,
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Conversion of 31 into (R)-2
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Vivar, A. Phytochemistry 1994, 36, 1081, where the optical rotation
for the natural 3 was reported to be in MeOH. However, in our hands
BBr3 (0.22 mL, 0.24 mmol) was added to a solution
of 31 (20 mg, 0.06 mmol) in CH2Cl2 (0.6 mL) stirred at
–78 ℃ under argon (balloon). After completion of the
addition, the mixture was stirred at ambient temperature
overnight (when TLC showed completion of the
reaction). Aq. sat. NaHCO3 was added. The mixture was
Chin. J. Chem. 2015, 33, 729—738
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Xu et al.
FULL PAPER
3 turned out almost insoluble in MeOH.
Furstner, A. Chem. Eur. J. 2010, 16, 12133.
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[16] The optical rotation for (R)-2 measured at c＝0.80 was very stable,
while the corresponding data recorded at c＝0.10 (as in the literature,
the ref. 2 above) fluctuated drastically (but always were negative).
(Lu, Y.)
738
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 729—738