Synthesis of the structure proposed for natural meliloester

Article abstract of DOI:10.1055/s-0032-1316776

In an attempt to establish the absolute configuration of meliloester, a natural product isolated from Melilotus alba, the literature structure was synthesized in an enantiopure form. Unexpectedly, the ¹H and ¹³C NMR data was completely incompatible with those reported for the natural product. The corresponding m-hydroxy isomer was also excluded as the structure for the natural product.

Full text of DOI:10.1055/s-0032-1316776

3296▌
PAPER
paper
Synthesis of the Structure Proposed for Natural Meliloester
Meliloester
Lu Ding,a,b Zhong-Han Li,b Xiao-Wei Lu,b Yikang Wu,*b Yan Li*a
a
Ministry-of-Education Key Laboratory for Synthesis and Application of Organic Functional Molecules and School of Chemistry and Chemical
Engineering, Hubei University, 11 Xueyuan Road, Wuhan 430062, P. R. of China
b
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
E-mail: yikangwu@sioc.ac.cn
Received: 17.07.2012; Accepted after revision: 20.08.2012
Crimmins4 to afford aldol 5 in enantiopure form in 69%
isolated yield.
Abstract: In an attempt to establish the absolute configuration of
meliloester, a natural product isolated from Melilotus alba, the lit-
erature structure was synthesized in an enantiopure form. Unexpect-
edly, the 1H and 13C NMR data was completely incompatible with
those reported for the natural product. The corresponding m-hy-
droxy isomer was also excluded as the structure for the natural prod-
uct.
To remove the redundant hydroxy group, 5 was first treat-
ed with O-phenyl carbonochloridothioate and 4-(dimeth-
ylamino)pyridine5 to afford the corresponding phenoxy
carbonothioate. Then a radical-mediated reduction was
carried out to deliver 8 under the tributylstannane and
2,2′-azobisisobutyronitrile5 conditions. Finally, reductive
cleavage using sodium borohydride in methanol afforded
the desired optically active alcohol 9.
Key words: esters, alcohols, natural products, aldol, phenols
Melilotus alba is one of the 25 known species of Melilotus
(Fabaceae). Many interesting compounds have already
been isolated from this species, including triterpenoid gly-
cosides, soyasapogenol, pterocarpanoids, flavonoids, and
triterpenoid saponin.1 Recently, another component, a
phenolic ester which has been named meliloester (1, Fig-
ure 1),2 was added to this list by Pakistani scientists.
O
O
O
O
EDCI, DMAP
HO
O
N
O
NH
Ph
+
CH2Cl2
98%
Ph
4
3
2
TiCl4, NMP, MeCHO
(+)-sparteine
69%
−78 °C to 0 °C
O
3'
6
1'
S
8
1
2
S
5
4
7
9
O
O
O
OH
6'
O
O
O
OPh
Cl
OPh
7'
OH
8'
6
O
N
3
O
N
1
[α]D25 −117.6 (c 0.17, MeOH)
Ph
DMAP, CH2Cl2
98%
Ph
5
7
Figure 1 The structure proposed for meliloester in the literature
along with the optical rotation
n-Bu3SnH, AIBN
88%
toluene, reflux
On the basis of the data from extensive spectroscopic
analyses, a planar structure2a was established for this opti-
cally active natural product. However, the absolute con-
figuration was not determined, although optical rotation
was measured. To complete the structural elucidation, we
have performed an enantioselective synthesis of this natu-
ral product.
O
N
(R)
O
NaBH4, MeOH
0 °C to r.t.
HO
O
55%
9
Ph
8
Scheme 1
The synthesis began with the construction of the alkoxy
unit (Scheme 1). The known3 chiral auxiliary 2 was con-
densed with hexanoic acid (3) in the presence of N-(3-di-
methylaminopropyl)-N′-ethylcarbodiimide (EDCI) and 4-
(dimethylamino)pyridine to give acyloxazolidinone 4. An
Evans’ aldol reaction was then performed under the con-
ditions [TiCl4, (+)-sparteine, NMP] developed by
It should be noted that direct ethylation of 4 could also af-
ford ent-8 (which would serve equally well). However,
because the alkylation was incomplete compared to the al-
dol reaction and the product could not be separated from
unreacted 4 by chromatography, the cleaner aldol ap-
proach was preferred. An additional advantage of using
the aldol reaction is that all undesired isomers could be
cleanly removed by column chromatography, providing
the major product with high diastereo- and enantiopurity.
SYNTHESIS 2012, 44, 3296–3300
Advanced online publication: 31.08.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316776; Art ID: SS-2012-H0597-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Meliloester
3297
The carboxylic unit was gained from known6 10 by hydro-
lysis in the presence of barium hydroxide octahydrate in
refluxing methanol (Scheme 2).7 The free acid 118 was
then condensed with the alcohol 9 using Shiina’s9 2-meth-
yl-6-nitrobenzoyl anhydride (MNBA) protocol resulting
in the formation of ester 13, which on saturation of the C–
C double bond and cleavage of the benzyl protecting
group by atmospheric hydrogenation over palladium on
carbon gave the end product (R)-1.
CO2H
CO2Et
Ba(OH)2·8H2O
MeOH, reflux
96%
15
14
OBn
OBn
O
12/9, DMAP
4 Å MS
Et3N, toluene
O
(R)
77%
O
16
OBn
CO2H
CO2Et
Ba(OH)2·8H2O
O
MeOH, reflux
98%
11
H2, Pd/C, THF
75%
10
OBn
OBn
12/9, DMAP
4 Å MS
73%
OH
NO2
O
O
NO2
(R)-1'
Et3N, toluene
[α]D28 −2.2 (c 0.45, MeOH)
O
O
Scheme 3
O
(R)
12
MNBA
were also inconsistent with the structure proposed for
meliloester. For instance, the natural product was chroma-
tographed with dichloromethane–methanol (9:1), a sol-
vent system normally suitable for highly polar
compounds, while both synthetic samples were of appar-
ently much lower polarity (chromatographed using a mix-
ture of ethyl acetate–petroleum ether). The chemical shift
for the ester carbonyl carbon in 13C NMR (δ = 169.34) is
also unusually low for this type of ester (normally around
δ = 175), not to mention the phenolic OH observed in 1H
NMR performed in methanol-d4. On the basis of all these
observations and reasoning, the structures 1 (or 1′) can
now be excluded as possibilities for the structure of the
natural product meliloester.
O
OBn
13
O
H2, Pd/C, THF
75%
OH
(R)-1
[α]D27 −1.2 (c 0.25, MeOH)
Scheme 2
Up to this point, our initial plan appeared to be approach-
ing its end, through comparison of the sign of the optical
rotation of the synthetic and the natural samples an assign-
ment of the absolute configuration of meliloester would
be achieved. However, the 1H and 13C NMR spectral data
of (R)-1, entirely unexpectedly, were incompatible with
those reported for the natural product in the literature, un-
ambiguously excluding any possibility of 1 being the
structure of the isolated natural product.
In summary, in an attempt to establish the absolute config-
uration of the natural meliloester, the proposed structure 1
was synthesized in an enantiopure form. However, the
spectroscopic data for the synthetic sample was funda-
mentally different from that reported for the natural prod-
uct. Similar large data discrepancies were also observed
with the corresponding m-OH isomer. It is therefore con-
cluded that the previously2a assigned structure for mel-
iloester is incorrect and that the spectroscopic data
previously reported for meliloester should be dissociated
from the structure 1.
We next synthesized the m-hydroxy isomer of (R)-1, be-
cause judging from the pattern of the aromatic signals in
1H NMR for the natural product, the p-OH isomer (sym-
metric aromatic protons) could be definitely excluded,
leaving the m-OH isomer as the most likely possible alter-
native.
Next, we used the known10 14 as the starting material for
a similar barium hydroxide octahydrate mediated hydro-
lysis (Scheme 3) to obtain the carboxylic acid 15. Subse-
quent coupling of 15 with alcohol 9 delivered ester 16.
Finally, removal of the benzyl protecting group and satu-
ration of the C–C double bond by hydrogenation gave the
desired (R)-1′.
The 1H and 13C NMR spectra data of (R)-1′ were also in-
compatible with those for the natural product and thus
eliminated the possibility that (R)-1′ is the structure for
the natural product (or its antipode). We also noticed sev-
eral other pieces of evidence in the original2a report, which
The NMR spectra were recorded on a Bruker Avance NMR spec-
trometer operating at 400 MHz (1H) with TMS as the internal stan-
dard. IR spectra were measured 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 polarimeter. Melting points were
uncorrected (measured on a hot stage melting point apparatus
equipped with a microscope). CH2Cl2 and toluene were dried with
activated 4 Å MS (molecular sieves). All chemicals were reagent
grade and used as purchased. Column chromatography was per-
formed on silica gel (300–400 mesh) under slightly positive pres-
sure. PE = petroleum ether (bp 60–90 °C).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3296–3300

3298
L. Ding et al.
PAPER
(S)-3-Hexanoyl-4-phenyloxazolidin-2-one (4)
tion and column chromatography (silica gel, PE–EtOAc, 10:1) af-
forded carbothioate 7 (180 mg, 0.41 mmol, 98%) as a colorless oil.
[α]D29 +123.3 (c 1.35, CHCl3).
EDCI (6.00 g, 31.2 mmol) was added to a soln of auxiliary 2 (3.40
g, 20.8 mmol), acid 3 (3.1 mL, 25 mmol) and DMAP (510 mg, 4.17
mmol) in anhyd CH2Cl2 (100 mL) stirred in an ice-water bath under
N2 (balloon). Stirring was continued at the same temperature for 10
min and then at r.t. overnight. The mixture was diluted with Et2O
(50 mL), washed with brine, and dried (anhyd Na2SO4). Removal of
the solvent by rotary evaporation and column chromatography (sil-
ica gel, PE–EtOAc, 4:1) gave 4 (5.30 g, 20.3 mmol, 98%) as a col-
orless oil; mp 57–58 °C.
FT-IR (film): 2957, 2929, 2870, 1781, 1703, 1491, 1384, 1287,
1202, 1101, 770 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.27 (m, 8 H), 7.13 (d,
J = 7.8 Hz, 2 H), 5.78–5.74 (m, 1 H), 5.42 (dd, J = 8.6, 3.5 Hz, 1 H),
4.64 (t, J = 8.8 Hz, 1 H), 4.42–4.37 (m, 1 H), 4.23 (dd, J = 9.0, 3.5
Hz, 1 H), 1.78–1.73 (m, 1 H), 1.57–1.49 (m, 1 H), 1.44 (d, J = 6.6
Hz, 3 H), 1.15–1.23 (m, 2 H), 1.07–1.03 (m, 2 H), 0.77 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.5, 172.4, 153.6, 153.4, 139.2,
129.5, 129.2, 128.8, 126.6, 126.0, 122.0, 81.3, 77.5, 77.1, 76.8,
69.8, 58.0, 46.3, 28.9, 27.5, 22.5, 16.6, 13.8.
[α]D28 +60.6 (c 1.92, CHCl3).
FT-IR (film, concd CH2Cl2 soln): 2956, 2931, 2871, 1782, 1708,
1457, 1385, 1328, 1200, 1080, 762, 700 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H), 5.39 (dd,
J = 8.6, 3.6 Hz, 1 H), 4.63 (t, J = 8.8 Hz, 1 H), 4.20 (dd, J = 8.9, 3.7
Hz, 1 H), 2.98–2.83 (m, 2 H), 1.55–1.63 (m, 2 H), 1.28–1.26 (m, 4
H), 0.86 (t, J = 6.2 Hz, 3 H).
MS (ESI): m/z = 464.4 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C24H27NO5SNa: 464.1502;
13C NMR (100 MHz, CDCl3): δ = 172.6, 153.5, 139.1, 128.9, 128.3,
found: 464.1497.
125.6, 69.7, 57.3, 57.2, 35.2, 30.9, 23.6, 22.1, 13.7, 13.6.
MS (ESI): m/z = 284.2 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C15H19NO3Na: 284.1257;
found: 284.1264.
(S)-3-[(R)-2-Ethylhexanoyl]-4-phenyloxazolidin-2-one (8)
A soln of 7 (174 mg, 0.41 mmol), AIBN (34 mg, 0.20 mmol), and
n-Bu3SnH (0.33 mL, 1.23 mmol) in anhyd degassed toluene (4 mL)
was stirred at 110 °C (bath) under N2 (balloon) for 8 h (TLC showed
completion). The solvent was removed on a rotary evaporator. The
residue was chromatographed (silica gel, PE–EtOAc, 15:1) to give
8 (104 mg, 0.36 mmol, 88%) as a colorless oil.
(S)-3-{(S)-2-[(R)-1-Hydroxyethyl]hexanoyl}-4-phenyloxazoli-
din-2-one (5)
TiCl4 (0.27 mL, 2.44 mmol) was added via a syringe to a soln of 4
(638 mg, 2.44 mmol) in anhyd CH2Cl2 (13 mL) stirred in an ice-
water bath under N2 (balloon), followed by (+)-sparteine (0.62 mL,
2.69 mmol). The mixture was stirred for 20 min, the bath was re-
placed with a –78 °C bath (dry ice/acetone). NMP (0.24 mL, 2.44
mmol) was introduced dropwise via another syringe. The mixture
was stirred at this temperature for 10 min. A soln of freshly distilled
MeCHO (0.21 mL, 3.67 mmol) in anhyd CH2Cl2 (5 mL) was intro-
duced slowly (using a syringe pump) over 1 h. After completion of
the addition, the mixture was stirred at –78 °C for 1 h before the bath
was allowed to warm to 0 °C. Stirring was continued at 0 °C for 1
h. Aq sat. NH4Cl (5 mL) was added, followed by Et2O (3 × 30 mL).
The phases were separated and the organic layer was washed with
brine and dried (anhyd Na2SO4). Removal of the solvent by rotary
evaporation and column chromatography (silica gel, PE–EtOAc,
2:1) afforded aldol 5 (514 mg, 1.69 mmol, 69%) as a colorless oil.
[α]D29 +47.0 (c 2.08, CHCl3).
FT-IR (film): 2960, 2932, 2872, 1782, 1702, 1457, 1385, 1196, 699
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 5.46 (dd,
J = 8.8, 3.8 Hz, 1 H), 4.66 (t, J = 8.9 Hz, 1 H), 4.24 (dd, J = 8.8, 3.8
Hz, 1 H), 3.77–3.73 (m, 1 H), 1.62–1.73 (m, 1 H), 1.61–1.38 (m, 3
H), 1.20–1.12 (m, 2 H), 1.05–1.01 (m, 2 H), 0.90 (t, J = 7.4 Hz, 3
H), 0.77 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.3, 153.5, 139.4, 129.1, 128.6,
126.0, 94.9, 69.6, 57.8, 44.2, 31.8, 28.8, 24.6, 22.7, 13.9, 11.7.
MS (ESI): m/z = 312.2 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C17H23NO3Na: 312.1570;
found: 312.1576.
[α]D28 +36.6 (c 1.00, CHCl3).
(R)-2-Ethylhexan-1-ol (9)
NaBH4 (22 mg, 0.57 mmol) was added to a soln of 8 (83 mg, 0.29
mmol) in MeOH (2.5 mL) stirred in an ice-water bath; stirring was
continued at r.t. for 3 h (TLC showed disappearance of 8). Aq 2 M
HCl (2 mL) was carefully added and the mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed
with brine and dried (anhyd Na2SO4). Removal of the solvent by ro-
tary evaporation and column chromatography (silica gel, CH2Cl2–
Et2O, 100:1) afforded alcohol 9 (21 mg, 0.16 mmol, 55%) as a col-
orless liquid.
FT-IR (film): 3504, 2957, 2930, 2871, 1780, 1701, 1458, 1384,
1320, 1198, 1082, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H), 5.48 (dd,
J = 8.9, 3.9 Hz, 1 H), 4.69 (t, J = 8.9 Hz, 1 H), 4.26 (dd, J = 8.9, 3.9
Hz, 1 H), 4.08–4.04 (m, 2 H), 2.77 (s, 1 H), 1.69–1.61 (m, 1 H),
1.49–1.42 (m, 1 H), 1.29–1.26 (m, 1 H), 1.19 (d, J = 6.0 Hz, 3 H),
1.17–0.92 (m, 3 H), 0.75 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.1, 154.1, 138.9, 129.0, 128.6,
126.0, 69.5, 68.6, 57.8, 48.5, 29.2, 27.5, 22.5, 19.3, 13.7.
[α]D27 –2.2 (c 0.60, CH2Cl2) [Lit.11 [α]D22 –2.1 (c 0.5, CH2Cl2)].
MS (ESI): m/z = 328.1 ([M + Na]+).
FT-IR (film): 3336, 2959, 2928, 2855, 1458, 1038 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C17H23NO4Na: 328.1519;
found: 328.1508.
1H NMR (400 MHz, CD2Cl2): δ = 3.43 (d, J = 4.5 Hz, 2 H), 1.30–
1.21 (m, 10 H), 0.83 (t, J = 7.0 Hz, 3 H), 0.81 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CD2Cl2): δ = 65.4, 42.4, 30.5, 29.5, 23.7, 23.5,
14.2, 11.3.
O-(2R,3S)-3-[(S)-2-Oxo-4-phenyloxazolidin-3-ylcarbonyl]hep-
tan-2-yl O-Phenyl Carbonothioate (7)
PhOCSCl (6, 0.12 mL, 0.84 mmol) was added to a soln of 5 (128
mg, 0.42 mmol) and DMAP (205 mg, 1.68 mmol) in anhyd CH2Cl2
(4 mL) stirred at r.t. under N2 (balloon). The mixture was stirred at
this temperature for 1 h (TLC showed completion of the reaction).
Aq sat. NH4Cl was added, followed by Et2O (3 × 20 mL). The phases
were separated and the organic layer was washed with brine and
dried (anhyd Na2SO4). Removal of the solvent by rotary evapora-
(E)-3-[2-(Benzyloxy)phenyl]acrylic Acid (11);
Typical Procedure
A mixture of ester 10 (400 mg, 1.4 mmol) and Ba(OH)2·8 H2O (670
mg, 2.1 mmol) in MeOH (14 mL) was stirred at reflux (80 °C bath)
for 1 h (TLC showed completion); the mixture was concentrated on
a rotary evaporator. To the residue was added EtOAc (50 mL), fol-
lowed by aq 0.5 M HCl (20 mL); the phases were separated. The
aqueous layer was extracted with EtOAc (2 × 20 mL). The com-
Synthesis 2012, 44, 3296–3300
© Georg Thieme Verlag Stuttgart · New York

PAPER
Meliloester
3299
bined organic layers were washed with brine and dried (anhyd
Na2SO4). Removal of the solvent by rotary evaporation and column
chromatography (silica gel, PE–EtOAc, 2:1) afforded acid 11 (350
mg, 1.37 mmol, 98%) as a white solid; mp 139–140 °C (Lit.8 136–
138 °C).
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 16 Hz, 1 H), 7.55 (d,
J = 7.5 Hz, 1 H), 7.44–7.30 (m, 6 H), 6.94–6.70 (m, 2 H), 6.56 (d,
J = 16.3 Hz, 1 H), 5.17 (s, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O3Na: 301.1774;
found: 301.1764.
(E)-3-[3-(Benzyloxy)phenyl]acrylic Acid (15)
Following the typical procedure for 11 using 14, chromatography
(PE–EtOAc, 2:1), gave 15 (802 mg, 96%) as a white solid; mp 152–
154 °C (Lit.12 151–153 °C).
1H NMR (400 MHz, DMSO-d6): δ = 12.44 (s, 1 H), 7.58 (d, J = 6.0
Hz, 1 H), 7.48–7.25 (m, 8 H), 7.06 (d, J = 7.8 Hz, 1 H), 6.57 (d,
J = 6.5 Hz, 1 H), 5.16 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 173.0, 157.6, 142.4, 136.5, 131.9,
129.2, 128.1, 127.2, 123.5, 121.1, 118.0, 112.9, 70.5.
13C NMR (100 MHz, DMSO-d6): δ = 167.6, 158.7, 143.8, 136.9,
135.7, 129.9, 128.4, 127.9, 127.8, 121.0, 119.6, 117.0, 113.8, 69.3.
(R)-2-Ethylhexyl (E)-3-[2-(Benzyloxy)phenyl]acrylate (13);
Typical Procedure
(R)-2-Ethylhexyl (E)-3-[3-(Benzyloxy)phenyl]acrylate (16)
Following the typical procedure for 13 using 15, chromatography
(PE–EtOAc, 20:1), gave 16 (28 mg, 77%) as a yellowish oil.
[α]D29 –3.1 (c 0.70, CHCl3).
A soln of alcohol 9 (13 mg, 0.10 mmol) in anhyd toluene (1 mL)
was added to a mixture of acid 11 (25 mg, 0.10 mmol), DMAP (25
mg, 0.10 mmol), MNBA 12 (69 mg, 0.20 mmol), anhyd Et3N (41
μL, 0.30 mmol) and powdered activated 4 Å MS (100 mg) in anhyd
toluene (1 mL). The mixture was stirred at r.t. for 3 h (TLC showed
completion). EtOAc (10 mL) was added and the solids were filtered
off. The filtrate was concentrated on a rotary evaporator. The resi-
due was chromatographed (silica gel, PE–EtOAc, 20:1) to give ester
13 (26 mg, 0.071 mmol, 73%) as a yellowish oil.
FT-IR (film): 2958, 2928, 1715, 1638, 1455, 1170, 1027, 781, 696
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 16.1 Hz, 1 H), 7.98–
7.29 (m, 6 H), 7.14–7.12 (m, 2 H), 6.99 (dd, J = 8.3, 1.5 Hz, 1 H),
6.42 (d, J = 15.8 Hz, 1 H), 5.09 (s, 2 H), 4.13–4.10 (m, 2 H), 1.65–
1.62 (m, 1 H), 1.44–1.26 (m, 8 H), 0.93 (t, J = 7.5 Hz, 3 H), 0.91 (t,
J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.1, 159.1, 144.4, 136.7, 135.9,
129.9, 128.6, 128.1, 127.5, 121.0, 118.7, 116.9, 114.0, 70.1, 67.0,
38.9, 30.5, 28.9, 23.8, 23.0, 14.0, 11.0.
[α]D29 –3.6 (c 1.00, CHCl3).
FT-IR (film): 2958, 2928, 2858, 1709, 1631, 1598, 1452, 1269,
1168, 1020, 750 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 16.0 Hz, 1 H), 7.54 (d,
J = 7.8 Hz, 1 H), 7.45–7.29 (m, 6 H), 6.97–6.95 (m, 2 H), 6.53 (d,
J = 16.1 Hz, 1 H), 5.15 (s, 2 H), 4.12–4.09 (m, 2 H), 1.40–1.37 (m,
1 H), 1.34–1.28 (m, 8 H), 0.91 (t, J = 6.5 Hz, 3 H), 0.89 (t, J = 6.0
Hz, 3 H).
MS (ESI): m/z = 389.5 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C24H30O3Na: 389.2087;
found: 389.2072.
13C NMR (100 MHz, CDCl3): δ = 167.7, 157.4, 139.7, 136.6, 131.4,
128.8, 128.7, 128.0, 127.2, 123.9, 121.1, 119.0, 112.7, 70.4, 66.8,
38.9, 30.5, 29.0, 23.9, 23.0, 14.1, 11.1.
(R)-2-Ethylhexyl 3-(3-Hydroxyphenyl)propanoate [(R)-1′]
Following the typical procedure for (R)-1 using 16, chromatography
(PE–EtOAc, 10:1), gave (R)-1′ (9 mg, 75%) as a yellowish oil.
MS (ESI): m/z = 389.4 ([M + Na]+).
[α]D28 –2.2 (c 0.45, MeOH), [α]D27 –6.8 (c 0.35, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C24H30O3Na: 389.2087;
found: 389.2097.
FT-IR (film): 3420, 2959, 2929, 2859, 1732, 1708, 1589, 1456,
1270, 1157, 999, 781, 695 cm–1.
1H NMR (400 MHz, CD3OD): δ = 7.06 (t, J = 7.8 Hz, 1 H), 6.67–
6.60 (m, 3 H), 3.97 (d, J = 5.8 Hz, 2 H), 2.84 (t, J = 7.4 Hz, 2 H),
2.61 (d, J = 7.5 Hz, 2 H), 1.53–1.48 (m, 1 H), 1.35–1.26 (m, 8 H),
0.90 (t, J = 6.5 Hz, 3 H), 0.87 (t, J = 7.6 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.14 (t, J = 7.6 Hz, 1 H), 6.77–
6.67 (m, 3 H), 5.30 (br s, 1 H, OH), 4.03–3.95 (m, 2 H), 2.90 (t,
J = 7.6 Hz, 2 H), 2.63 (d, J = 7.8 Hz, 2 H), 1.56–1.53 (m, 1 H),
1.36–1.26 (m, 8 H), 0.89 (t, J = 6.6 Hz, 3 H), 0.87 (t, J = 7.8 Hz, 3
H).
13C NMR (100 MHz, CD3OD): δ = 174.9, 158.6, 143.4, 130.5,
120.5, 116.7, 114.2, 67.8, 40.2, 36.8, 32.0, 31.5, 30.1, 24.8, 24.0,
14.4, 11.4.
13C NMR (100 MHz, CDCl3): δ = 173.4, 155.6, 142.2, 129.7, 120.5,
115.2, 113.2, 67.0, 38.7, 35.7, 30.8, 30.3, 28.9, 23.7, 22.9, 14.0,
10.9.
MS (ESI): m/z = 301.3 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O3Na: 301.1774;
(R)-2-Ethylhexyl 3-(2-Hydroxyphenyl)propanoate [(R)-1];
Typical Procedure
A mixture of 13 (26 mg, 0.071 mmol) and 10% Pd/C (26 mg) in
THF (0.7 mL) was stirred at r.t. under atmospheric H2 for 7 h (TLC
showed completion). The mixture was diluted with EtOAc. The sol-
ids were filtered off. The filtrate was concentrated on a rotary evap-
orator. The residue was chromatographed (silica gel, PE–EtOAc,
10:1) to give (R)-1 (15 mg, 0.053 mmol, 75%) as a yellowish oil.
[α]D28 –1.2 (c 0.25, MeOH); [α]D27 –3.3 (c 0.30, CHCl3).
FT-IR (film): 3420, 2960, 2928, 1709, 1458, 1360, 1268, 1099, 752
cm–1.
1H NMR (400 MHz, CD3OD): δ = 7.05–6.98 (m, 2 H), 6.75–6.70
(m, 2 H), 3.97 (d, J = 5.8 Hz, 2 H), 2.88 (t, J = 7.6 Hz, 2 H), 2.62 (t,
J = 7.5 Hz, 2 H), 1.55–1.51 (m, 1 H), 1.36–1.27 (m, 8 H), 0.91 (t,
J = 6.4 Hz, 3 H), 0.88 (t, J = 7.4 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.19 (s, 1 H), 7.12–7.07 (m, 2 H),
6.89–6.85 (m, 2 H), 4.04–3.96 (m, 2 H), 2.90 (t, J = 6.4 Hz, 2 H),
2.72 (t, J = 6.4 Hz, 2 H), 1.55–1.52 (m, 1 H), 1.34–1.24 (m, 8 H),
0.87 (t, J = 6.7 Hz, 3 H), 0.85 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CD3OD): δ = 175.5, 156.5, 131.0, 128.5,
128.0, 120.5, 115.9, 67.7, 40.2, 35.3, 31.6, 30.1, 27.2, 24.9, 24.0,
14.4, 11.4.
found: 301.1766.
Acknowledgment
13C NMR (100 MHz, CDCl3): δ = 175.9, 154.3, 130.5, 128.0, 127.4,
120.8, 117.3, 67.8, 38.6, 35.2, 30.3, 28.8, 24.6, 23.7, 22.9, 14.0,
10.9.
This work was supported by the National Basic Research Program
of China (the 973 Program, 2010CB833200), the National Natural
Science Foundation of China (21172247, 21032002, 20921091,
20672129, 20621062, 20772143), and the Chinese Academy of Sci-
ences.
MS (ESI): m/z = 279.1 ([M + H]+).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3296–3300

3300
L. Ding et al.
PAPER
(5) Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc.
1983, 105, 4059.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(6) Das, S. K.; Panda, G. Tetrahedron 2008, 64, 4162.
(7) Anderson, M. O.; Moser, J.; Sherrill, J.; Guy, R. K. Synlett
2004, 2391.
References
(8) Welter, T. R. US 4720559, 1988.
(1) (a) Kang, S. S. J. Nat. Prod. 1988, 51, 335. (b) Nicollier, G.
F.; Thompson, A. C. J. Agric. Food Chem. 1982, 30, 760.
(c) Khodakov, G. V.; Akimov, Y. A.; Shashkov, A. S.;
Kintya, P. K.; Grishkovets, V. I. Chem. Nat. Compd. (Engl.
Transl.) 1994, 30, 704. (d) Miyase, T.; Ohtsubo, A.; Ueno,
A.; Noro, T.; Kuroyanagi, M.; Fukushima, S. Chem. Pharm.
Bull. 1982, 30, 1986. (e) Nicollier, G. F.; Thompson, A. C.
J. Nat. Prod. 1983, 46, 183.
(2) (a) Khatoon, R.; Saba, N.; Zahoor, A.; Summer, S.; Ahmad,
V. U. Nat. Prod. Commun. 2012, 7, 61. The structure 1 was
previously mentioned in two patents, see: (b) Rudolph, T.;
Buchholz, H. WO 2006111233, 2006. (c) Rudolph, T.;
Buchholz, H. WO 2006111234, 2006.
(9) (a) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002,
43, 7535. (b) Shiina, I.; Kubota, M.; Oshiumi, H.;
Hashizume, M. J. Org. Chem. 2004, 69, 1822. (c) For an
interesting case showing the advantage of MNBA, see: Wu,
Y.-K.; Yang, Y.-Q. J. Org. Chem. 2006, 71, 4296.
(10) El-Batta, A.; Jiang, C.; Zhao, W.; Anness, R.; Cooksy, A. L.;
Bergdahl, M. J. Org. Chem. 2007, 72, 5244; but the
synthesis was achieved via a Wittig reaction of the
corresponding aldehyde under the conditions given in ref. 7
above.
(11) Hodgson, D. M.; Kaka, N. S. Angew. Chem. Int. Ed. 2008,
47, 9958.
(12) Connor, D. T.; Cetenko, W. A.; Mullican, M. D.; Sorenson,
R. J.; Unangst, P. C.; Weikort, R. J.; Adolphson, R. L.;
Kennedy, J. A.; Thueson, D. O.; Wright, C. D.; Conroy, M.
C. J. Med. Chem. 1992, 35, 958.
(3) For a practical high-yielding route to such auxiliaries, see:
Wu, Y.-K.; Shen, X. Tetrahedron: Asymmetry 2000, 11,
4359.
(4) Crimmins, M. T.; She, J. Synlett 2004, 1371.
Synthesis 2012, 44, 3296–3300
© Georg Thieme Verlag Stuttgart · New York