Synthesis and absolute configurations of six natural phenylpropanoids

Article abstract of DOI:10.1002/ejoc.201402096

In an effort to find answers to the tantalizing questions about the absolute configurations of a group of long-known natural phenylpropanoids with very similar structures but different signs for the optical rotations, the compounds in question were synthe

Full text of DOI:10.1002/ejoc.201402096

FULL PAPER
DOI: 10.1002/ejoc.201402096
Synthesis and Absolute Configurations of Six Natural Phenylpropanoids
Xue-Lian Liu,[a,b] Hui-Jun Chen,[a] Yang-Yang Yang,[a] Yikang Wu,*[a] and Jun You*[b]
Keywords: Natural products / Alkylation / Esters / Alcohols / Aldehydes
In an effort to find answers to the tantalizing questions about
the absolute configurations of a group of long-known natural
phenylpropanoids with very similar structures but different
signs for the optical rotations, the compounds in question
were synthesized in enantiomerically pure form using Evans
asymmetric alkylation to generate the stereogenic centres
with predefined absolute configurations. The 1H and 13C
NMR spectra of the synthetic products were very consistent
with those reported for their natural counterparts. In most
cases, the optical rotations were also consistent with the cor-
responding data for the natural samples. The new findings
not only allowed unequivocal assignments of the absolute
configurations for the natural products, but also revealed that
the configurations of closely related compounds from the
same plant may be different.
nitidum (4[2]), Flindersia australis (5[1b]), and Fagara
zanthoxyloides (5 and 6[3]), respectively. Although their
molecular architectures are by no means complex, for un-
specified reasons their absolute configurations were not de-
termined in the original studies, creating tantalizing ques-
tions for those who wish to gain complete structural infor-
mation about these compounds. And judging by the time
already elapsed since the isolation of these compounds (10–
20 years), it seems that the situation will remain unchanged
unless a synthetic study is carried out. Therefore, we synthe-
sized compounds 1–6 in enantiopure form(s), which al-
lowed unambiguous assignments of the absolute configura-
tions of their natural counterparts. In this paper, we de-
scribe the details of this endeavour.
Introduction
Natural phenylpropanoids 1–6 (Figure 1) were obtained
from the plants Aralia bipinnata (1–3[1]), Xanthoxylum
Results and Discussion
Our synthesis began with the alkylation of p-hydroxy-
benzaldehyde (7) with ethyl 4-bromobutanoate in the pres-
ence of K2CO3 to give the intermediate ester (Scheme 1),
which was directly hydrolysed with NaOH to give acid 8[4]
in 99% overall yield. Chiral oxazolidinone auxiliary 9[5] was
then introduced with the aid of EDCI. The unprotected al-
dehyde group survived all these steps without causing any
adverse effects.
Figure 1. The planar structures for 1–6 provided in the literature
along with corresponding literature optical rotation measurements
for the natural samples.
The chain extension from the aldehyde group in 10
[a] State Key Laboratory of Bioorganic and Natural Products was achieved using
a Wittig reaction with either
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Ph3P=CHCO2Et or Ph3P=CHCO2Me. The (E)/(Z) ratio
was ca. 94:6, and the (E) and (Z) isomers were separable
from each other on silica gel in each case. The key enantio-
selective alkylation was then performed on the isolated pure
(E) isomers under the widely used conditions introduced by
Evans[6] et al. in the early 1980s. Thus, using NaN-
(SiMe3)2 (NaHMDS) as the base, deprotonation of 11a or
11b in THF at –78 °C followed by treatment with MeI pro-
Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
E-mail: yikangwu@sioc.ac.cn
http://www.sioc.ac.cn
[b] Key Laboratory of Green Chemical Technology of College of
Heilongjiang Province, College of Chemical and Environmental
Engineering, Harbin University of Science and Technology,
Harbin 150040, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402096.
Eur. J. Org. Chem. 2014, 3451–3459
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
Scheme 2. Reagents and conditions: a) DIBAL-H, CH2Cl2, –78 °C,
2 h, then to room temp. 5 h, 83% from 13 or 98% from (S)-4;
b) MnO2, CH2Cl2, room temp., 20 h, 80%; c) H2 (1 atm), Pd-C,
EtOH, room temp., 12 h, 96%; DIBAL-H = diisobutylaluminum
hydride.
Scheme 1. Reagents and conditions: a) (i) Br(CH2)3CO2Et, K2CO3,
DMF, room temp., 12 h; (ii) NaOH, H2O, 99%; b) 9, EDCI,
CH2Cl2, DMAP, room temp., 14 h, 78%; c) Ph3P=CHCO2Et,
CH2Cl2, room temp., 23 h, 82% for 11a [(E)/(Z) = 94:6], or
Ph3P=CHCO2Me, CH2Cl2, room temp., 20 h, 79% for 11b [(E)/(Z)
= 96:4]; d) NaN(SiMe3)2, THF, MeI, –78 °C to room temp. 56%
for 12a, 46% for 12b; e) NaBH4, THF/H2O, room temp., 12 h, 87%
13; f) NaBH4, THF/H2O, room temp., 18 h, 90% for (S)-4; EDCI
= N-(3-dimethylaminopropyl)-N-ethylcarbodiimide, DMAP = 4-
(dimethylamino)pyridine.
Hydrogenation of (S)-2 over Pd-C (10%) delivered (S)-5,
1
whose H and 13C NMR spectra were identical with those
reported for natural 5. The optical rotation was also consis-
tent with that of the natural product, confirming the abso-
lute configuration of natural 5 as (S).
To access (R)-1, the natural enantiomer, we next carried
out the synthesis shown in Scheme 3. Using EDCI[9] as the
condensing agent, acid 8 was connected to chiral auxiliary
vided the desired product (i.e., 12a or 12b) in 56 or 46% 14[5] to give 15. Asymmetric alkylation was then performed
yield, respectively, as an inseparable mixture of dia- similarly to the alkylation of 11 to give 12, as mentioned
stereomers [presumably with de = 87.7%, as deduced later above. This gave 17 in 84% yield [as an inseparable mixture
from the ee value of (S)-4]. It is interesting to note that the of diastereomers, presumably with de = 90.2%, as deduced
ester and the conjugate alkene functionalities did not cause from the ee value of (R)-4]. Reductive removal of the chiral
any serious problems in this carbanion-mediated alkylation. auxiliary with NaBH4/THF/H2O gave (R)-4, whose 1H and
Compounds 12a and 12b were next separately treated 13C NMR spectra and optical rotation sign were consistent
with NaBH4 in THF/H2O[7] to remove the chiral auxiliary, with those reported for natural 4. This confirmed the (R)
which gave 13 and (S)-4 (87.7% ee by chiral HPLC) in 87 configuration of natural 4. Upon further reduction of (R)-
1
and 90% yields, respectively. Because the optical rotation 4 with DIBAL-H, (R)-1 was obtained, whose H and 13C
of (S)-4 is opposite to that of natural 4, the configuration NMR spectra and optical rotation were consistent with
of the latter is expected to be (R) (vide infra).
those reported for natural 1. This proved that the absolute
Reduction (Scheme 2) of the ester group in 13 or (S)-4 configuration of natural 1 is (R).
with DIBAL-H led to (S)-2 (87.2% ee by chiral HPLC),
(R)-3 was synthesized as shown in Scheme 4. Instead of
1
whose H and 13C NMR spectra and optical rotation were reduction with NaBH4, as in the synthesis of 1, 4, and 5
consistent with those reported for natural 2. The absolute shown above, the chiral auxiliary was removed from the
configuration of natural 2 thus can be reliably assigned as substrate by perhydrolysis under the H2O2/LiOH[10] condi-
(S).
tions introduced by Evans. The resulting acid (i.e., 18) was
Selective oxidation of the allylic alcohol in (S)-2 with then treated with DIBAL-H to selectively reduce the ester
[8]
MnO2 gave the corresponding aldehyde [i.e., (S)-1]. Be- group to an alcohol. The carboxylic group was readily con-
cause natural 1 and 2 were isolated from the same plant at verted into its methyl ester by exposure to Me3SiCHN2.[11]
the same time, one would well expect that these two com- The final transformation of allylic acohol 20 into end prod-
pounds had the same absolute configuration. However, very uct (R)-3 was achieved by oxidation with MnO2. Unfortu-
interestingly, this aldehyde turned out to be the antipode of nately, this time we obtained the antipode of the natural
natural 1, as shown by the opposite sign of its optical rota- product, as the sign of the optical rotation clearly showed.
tion. Thus, the opposite signs of the optical rotations of
Using the same sequence but with 12b instead of 17 as
natural 1 and 2 are not a result of the electron-withdrawing the starting material, as shown in Scheme 5, natural
nature of the aldehyde group (in 1) compared with the re- enantiomer (S)-3 was obtained, which confirmed that natu-
lated alcohol (in 2).
ral 3 does indeed have an (S) configuration.
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Synthesis of Six Natural Phenylpropanoids
Scheme 5. Reagents and conditions: a) LiOH, H2O2, THF/H2O,
room temp., 3 h, 89% b) DIBAL-H, CH2Cl2, –78 °C, 3.5 h, then
r.t. 12 h, 83%; c) Me3SiCHN2, Et2O/MeOH, 0 °C, 5 min, 92%;
d) MnO2, CH2Cl2, room temp., 40 h, 86%.
sired triol (i.e., 21) in 23% yield, along with an unidentified
compound as the major product. The newly formed vicinal
diol functionality was then oxidatively cleaved with NaIO4.
The intermediate aldehyde was reduced immediately with
Scheme 3. Reagents and conditions: a) 14, EDCI, CH2Cl2, DMAP,
room temp., 13 h, 90%; b) Ph3P=CHCO2Me, CH2Cl2, room temp.,
14 h, 82% (E)/(Z) = 96:4; c) NaN(SiMe3)2, THF, MeI, –78 °C to
room temp. 84% for 17; d) NaBH4, THF/H2O, room temp., 13 h,
96%; e) DIBAL-H, CH2Cl2, –78 °C, 3 h, then r.t. 4 h, 73% [along
with 24% of recovered (R)-4]; f) MnO2, CH2Cl2, room temp., 20 h,
84%; g) H2 (1 atm), Pd-C, EtOH, room temp., 3 h, 100%; DIBAL-
H = diisobutylaluminum hydride.
1
NaBH4 to give the end product, diol 6. As the H and 13C
NMR spectra of this compound were fully consistent with
those reported for natural 6, and the signs for the optical
rotations were negative in both cases, natural 6 must have
an (S) configuration.
Scheme 6. Reagents and conditions: a) (i) BH3·Me2S, THF, room
temp., 9 h; (ii) H2O2, NaOH, 23% from (S)-2; b) (i) NaIO4, EtOH/
H2O, room temp., 20 min; (ii) NaBH4, EtOH/H2O, room temp.,
10 min, 57% from 21.
The large discrepancy between the absolute values of the
optical rotations for natural and synthetic 6 may deserve a
few more words here. To exclude potential errors due to low
sample concentrations, which have been observed[12] with
some other diols, we took advantage of the quantities ample
(compared with the natural products) of the synthetic
samples, and measured the optical rotations at a range of
concentrations (see Supporting Information). In the case of
Scheme 4. Reagents and conditions: a) LiOH, H2O2, THF/H2O,
room temp., 1.5 h, 96%; b) DIBAL-H, CH2Cl2, –78 °C, 2 h, then
r.t. 12 h, 48% (along with 47% recovered 18); c) Me3SiCHN2,
Et2O/MeOH, 0 °C, 20 min, 96%; d) MnO2, CH2Cl2, room temp.,
40 h, 74%.
To gain access to diol 6, the (S)-2 synthesized in (S)-6, the data measured at concentrations ranging from c
Scheme 6 was treated with BH3, followed by oxidation with = 0.10 to 0.60 all fell into the –6.6 to –8.4 region, which by
H2O2 in the presence of NaOH. The reaction gave the de- no means could come close to –37. These self-consistent
Eur. J. Org. Chem. 2014, 3451–3459
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X.-L. Liu, H.-J. Chen, Y.-Y. Yang, Y. Wu, J. You
FULL PAPER
mixture was washed with water and brine, and the organic phase
was dried with anhydrous Na2SO4. Removal of the solvent by ro-
tary evaporation and column chromatography (PE/EtOAc, 3:1) on
silica gel gave 10 (664 mg, 1.88 mmol, 78% from 8) as a colourless
oil. Data for 10: M.p. 70–72 °C. [α]2D6 = +44.0 (c = 1.00, CHCl3);
data, along with the enantiopurity of the synthetic sample
(88% ee), argue convincingly for their reliability. Indeed,
judging from the close structural relationship between 6 and
5, there is no reason to expect that the optical rotation of
6 should be very different from that of 5.
1
[α]2D7 = +44.5 (c = 1.00, CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 9.88 (s, 1 H), 7.81 (d, J = 8.6 Hz, 2 H), 7.40–7.33 (m, 3 H), 7.32–
7.28 (m, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 5.44 (dd, J = 8.9, 3.7 Hz,
1 H), 4.70 (t, J = 8.9 Hz, 1 H), 4.30 (dd, J = 9.0, 3.7 Hz, 1 H), 4.06
(t, J = 6.0 Hz, 2 H), 3.20 (dt, J = 18.1, 7.2 Hz, 1 H), 3.14 (dt, J =
18.1, 7.0 Hz, 1 H), 2.14 (quint, J = 6.7 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 190.7, 171.9, 163.8, 153.7, 138.9, 131.9,
129.9, 129.2, 128.7, 125.8, 114.7, 70.0, 66.9, 57.5, 31.9, 23.4 ppm.
Conclusions
Using Evans asymmetric alkylation to create the stereo-
genic centres in the substrates, phenylpropanoids 1–6 were
synthesized in enantiopure form(s). The chiral-auxiliary-in-
duced asymmetric alkylation was examined for the first
time in the presence of potentially interfering functionalities
(to the best of our knowledge). The synthetic samples with
reliable absolute configurations and known optical purities
helped us to assign the absolute configurations of their nat-
ural counterparts on an unequivocal basis. Thus, the tanta-
lizing questions about the absolute configurations of these
natural products raised by the incomplete structural assign-
ments in the literature years ago are solved (at least for 1–
3, 5, and 6). This set of compounds is the first with this
particular type of stereogenic centres with known configu-
rations and optical rotations, and thus these compounds
may potentially serve as references (not available to date)
for other related compounds. It is also interesting to note
that, for instance, natural 1 and 2 have opposite configura-
tions, despite their common biological origin. Such unex-
pected structural knowledge might be explained by the
study of e.g., biosynthetic pathways and related enzy-
mology.
FTIR (film of a conc. solution in CH Cl ): ν = 2924, 2854, 2739,
˜
2
2
1779, 1688, 1599, 1577, 1509, 1470, 1456, 1384, 1314, 1257, 1212,
1159, 1112, 1080, 1042, 833, 701 cm–1. ESI-MS: m/z = 354.4 [M +
H]+. ESI-HRMS: calcd. for C20H19NO5Na [M + Na]+ 376.1155;
found 376.1168.
Wittig Reaction of 10 To Give 11a: A mixture of 10 (152 mg,
0.43 mmol) and Ph3P=CHCO2Et (150 mg, 0.43 mmol) in dry
CH2Cl2 (10 mL) was stirred at ambient temperature for 14 h. An-
other portion of Ph3P=CHCO2Et (75 mg, 0.22 mmol) was added.
The mixture was stirred at the same temperature for another 9 h,
after which TLC showed completion of the reaction. The mixture
was purified by chromatography (PE/EtOAc, 3:1) on silica gel to
give 11a (149 mg, 0.35 mmol, 82% from 10) as a white powder.
Data for 11a: M.p. 92–93 °C. [α]2D4 = +31.3 (c = 1.00, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 16.0 Hz, 1 H), 7.37 (d,
J = 8.7 Hz, 2 H), 7.31–7.19 (m, 5 H), 6.76 (d, J = 8.7 Hz, 2 H),
6.22 (d, J = 16.2 Hz, 1 H), 5.35 (dd, J = 8.7, 3.7 Hz, 1 H), 4.61 (t,
J = 8.8 Hz, 1 H), 4.23–4.14 (m, 3 H), 3.92 (t, J = 6.0 Hz, 2 H),
3.11 (dt, J = 17.9, 7.1 Hz, 1 H), 3.05 (dt, J = 18.0, 6.9 Hz, 1 H),
2.03 (quint, J = 6.6 Hz, 2 H), 1.26 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 172.0, 167.3, 160.5, 153.7, 144.2,
139.0, 129.6, 129.2, 128.7, 127.2, 125.9, 115.7, 114.8, 70.0, 66.6,
60.3, 57.6, 32.0, 23.6, 14.3 ppm. FTIR (KBr): ν = 3066, 3027, 2981,
˜
Experimental Section
2933, 2882, 1794, 1765, 1702, 1633, 1604, 1573, 1359, 1334, 1311,
1250, 1170, 828 cm–1. ESI-MS: m/z = 446.6 [M + Na]+. ESI-
HRMS: calcd. for C24H25NO6Na [M + Na]+ 446.1574; found
446.1590.
General Methods: NMR spectra were recorded with a Bruker
Avance NMR spectrometer operating at 400 MHz for 1H, unless
otherwise stated. IR spectra were measured with a Nicolet 380 In-
frared spectrophotometer. ESI-MS data were acquired with a Shi-
madzu LCMS-2010EV mass spectrometer. ESI-HRMS data were
obtained with a Bruker APEXIII 7.0 Tesla FTMS spectrometer.
EI-MS spectra were recorded with an Agilent Technologies 5973N
spectrometer. EI-HRMS data were acquired with a Waters Micro-
mass GCT Premier instrument. Optical rotations were measured
with a Jasco P-1030 polarimeter [except for those values for (R)-4
measured at the less common wavelengths, which were measured
with a Rudolph Autopol VI polarimeter]. Melting points were mea-
sured with a hot-stage melting point apparatus equipped with a
microscope. Dry THF was distilled from Na/Ph2CO under argon
before use. Dry toluene and CH2Cl2 were dried with activated 4 Å
MS (molecular sieves). All reagents were reagent grade, and were
used as supplied. Column chromatography was performed on silica
Wittig Reaction of 10 To Give 11b: Following the procedure used
for the conversion of 10 into 11a, but with Ph3P=CHCO2Me in-
stead of Ph3P=CHCO2Et, purification by chromatography (PE/
EtOAc, 3:1) gave 11b (201 mg, 0.491 mmol, 79% from 10) as a
white powder. Data for 11b: M.p. 120–123 °C. [α]2D6 = +26.7 (c =
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J =
15.8 Hz, 1 H), 7.44 (d, J = 8.9 Hz, 2 H), 7.38–7.27 (m, 5 H), 6.83
(d, J = 8.9 Hz, 2 H), 6.30 (d, J = 15.9 Hz, 1 H), 5.42 (dd, J = 8.6,
3.7 Hz, 1 H), 4.69 (dt, J = 1.1, 8.8 Hz, 1 H), 4.32–4.25 (m, 1 H),
3.99 (t, J = 6.3 Hz, 2 H), 3.79 (s, 3 H), 3.19 (dt, J = 17.9, 7.0 Hz,
1 H), 3.12 (dt, J = 17.9, 7.0 Hz, 1 H), 2.11 (quint, J = 6.6 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0, 167.8, 160.6,
153.7, 144.5, 139.0, 129.7, 129.2, 128.8, 127.1, 125.9, 115.2, 114.8,
70.0, 66.6, 57.6, 51.5, 32.0, 23.6 ppm. FTIR (KBr): ν = 3025, 2994,
˜
gel (300–400 mesh) under
a slightly positive pressure. PE
2949, 2923, 2871, 1775, 1700, 1635, 1603, 1573, 1511, 1472, 1434,
1378, 1291, 1147, 829 cm–1. ESI-MS: m/z = 432.3 [M + Na]+. ESI-
HRMS: calcd. for C23H23NO6Na [M + Na]+ 432.1418; found
432.1409.
(chromatography solvent) stands for petroleum ether (b.p. 60–
90 °C).
Condensation of 8 with 9 To Give 10: A mixture of acid 8 (500 mg,
2.40 mmol), chiral auxiliary 9 (430 mg, 2.64 mmol), EDCI (690 mg,
3.60 mmol), and DMAP (59 mg, 0.48 mmol) in dry CH2Cl2 Methylation of 11a To Give 12a: NaHMDS (1.0 m solution in THF;
(10 mL) was stirred at ambient temperature for 14 h. When TLC
showed that the reaction was complete, the mixture was concen-
trated on a rotary evaporator. EtOAc was added to the residue, the
3.35 mL, 3.35 mmol) was added dropwise to a stirred solution of
11a (1.290 g, 3.05 mmol) in dry THF (20 mL) at –78 °C (EtOH/dry
ice bath) under argon (balloon). The mixture was stirred at the
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Synthesis of Six Natural Phenylpropanoids
same temperature for 2.5 h, then MeI (0.39 mL, 7.62 mmol) was
added. The mixture was stirred for 11.5 h, during which time the
bath was allowed to warm up from –78 °C to –5 °C. Saturated
aqueous NH4Cl (2 mL) was then added. The mixture was concen-
trated on a rotary evaporator. The residue was extracted with
EtOAc (3ϫ50 mL). The combined organic layers were washed with
water and brine, and then dried with anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(PE/EtOAc, 3:1) on silica gel gave 12a (745 mg, 1.70 mmol, 56%
δ = 167.8, 160.7, 144.5, 129.7, 127.1, 115.2, 114.8, 67.9, 66.3, 51.5,
33.1, 32.6, 16.7 ppm. FTIR (KBr): ν = 3521, 2975, 2955, 2932,
˜
2875, 1698, 1633, 1604, 1511, 1473, 1448, 1423, 1332, 1306, 1288,
1257, 1206, 1175, 1051, 1010, 984, 828 cm–1. ESI-MS: m/z = 265.2
[M + H]+. ESI-HRMS: calcd. for C15H20O4Na [M + Na]+
287.1254; found 287.1253.
Reductive Cleavage of the Chiral Auxiliary in 12a To Give 13: The
procedure described above for the conversion of 12b into (S)-4 was
used, but with 12a instead of 12b. After purification by chromatog-
raphy (PE/EtOAc, 3:1), this gave 13 (115 mg, 0.413 mmol, 87%
from 11a) as a white powder. Data for 12a: M.p. 74–74 °C. [α]2D6
=
1
+115.5 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.63
(d, J = 15.9 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.41–7.30 (m, 3
H), 7.27 (dd, J = 8.3, 1.6 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 6.30
(d, J = 16.3 Hz, 1 H), 5.41 (dd, J = 8.8, 3.9 Hz, 1 H), 4.58 (t, J =
8.7 Hz, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 4.21 (dd, J = 9.5, 3.6 Hz,
1 H), 4.10–3.95 (m, 3 H), 2.22 (ddt, J = 14.4, 8.3, 6.2 Hz, 1 H),
1.88 (dq, J = 14.0, 5.6 Hz, 1 H), 1.33 (t, J = 7.3 Hz, 3 H), 1.20 (d,
J = 6.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.8,
167.3, 160.5, 153.3, 144.1, 139.1, 129.7, 129.2, 128.7, 127.2, 125.6,
115.8, 114.8, 69.7, 65.8, 60.3, 57.7, 34.8, 32.3, 17.8, 14.3 ppm. FTIR
from 12a) as a white powder. Data for 13: M.p. 75–78 °C. [α]2D4
=
1
–5.1 (c = 1.00, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.63 (d,
J = 16.5 Hz, 1 H), 7.46 (d, J = 8.3 Hz, 2 H), 6.89 (d, J = 8.5 Hz,
2 H), 6.30 (d, J = 15.7 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.11–
4.02 (m, 2 H), 3.55 (d, J = 6.1 Hz, 2 H), 1.98–1.88 (m, 2 H), 1.85
(br. s, 1 H), 1.72–1.64 (m, 1 H), 1.33 (t, J = 7.4 Hz, 3 H), 1.00 (d,
J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.4,
160.6, 144.2, 129.7, 127.2, 115.7, 114.8, 67.9, 66.3, 60.3, 33.1, 32.6,
16.7, 14.3 ppm. FTIR (KBr): ν = 3364, 2972, 2949, 2932, 2913,
˜
2872, 1704, 1633, 1604, 1513, 1424, 1313, 1256, 1178, 1045, 985,
831 cm–1. ESI-MS: m/z = 279.2 [M + H]+. ESI-HRMS: calcd. for
C16H22O4Na [M + Na]+ 301.1410; found 301.1420.
(KBr): ν = 3063, 3030, 2978, 2938, 2881, 1782, 1708, 1633, 1602,
˜
1513, 1386, 1242, 1159, 826 cm–1. ESI-MS: m/z = 460.4 [M + Na]+.
ESI-HRMS: calcd. for C25H27NO6Na [M + Na]+ 460.1731; found
460.1737.
DIBAL-H Reduction of (S)-4 To Give (S)-2: DIBAL-H (1.0 m solu-
tion in cyclohexane; 4.2 mL, 4.2 mmol) was added to a stirred solu-
tion of (S)-4 (371 mg, 1.405 mmol) in dry CH2Cl2 (5 mL) at –78 °C
(EtOH/dry ice bath) under argon (balloon). The mixture was
stirred at the same temperature for 2 h, then satd. aq. sodium po-
tassium tartrate (2 mL) was added carefully, followed by CH2Cl2
(4 mL). Stirring was continued at ambient temperature for 5.5 h,
after which time the system had become a two-phase clear mixture.
The phases were separated. The aqueous layer was extracted with
CH2Cl2 (2ϫ60 mL). The combined organic layers were washed in
turn with water and brine, and dried with anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and column chromatog-
raphy (PE/EtOAc, 1:1) on silica gel gave (S)-2 [327 mg,
1.373 mmol, 98% from (S)-4] as a white powder. Data for (S)-2:
M.p. 70–71 °C. [α]2D7 = –6.9 (c = 1.00, CHCl3); [α]2D7 = –4.5 (c =
0.21, MeOH) [ref.[1a] data for natural 2: [α]2D4 = –5.1 (c = 0.21,
MeOH)]. ee = 87.2% [tR for (S)-2 = 59.927 min, tR for (R)-2 =
64.427 min], as measured by HPLC with a Phenomenex Lux 5 μm
Amylose-2 column (25ϫ0.46 cm), eluting with n-hexane/iPrOH,
9:1, at a flow rate of 0.7 mL/min, with the UV detector set to
Methylation of 11b To Give 12b: The procedure described above for
the conversion of 11a into 12a was used, but with 11b instead of
11a. This gave 12b (1.014 g, 2.396 mmol, 46% from 11b) as a white
powder. Data for 12b: M.p. 107–111 °C. [α]2D7 = +123.1 (c = 0.50,
CHCl3), [α]2D7 = +121.4 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.64 (d, J = 15.8 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 2 H),
7.42–7.26 (m, 5 H), 6.88 (d, J = 8.7 Hz, 2 H), 6.31 (d, J = 15.8 Hz,
1 H), 5.41 (dd, J = 8.8, 4.0 Hz, 1 H), 4.59 (t, J = 9.0 Hz, 1 H), 4.22
(dd, J = 8.9, 3.9 Hz, 1 H), 4.09–3.95 (m, 3 H), 3.79 (s, 3 H), 2.22
(ddt, J = 14.2, 8.2, 6.0 Hz, 1 H), 1.88 (dq, J = 13.3, 6.5 Hz, 1 H),
1.21 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
175.8, 167.7, 160.6, 153.3, 144.5, 139.1, 129.7, 129.2, 128.7, 127.2,
125.7, 115.3, 114.8, 69.8, 65.8, 57.7, 51.6, 34.8, 32.3, 17.8 ppm.
FTIR (KBr): ν = 3066, 2982, 2948, 1778, 1699, 1633, 1603, 1513,
˜
1454, 1390, 1250, 1204, 1167, 1037, 834, 747 cm–1. ESI-MS: m/z =
446.3 [M + Na]+. ESI-HRMS: calcd. for C24H25NO6Na [M +
Na]+ 446.1574; found 446.1562.
Reductive Cleavage of the Chiral Auxiliary in 12b To Give (S)-4:
NaBH4 (196 mg, 5.182 mmol) was added to a stirred solution of
12b (731 mg, 1.727 mmol) in THF (8 mL) and H2O (1 mL) at am-
bient temperature. After 18 h, TLC showed that the reaction was
complete. The mixture was extracted with EtOAc (2ϫ50 mL). The
combined organic layers were washed with water and brine, and
then dried with anhydrous Na2SO4. Removal of the solvent by ro-
tary evaporation and column chromatography (PE/EtOAc, 5:2) on
silica gel gave (S)-4 (411 mg, 1.556 mmol, 90% from 12b) as a white
powder. Data for (S)-4: M.p. 57–58 °C. [α]2D6 = –4.85 (c = 1.00,
MeOH); [α]2D7 = –5.75 (c = 0.50, MeOH); [α]2D7 = –7.06 (c = 0.25,
MeOH); [α]2D7 = –10.9 (c = 0.20, MeOH) [ref.[2] data for natural 4:
[α]500 = +4.34 (c = 0.23, MeOH); cf. also the data at different wave-
lengths for (R)-4 below]. ee = 87.7% [tR for (S)-4 = 16.577 min, tR
for (R)-4 = 15.627 min], as measured by HPLC with a Phenomenex
Lux 5 μm Cellulose-3 column (25ϫ0.46 cm), eluting with n-hex-
1
214 nm. H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 8.5 Hz, 2
H), 6.85 (d, J = 8.7 Hz, 2 H), 6.55 (d, J = 16.0 Hz, 1 H), 6.23 (dt,
J = 15.8, 6.0 Hz, 1 H), 4.29 (dd, J = 5.9, 1.2 Hz, 2 H), 4.07 (dt, J
= 9.6, 5.8 Hz, 1 H), 4.02 (ddd, J = 9.5, 7.2, 6.0 Hz, 1 H), 3.55 (d,
J = 5.6 Hz, 2 H), 1.97–1.86 (m, 2 H), 1.72–1.63 (m, 3 H, including
2 OH), 1.00 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.5, 130.9, 129.5, 127.7, 126.3, 114.6, 67.9, 66.2,
63.9, 33.2, 32.8, 16.8 ppm. FTIR (KBr): ν = 3306, 2933, 2874,
˜
1604, 1511, 1244, 1174, 1059, 970, 833 cm–1. ESI-MS: m/z = 259.2
[M + Na]+. ESI-HRMS: calcd. for C14H20O3Na [M + Na]+
259.1305; found 259.1306.
DIBAL-H Reduction 13 To Give (S)-2: DIBAL-H (1.0 m solution
in cyclohexane; 1.3 mL, 1.3 mmol) was added to a stirred solution
of 13 (121 mg, 0.435 mmol) in dry CH2Cl2 (4 mL) at –72 °C
(EtOH/dry ice bath) under argon (balloon). The mixture was
ane/iPrOH, 8:2, at a flow rate of 0.7 mL/min, with the detector set
1
to 214 nm. H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 16.2 Hz, stirred at the same temperature for 1.5 h, and then satd. aq. sodium
1 H), 7.46 (d, J = 8.9 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 2 H), 6.31 (d,
J = 15.9 Hz, 1 H), 4.12–4.01 (m, 2 H), 3.79 (s, 3 H), 3.55 (d, J =
5.9 Hz, 2 H), 2.00–1.87 (m, 2 H), 1.79 (br. s, 1 H), 1.72–1.64 (m, 1
potassium tartrate (2 mL) was added carefully, followed by CH2Cl2
(4 mL). Stirring was continued at ambient temperature for 5 h, af-
ter which time the system had become a two-phase clear mixture.
H), 1.00 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): The phases were separated. The aqueous layer was extracted with
Eur. J. Org. Chem. 2014, 3451–3459
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3455

X.-L. Liu, H.-J. Chen, Y.-Y. Yang, Y. Wu, J. You
FULL PAPER
CH2Cl2 (3ϫ10 mL). The combined organic layers were washed in
turn with water and brine, and then dried with anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column
chromatography (PE/EtOAc, 1:1) on silica gel gave (S)-2 (85 mg,
0.36 mmol, 83% from 13) as a white powder, along with recovered
13 (20 mg, 0.072 mmol, 17%). For data for (S)-2, see above.
chromatography (PE/EtOAc, 1:2) on silica gel gave intermediate 21
[24 mg, 23% from (S)-2] as a colourless oil.
This material was directly dissolved in EtOH (1 mL), and a solu-
tion of NaIO4 (30 mg, 0.142 mmol) in H2O (0.2 mL) was added.
The milky mixture was stirred at ambient temperature for 20 min,
after which time TLC showed that the reaction was complete.
NaBH4 (5 mg, 0.132 mmol) was then added to the mixture. Stirring
was continued at the same temperature for another 10 min, and
then satd. aq. NH4Cl (1 mL) was added. The mixture was extracted
with EtOAc (2ϫ35 mL). The combined organic layers were washed
in turn with water and brine, and then dried with anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (PE/EtOAc, 1:1) on silica gel gave (S)-6 (12 mg,
0.0535 mmol, 57% from 21) as a white powder. Data for (S)-6:
M.p. 68–70 °C. [α]2D5 = –7.1 (c = 0.60, MeOH); [α]2D6 = –6.6 (c =
0.30, MeOH); [α]2D6 = –7.6 (c = 0.20, MeOH); [α]2D4 = –8.0 (c = 0.12,
MeOH); [α]2D4 = –8.4 (c = 0.10, MeOH) [ref.[3] data for natural 6:
[α]2D3 = –37 (c = 0.1, MeOH)]. 1H NMR (500 MHz, CDCl3): δ =
7.13 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 4.05 (dt, J =
9.1, 6.0 Hz, 1 H), 4.00 (ddd, J = 8.9, 6.9, 6.1 Hz, 1 H), 3.81 (t, J =
6.3 Hz, 2 H), 3.54 (d, J = 5.9 Hz, 2 H), 2.80 (t, J = 6.7 Hz, 2 H),
MnO2 Oxidation of (S)-2 To Give (S)-1: A mixture of activated
MnO2 (88%, 66 mg, 0.64 mmol) and (S)-2 (20 mg, 0.0847 mmol)
in dry CH2Cl2 (0.5 mL) was stirred at ambient temperature for
20 h, after which time TLC showed that the reaction was complete.
The solids were removed by filtration [washing with CH2Cl2
(40 mL)]. The combined filtrate and washings were concentrated
on a rotary evaporator to dryness to give rather pure (S)-1 [16 mg,
0.0683 mmol, 80% from (S)-2] as a white powder. Data for (S)-1:
M.p. Ͻ26 °C. [α]2D7 = –5.50 (c = 1.00, CHCl3); [α]2D4 = –5.42 (c =
0.50, MeOH); [α]2D4 = –6.95 (c = 0.20, MeOH); [α]2D5 = –6.70 (c =
0.14, MeOH); [α]2D5 = –7.58 (c = 0.10, MeOH); [α]2D5 = –10.03 (c =
0.08, MeOH); [α]2D5 = –10.85 (c = 0.07, MeOH); [α]2D5 = –13.12 (c
= 0.05, MeOH); [α]2D5 = –22.72 (c = 0.025, MeOH) [ref.[1a] data for
natural 1: [α]2D7 = +5.7 (c = 0.15, MeOH)]. 1H and 13C NMR,
FTIR, and ESI-MS spectroscopic data were the same as those for
(R)-1 (the natural isomer) given below. ESI-HRMS: calcd. for 1.94–1.86 (m, 2 H), 1.81–1.73 (br., 2 H, 2 OH), 1.71–1.63 (m, 1 H),
C14H18O3Na [M + Na]+ 257.1148; found 257.1143.
0.99 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
157.5, 130.5, 130.0, 114.6, 67.9, 66.2, 63.8, 38.2, 33.3, 32.8,
Hydrogenation of (S)-2 To Give (S)-5: A mixture of (S)-2 (50 mg,
0.21 mmol) and Pd/C (10%; 5 mg) in commercially sourced anhy-
drous EtOH (2 mL) was stirred at ambient temperature under H2
(atmospheric pressure) for 12 h, after which time TLC showed that
the reaction was complete. The solids were removed by filtration
[washing with EtOH (50 mL)]. The combined filtrate and washings
were concentrated on a rotary evaporator. The residue was purified
by chromatography (PE/EtOAc, 1:1) on silica gel to give (S)-5
(48 mg, 0.20 mmol, 96%) as a white powder. Data for (S)-5: M.p.
56–57 °C. [α]2D7 = –4.10 (c = 0.50, MeOH); [α]2D7 = –4.34 (c = 0.20,
MeOH); [α]2D7 = –3.6 (c = 0.40, MeOH); [α]2D7 = –6.97 (c = 1.00,
CHCl3) [ref.[3] data for natural 5: [α]2D3 = –9.2 (c = 0.22, MeOH)].
ee = 87.0% [tR for (S)-5 = 7.363 min, tR for (R)-5 = 6.460 min], as
measured by HPLC with a Phenomenex Lux 5 μm Cellulose-4 col-
umn (25ϫ0.46 cm), eluting with MeCN/H2O, 9:1, at a flow rate of
0.7 mL/min, with the UV detector set to 254 nm. 1H NMR
(400 MHz, CDCl3): δ = 7.11 (d, J = 8.5 Hz, 2 H), 6.83 (d, J =
8.8 Hz, 2 H), 4.05 (dt, J = 9.5, 5.8 Hz, 1 H), 4.00 (ddd, J = 8.6,
7.1, 5.5 Hz, 1 H), 3.67 (t, J = 6.5 Hz, 2 H), 3.55 (d, J = 5.4 Hz, 2
H), 2.65 (t, J = 7.8 Hz, 2 H), 1.95–1.82 (m, 4 H), 1.73–1.63 (m, 1
H), 1.65–1.57 (br. s, 2 H, 2 OH), 1.00 (d, J = 6.8 Hz, 3 H) ppm.
16.8 ppm. FTIR (film of a conc. solution in CH Cl ): ν = 3285,
˜
2
2
2922, 2870, 1608, 1581, 1512, 1455, 1372, 1298, 1248, 1209, 1179,
1115, 1051, 1033, 968, 919, 828 cm–1. ESI-MS: m/z = 225.1 [M +
H]+. ESI-HRMS: calcd. for C13H20O3Na [M + Na]+ 247.1305;
found 247.1312.
Condensation of 8 with 14 To Give 15: The procedure described
above for the conversion of 8 into 10 was used,but with 14 instead
of 9. Purification by chromatography (PE/EtOAc, 3:1) gave 15
(6.336 g, 17.26 mmol, 90% from 8) as a white powder. Data for 15:
M.p. 84–85 °C. [α]2D0 = –51.8 (c = 1.03, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 9.89 (s, 1 H), 7.84 (d, J = 8.5 Hz, 2 H),
7.36–7.27 (m, 3 H), 7.21 (d, J = 6.7 Hz, 2 H), 7.01 (d, J = 8.5 Hz,
2 H), 4.69 (dq, J = 13.1, 3.5 Hz, 1 H), 4.21 (dt, J = 13.1, 8.0 Hz, 2
H), 4.12 (t, J = 6.1 Hz, 2 H), 3.31 (dd, J = 13.4, 3.5 Hz, 1 H), 3.20
(dt, J = 17.8, 7.2 Hz, 1 H), 3.15 (dt, J = 18.2, 7.0 Hz, 1 H), 2.78
(dd, J = 13.5, 9.7 Hz, 1 H), 2.24 (quint, J = 6.6 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 190.7, 172.3, 163.7, 153.4, 135.1,
131.9, 129.8, 129.3, 128.8, 127.3, 114.6, 66.9, 66.2, 55.0, 37.7, 31.9,
23.5 ppm. FTIR (film of a conc. solution in CH Cl ): ν = 3070,
˜
2
2
3030, 3009, 2967, 2942, 2878, 2848, 2757, 1784, 1704, 1683, 1601,
13C NMR (100 MHz, CDCl3): δ = 157.0, 134.0, 129.3, 114.4, 68.0, 1577, 1386, 1355, 1247, 1205, 1159, 1045, 990, 933, 853, 820, 745,
66.2, 62.3, 34.4, 33.4, 32.9, 31.1, 16.8 ppm. FTIR (film of a conc. 701 cm–1. ESI-MS: m/z = 390.3 [M + Na]+. ESI-HRMS: calcd. for
solution in CH Cl ): ν = 3348, 2927, 2873, 1611, 1582, 1512, 1472, C21H21NO5Na [M + Na]+ 390.1312; found 390.1320.
˜
2
2
1455, 1388, 1301, 1243, 1176, 1111, 1041, 983, 911, 832 cm–1. ESI-
MS: m/z = 239.2 [M + H]+. ESI-HRMS: calcd. for C14H22O3Na
[M + Na]+ 261.1461; found 261.1469.
Wittig Reaction of 15 with Ph3P=CHCO2Me To Give 16: A mixture
of 15 (4.000 g, 10.90 mmol) and Ph3P=CHCO2Me (9.100 g,
27.24 mmol) in CH2Cl2 (20 mL) was stirred at ambient temperature
for 14 h, after which time TLC showed that the reaction was com-
plete. The mixture was concentrated by rotary evaporation. The
residue was purified by chromatography (PE/EtOAc, 5:2) on silica
gel to give 16 (3.757 g, 8.878 mmol, 82% from 15) as a white pow-
der. (E)/(Z) = 96:4, as seen by 1H NMRspectroscopy; after
recrystallization from EtOAc, (E)/(Z) = 98:2. Data for 16: M.p.
Conversion of (S)-2 into (S)-6: BH3·Me2S (2 m solution in THF;
1.05 mL, 2.1 mmol) was added to a stirred solution of (S)-2
(100 mg, 0.42 mmol) in dry THF (2 mL) in an ice–water bath under
argon (balloon). After the addition was complete, the mixture was
stirred at ambient temperature for 9 h, after which time TLC
showed that the reaction was complete. The flask was opened and
cooled in an ice–water bath, and NaOH (6 n aq.; 0.5 mL) was
added slowly, followed by H2O2 (30%; 1 mL). The mixture was
stirred at ambient temperature for 5 h, then it was extracted with
CH2Cl2 (2ϫ40 mL). The combined organic layers were washed in
turn with water and brine, and then dried with anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column
1
124–126 °C. [α]2D6 = –42.2 (c = 1.00, CHCl3). H NMR (400 MHz,
CDCl3): δ = 7.65 (d, J = 15.9 Hz, 1 H), 7.47 (d, J = 8.7 Hz, 2 H),
7.36–7.27 (m, 3 H), 7.21 (d, J = 6.6 Hz, 2 H), 6.90 (d, J = 8.7 Hz,
2 H), 6.31 (d, J = 15.7 Hz, 1 H), 4.78 (dq, J = 13.2, 3.4 Hz, 1 H),
4.21 (t, J = 9.4 Hz, 1 H), 4.18 (dd, J = 9.0, 3.3 Hz, 1 H), 4.10 (t, J
= 6.2 Hz, 2 H), 3.79 (s, 3 H), 3.31 (dd, J = 13.5, 3.4 Hz, 1 H), 3.19
3456
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3451–3459

Synthesis of Six Natural Phenylpropanoids
(dt, J = 17.8, 7.2 Hz, 1 H), 3.13 (dt, J = 17.0, 7.2 Hz, 1 H), 2.88
(dd, J = 13.3, 9.6 Hz, 1 H), 2.21 (quint, J = 6.6 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.5, 167.7, 160.6, 153.4, 144.5,
135.2, 129.7, 129.4, 128.9, 127.4, 127.1, 115.2, 114.8, 66.7, 66.3,
system had become a two-phase clear mixture. The phases were
separated. The aqueous layer was extracted with CH2Cl2
(2ϫ50 mL). The combined organic layers were washed in turn with
water and brine, and dried with anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (PE/
EtOAc, 1:1) on silica gel gave (R)-2 [41 mg, 0.174 mmol, 73% from
55.1, 51.5, 37.9, 32.0, 23.7 ppm. FTIR (KBr): ν = 3067, 3029, 2949,
˜
2918, 2882, 1782, 1704, 1633, 1603, 1434, 1388, 1352, 1289, 1252,
1209, 1170, 985, 830, 762, 703 cm–1. ESI-MS: m/z = 446.4 [M +
Na]+. ESI-HRMS: calcd. for C24H25NO6Na [M + Na]+ 446.1574;
found 446.1586.
(R)-4] as a white powder. Data for (R)-2: M.p. 64–68 °C. [α]2D3
=
+3.47 (c = 0.4, MeOH); [α]2D3 = +4.14 (c = 0.21, MeOH) [ref.[1a]
data for natural 2: [α]2D4 = –5.1 (c = 0.21, MeOH)]. ee = 90.3% [tR
for (R)-2 = 63.777 min, tR for (S)-2 = 60.477 min], as measured by
Methylation of 16 To Give 17: The procedure described above for
the conversion of 11a into 12a was used, but with 16 instead of 11a.
Purification by chromatography (PE/EtOAc, 3:1) gave 17 (1.113 g,
2.546 mmol, 84% from 16) as a white powder. Data for 17: M.p.
HPLC with
a Phenomenex Lux 5 μm Amylose-2 column
(25ϫ0.46 cm), eluting with n-hexane/iPrOH, 9:1, at a flow rate of
0.7 mL/min, with the UV detector set to 214 nm. 1H NMR
(400 MHz, CDCl3): δ = 7.32 (d, J = 8.6 Hz, 2 H), 6.85 (d, J =
8.9 Hz, 2 H), 6.55 (d, J = 15.7 Hz, 1 H), 6.24 (dt, J = 15.9, 5.9 Hz,
1 H), 4.30 (dd, J = 6.1, 1.6 Hz, 2 H), 4.08 (dt, J = 9.7, 5.8 Hz, 1
H), 4.02 (ddd, J = 9.3, 6.9, 5.6 Hz, 1 H), 3.56 (d, J = 5.7 Hz, 2 H),
1.97–1.87 (m, 2 H), 1.74–1.63 (m, 1 H), 1.00 (d, J = 6.6 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 158.5, 130.8, 129.5, 127.6,
126.3, 114.6, 67.9, 66.1, 63.8, 33.2, 32.7, 16.8 ppm. FTIR (film of
1
100–101 °C. [α]2D4 = –72.3 (c = 1.00, CHCl3). H NMR (400 MHz,
CDCl3): δ = 7.63 (d, J = 15.9 Hz, 1 H), 7.45 (d, J = 8.9 Hz, 2 H),
7.36–7.27 (m, 3 H), 7.22–7.19 (m, 2 H), 6.86 (d, J = 8.8 Hz, 2 H),
6.30 (d, J = 15.8 Hz, 1 H), 4.65 (ddt, J = 9.3, 8.0, 3.2 Hz, 1 H),
4.16–4.12 (m, 1 H), 4.11–4.05 (m, 2 H), 4.04–3.96 (m, 2 H), 3.79
(s, 3 H), 3.25 (dd, J = 13.6, 3.2 Hz, 1 H), 2.78 (dd, J = 13.2, 9.6 Hz,
1 H), 2.29 (ddt, J = 14.0, 8.0, 6.0 Hz, 1 H), 1.95 (dq, J = 13.9,
6.0 Hz, 1 H), 1.32 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 176.5, 167.7, 160.5, 153.0, 144.4, 135.2, 129.7, 129.4,
128.9, 127.4, 127.2, 115.3, 114.7, 66.0, 65.9, 55.3, 51.6, 37.9, 34.8,
a conc. solution in CH Cl ): ν = 3383, 3030, 2925, 2876, 1714,
˜
2
2
1699, 1633, 1605, 1574, 1512, 1506, 1471, 1452, 1433, 1393, 1303,
1248, 1173, 1113, 1087, 1017, 969, 933, 837, 798 cm–1. ESI-MS:
m/z = 259.2 [M + Na]+. ESI-HRMS: calcd. for C14H20O3Na [M +
Na]+ 259.1305; found 259.1306.
32.7, 18.0 ppm. FTIR (KBr): ν = 3031, 2950, 2890, 1787, 1765,
˜
1711, 1698, 1634, 1602, 1511, 1481, 1385, 1252, 1197, 1174, 1013,
985, 826, 762, 725, 698 cm–1. ESI-MS: m/z = 460.3 [M + Na]+. MnO2 Oxidation of (R)-2 To Give (R)-1: A mixture of (R)-2 (25 mg,
ESI-HRMS: calcd. for C25H27NO6Na [M + Na]+ 460.1731; found
460.1738.
0.1059 mmol) and activated MnO2 (88%, 78 mg, 0.794 mmol) in
dry CH2Cl2 (1 mL) was stirred at ambient temperature for 20 h,
after which time TLC showed that the reaction was complete. The
solids were removed by filtration [washing with CH2Cl2 (70 mL)].
The combined filtrate and washings were washed with water and
brine, and then dried with anhydrous Na2SO4. Removal of the sol-
vent by rotary evaporation gave rather pure (R)-1 [21 mg,
0.0897 mmol, 84% from (R)-2] as a white powder. Data for (R)-1:
M.p. Ͻ26 °C. [α]2D1 = +4.3 (c = 0.19, MeOH) [ref.[1a] data for natural
1: [α]2D4 = +5.7 (c = 0.15, MeOH)]. 1H NMR (400 MHz, CDCl3): δ
= 9.57 (d, J = 7.8 Hz, 1 H), 7.44 (d, J = 8.9 Hz, 2 H), 7.35 (d, J =
15.7 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 2 H), 6.53 (dd, J = 15.9, 7.8 Hz,
1 H), 4.00 (dt, J = 9.6, 6.5 Hz, 1 H), 4.05 (dt, J = 9.4, 6.1 Hz, 1
H), 3.49 (d, J = 5.6 Hz, 2 H), 1.90 (dt, J = 12.6, 6.1 Hz, 1 H), 1.84
(dt, J = 12.3, 6.1 Hz, 1 H), 1.84–1.74 (br. s, 1 H), 1.61 (dq, J =
13.1, 6.5 Hz, 1 H), 0.94 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 193.8, 161.5, 152.8, 130.4, 126.7, 126.4,
Reductive Cleavage of the Chiral Auxiliary in 17 To Give (R)-4: The
procedure described above for the conversion of 12b into (S)-4 was
used, but with 17 as starting material. This gave (R)-4 (174 mg,
0.659 mmol, 96% from 17) as a white powder. Data for (R)-4: M.p.
60–61 °C. [α]2D3 = +4.5 (c = 0.26, MeOH); [α]2D3 = +4.2 (c = 0.55,
MeOH); the [α]20 (c = 0.40, MeOH) for (R)-4 was also measured
on another polarimeter (Rudolph Autopol VI, with changeable
wavelength): +3.4 (633 nm), +4.6 (589 nm), +5.8 (546 nm), +8.7
(436 nm), +9.5 (405 nm); data were also measured at a lower con-
centration (c = 0.23, MeOH): +3.1 (633 nm), +5.3 (589 nm), +6.4
(546 nm), +9.6 (436 nm), +9.3 (405 nm); [ref.[2] data for natural 4:
[α]500 = +4.34 (c = 0.23, MeOH)]. ee = 90.2% [tR for (R)-4 =
15.417 min, tR for (S)-4 = 16.727 min], as measured by HPLC with
a Phenomenex Lux 5 μm Cellulose-3 column (25ϫ0.46 cm), elut-
ing with n-hexane/iPrOH, 8:2, at a flow rate of 0.7 mL/min, with
115.0, 67.8, 66.4, 33.0, 32.6, 16.7 ppm. FTIR (film): ν = 3439, 3037,
˜
1
the UV detector set to 214 nm. H NMR (400 MHz, CDCl3): δ =
2957, 2926, 2874, 1673, 1621, 1600, 1570, 1511, 1473, 1426, 1392,
1308, 1259, 1175, 1129, 1014, 973, 819 cm–1. ESI-MS: m/z = 235.1
[M + H]+. ESI-HRMS: calcd. for C14H19O3 [M + H]+ 235.13287;
found 235.1331.
7.65 (d, J = 15.9 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 2 H), 6.89 (d, J =
8.8 Hz, 2 H), 6.31 (d, J = 16.0 Hz, 1 H), 4.06 (ddd, J = 12.5, 9.2,
7.3 Hz, 1 H), 4.09 (dt, J = 9.2, 6.6 Hz, 1 H), 3.79 (s, 3 H), 3.55 (d,
J = 5.6 Hz, 2 H), 1.99–1.87 (m, 2 H), 1.83 (br. s, 1 H), 1.72–1.62
(m, 1 H), 1.00 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.8, 160.7, 144.5, 129.7, 127.1, 115.2, 114.8, 67.9,
Hydrogenation of (R)-2 To Give (R)-5: The procedure described
above for the conversion of (S)-2 into (S)-5 was used [with (R)-2
66.2, 51.6, 33.1, 32.6, 16.7 ppm. FTIR (film): ν = 3322, 2927, 2873, instead of (S)-2 as the starting material]. This gave (R)-5 (6 mg,
˜
1714, 1636, 1604, 1574, 1513, 1456, 1434, 1288, 1259, 1171, 1111,
1014, 983, 831, 818 cm–1. ESI-MS: m/z = 265.2 [M + H]+. ESI-
HRMS: calcd. for C15H20O4Na [M + Na]+ 287.1254; found
287.1257.
0.025 mmol, 100%) as a white solid. Data for (R)-5: M.p. 56–57 °C.
[α]2D4 = +5.7 (c = 0.25, MeOH). ee = 88.0% [tR for (R)-5 =
6.451 min, tR for (S)-5 = 7.379 min], as measured by HPLC with a
Phenomenex Lux 5 μm Cellulose-4 column (25ϫ0.46 cm), eluting
with MeCN/H2O, 9:1, at a flow rate of 0.7 mL/min, with the UV
detector set to 254 nm. Other data were the same as those reported
DIDBAL-H Reduction of (R)-4 To Give (R)-2: DIBAL-H (1.0 m
solution in cyclohexane; 0.48 mL, 0.48 mmol) was added to a
stirred solution of (R)-4 (63 mg, 0.242 mmol) in dry CH2Cl2 (3 mL)
at –78 °C (EtOH/dry ice bath) under argon (balloon). The mixture
was stirred at the same temperature for 1 h, then satd. aq. NH4Cl
(2 mL) was added carefully, followed by CH2Cl2 (4 mL). Stirring
was continued at ambient temperature for 4 h, after which time the
for (S)-5. ESI-HRMS: calcd. for C14H22O3Na [M
261.14612; found 261.1467.
+
Na]+
Conversion of 17 into 18: H2O2 (30%; 0.18 mL) was added to a
stirred solution of 17 (400 mg, 0.915 mmol) and LiOH (monohy-
drate; 46 mg, 1.098 mmol) in THF (5 mL) and H2O (0.5 mL) in an
Eur. J. Org. Chem. 2014, 3451–3459
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3457

X.-L. Liu, H.-J. Chen, Y.-Y. Yang, Y. Wu, J. You
FULL PAPER
ice–water bath. Stirring was continued at the same temperature for
1.5 h, after which time TLC showed that the reaction was complete.
Saturated aqueous Na2SO3 (2 mL) was added (to decompose the
peroxide). HCl (1 n aq.; 4 drops from a pipette) was then added,
to acidify the mixture to ca. pH 2. The mixture was extracted with
EtOAc (2ϫ40 mL). The combined organic layers were washed in
turn with water and brine, and dried with anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and chromatography
(PE/EtOAc, 3:2) gave pure 18 (244 mg, 0.877 mmol, 96% from 17)
as a white powder. Data for 18: M.p. 50–52 °C. [α]2D5 = –36.6 (c =
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J =
16.2 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H),
6.30 (d, J = 15.8 Hz, 1 H), 4.06 (t, J = 6.1 Hz, 2 H), 3.79 (s, 3 H),
2.79 (br. sext, J = 7.0 Hz, 1 H), 2.28–2.18 (m, 1 H), 1.97–1.87 (m,
1 H), 1.29 (d, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 182.3, 167.9, 160.5, 144.6, 129.7, 127.1, 115.1, 114.7, 65.5, 51.6,
NMR (100 MHz, CDCl3): δ = 176.7, 158.4, 130.7, 129.4, 127.6,
126.3, 114.5, 65.5, 63.7, 51.6, 36.2, 32.9, 17.1 ppm. FTIR (film): ν
˜
= 3446 (br), 3032, 2955, 2926, 2853, 1731, 1606, 1575, 1510, 1456,
1434, 1377, 1247, 1196, 1173, 1137, 1069, 1012, 967, 839, 800 cm–1.
ESI-MS: m/z
= 287.2 [M +
Na]+. ESI-HRMS: calcd. for
C15H18O5Na [M + Na]+ 287.1254; found 287.1253.
MnO2 Oxidation of 20 To Give (R)-3: A mixture of 20 (44 mg,
0.1666 mmol) and activated MnO2 (88%, 108 mg, 1.09 mmol) in
dry CH2Cl2 (1 mL) was stirred at ambient temperature for 40 h,
after which time TLC showed that the reaction was complete. The
solids were removed by filtration. The filtrate was concentrated by
rotary evaporation. The residue was purified by chromatography
(PE/EtOAc, 3:1) on silica gel to give (R)-3 (32 mg, 0.122 mmol,
74% from 20) as a colourless oil. Data for (R)-3: [α]2D6 = –34.9 (c
= 1.55, MeOH); [α]2D6 = –34.9 (c = 0.44, MeOH); [α]2D6 = –34.9 (c
= 0.22, MeOH); [α]2D6 = –31.0 (c = 0.11, MeOH); [α]2D6 = –29.4 (c
= 0.07, MeOH) [ref.[1a] data for natural 3: [α]2D4 = +29.4 (c = 0.07,
36.2, 32.5, 17.0 ppm. FTIR (film of a conc. solution in CH Cl ): ν
˜
2
2
= 3201 (br), 3075, 3037, 2952, 2878, 1714 (br), 1633, 1604, 1574,
1512, 1464, 1435, 1304, 1289, 1254, 1202, 1172, 1041, 983, 937,
829 cm–1. ESI-MS: m/z = 279.2 [M + H]+. ESI-HRMS: calcd. for
C15H18O5Na [M + Na]+ 301.1046; found 301.1045.
1
MeOH)]. H NMR (400 MHz, CDCl3): δ = 9.65 (d, J = 7.9 Hz, 1
H), 7.51 (d, J = 8.8 Hz, 2 H), 7.42 (d, J = 15.8 Hz, 1 H), 6.92 (d,
J = 8.8 Hz, 2 H), 6.61 (dd, J = 15.8, 7.8 Hz, 1 H), 4.07 (dt, J =
9.8, 6.0 Hz, 1 H), 4.04 (dt, J = 9.9, 6.1 Hz, 1 H), 3.69 (s, 3 H), 2.75
(br. sext, J = 7.0 Hz, 1 H), 2.21 (ddt, J = 14.3, 8.3, 6.1 Hz, 1 H),
1.91 (dq, J = 14, 6.1 Hz, 1 H), 1.25 (d, J = 6.9 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 193.7, 176.5, 161.4, 152.7, 130.3,
126.8, 126.4, 115.0, 65.8, 51.7, 36.2, 32.7, 17.2 ppm. FTIR (film):
Conversion of 18 into 20 via 19: DIBAL-H (1.0 m solution in cyclo-
hexane; 1.35 mL, 1.35 mmol) was added to a stirred solution of 18
(188 mg, 0.676 mmol) in dry CH2Cl2 (3.3 mL) at –78 °C (EtOH/
dry ice bath) under argon (balloon). The mixture was stirred at the
same temperature for 2 h, then satd. aq. sodium potassium tartrate
(2 mL) was added slowly, followed by CH2Cl2 (4 mL). Stirring was
continued at ambient temperature for 12 h, after which time the
system had become a two-phase clear mixture. The phases were
separated. The aqueous layer was extracted with CH2Cl2
(3ϫ50 mL). The combined organic layers were washed in turn with
water and brine, and then dried with anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(PE/EtOAc, 1:2) on silica gel gave 19 (79 mg, 0.316 mmol, 48%
from 18) as a white powder, along with recovered 18 (88 mg,
0.318 mmol, 47%). Some characteristic data for 19: M.p. 88–90 °C.
ν = 2976, 2950, 2882, 2828, 1732, 1674, 1621, 1602, 1573, 1511,
˜
1473, 1434, 1362, 1303, 1250, 1195, 1175, 1128, 1072, 1047, 1011,
971, 848, 818 cm–1. ESI-MS: m/z = 263.2 [M + H]+. ESI-HRMS:
calcd. for C15H18O4Na [M + Na]+ 285.1097; found 285.1096.
Conversion of 12b into ent-18: The procedure described above for
the conversion of 17 into 18 was used (with 12b as the substrate
instead of 17). Purification by chromatography (PE/EtOAc, 3:2)
gave ent-18 as a white powder (79 mg, 0.284 mmol, 89% from 12b).
Data for ent-18: M.p. 50–54 °C. [α]2D6 = +35.8 (c = 1.00, CHCl3).
1H and 13C NMR, FTIR and ESI-MS spectroscopic data were the
same as those for 18. ESI-HRMS: calcd. for C15H18O5Na [M +
Na]+ 301.1046; found 301.1043.
1
[α]2D6 = –35.9 (c = 0.75, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.29 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 6.53 (d, J =
15.7 Hz, 1 H), 6.22 (dt, J = 15.8, 6.1 Hz, 1 H), 4.29 (dd, J = 5.7,
1.3 Hz, 2 H), 4.03 (t, J = 6.1 Hz, 2 H), 2.78 (br. sext, J = 7.1 Hz,
1 H), 2.21 (ddt, J = 13.8, 8.0, 6.1 Hz, 1 H), 1.92 (dq, J = 14.3,
6.0 Hz, 1 H), 1.28 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 181.5, 158.5, 131.0, 129.5, 127.7, 126.2, 114.6, 65.5,
Conversion of ent-18 into ent-20 via ent-19: The procedure described
above for the conversion of 18 into 20 via 19 was used (with ent-
18 and ent-19 instead of 18 and 19, respectively). After chromatog-
raphy (PE/EtOAc, 1:2), ent-19 (39 mg, 0.156 mmol, 83% from ent-
18) was obtained as a white powder. Data for ent-19: M.p. 87–
88 °C. [α]2D6 = +31.4 (c = 1.00, CHCl3). H and 13C NMR, FTIR,
63.9, 36.1, 32.7, 17.1 ppm. FTIR (film of a solution in CH Cl ): ν
1
˜
2
2
= 3305 (br), 3075, 2954, 2924, 2853, 1729, 1684, 1605, 1512, 1458,
1269, 1247, 1218, 1174, 1083, 1056, 1004, 969, 834 cm–1. EI-MS:
m/z = 250 [M]+.
and ESI-MS spectroscopic data were the same as those for 19.
After chromatography (PE/EtOAc, 2:1), ent-20 (22 mg,
0.083 mmol, 92% from ent-19) was obtained as a white powder.
Data for ent-20: M.p. 39–41 °C. [α]2D6 = +31.2 (c = 1.00, CHCl3).
1H and 13C NMR, FTIR, and ESI-MS spectroscopic data were the
same as those reported for 20. ESI-HRMS: calcd. for C15H20O4Na
[M + Na]+ 287.1254; found 287.1252.
The compound 19 (46 mg, 0.184 mmol) obtained as described
above was dissolved in Et2O (1 mL) and MeOH (1 mL). The solu-
tion was cooled in an ice–water bath, and Me3SiCHN2 (2 m solu-
tion in hexanes; 0.4 mL, 0.8 mmol) was added. The transparent
yellowish solution was stirred at the same temperature for 20 min,
after which time TLC showed that the reaction was complete. The
solvents were removed on a rotary evaporator. The residue was
purified by chromatography (PE/EtOAc, 2:1) on silica gel to give
ester 20 (47 mg, 0.178 mmol, 96% from 19) as a white crystalline
solid. Data for 20: M.p. 38–41 °C. [α]2D6 = –31.9 (c = 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.7 Hz, 2 H), 6.82
(d, J = 8.8 Hz, 2 H), 6.53 (d, J = 15.7 Hz, 1 H), 6.21 (dt, J = 15.8,
MnO2 Oxidation of ent-20 To Give (S)-3: The procedure described
above for the MnO2 oxidation of 20 to give (R)-3 above was used.
Purification by chromatography (PE/EtOAc, 3:1) gave (S)-3 (18 mg,
0.069 mmol, 86% from ent-20) as a colourless oil. Data for (S)-3:
[α]2D5 = +36.7 (c = 0.85, MeOH); [α]2D5 = +37.6 (c = 0.43, MeOH);
[α]2D5 = +37.4 (c = 0.21, MeOH); [α]2D6 = +36.9 (c = 0.11, MeOH);
[α]2D6 = +37.7 (c = 0.07, MeOH) [ref.[1a] data for natural 3: [α]2D4
=
6.0 Hz, 1 H), 4.28 (dd, J = 6.0, 1.3 Hz, 2 H), 3.98 (dt, J = 1.8, +29.4 (c = 0.07, MeOH)]. H and 13C NMR, FTIR, and ESI-MS
1
6.2 Hz, 2 H), 3.68 (s, 3 H), 2.74 (br. sext, J = 7.0 Hz, 1 H), 2.18
(ddt, J = 14.2, 8.0, 6.0 Hz, 1 H), 2.10–1.90 (br., 1 H, OH), 1.87
spectroscopic data were the same as those reported for (R)-3. ESI-
HRMS: calcd. for C15H18O4Na [M + Na]+ 285.1097; found
(dq, J = 13.8, 6.2 Hz, 1 H), 1.23 (d, J = 6.9 Hz, 3 H) ppm. 13C 285.1101.
3458
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3451–3459

Synthesis of Six Natural Phenylpropanoids
[5] For a high-yielding, low-cost, practical access to such chiral
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra, FTIR spectra for all
new compounds.
[6] For the original methodology report, see: a) D. A. Evans,
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Ribe, R. K. Kondru, D. N. Beratan, P. Wipf, J. Am. Chem. Soc.
2000, 122, 4608–4617; c) A. K. Ghosh, G. Gong, J. Am. Chem.
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Y.-J. Kim, H.-Y. Lee, Y. Yoon, Tetrahedron 2013, 69, 7810–
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Acknowledgments
This work was supported by the National Basic Research Program
of China 973 Program, grant number 2010CB833200), the National
Natural Science Foundation of China (NSFC) (grant numbers
21372248, 21172247, 21032002), and the Chinese Academy of Sci-
ences. One of the referees is thanked for showing the necessity of
measuring the optical rotation for (R)-4 at wavelengths comparable
to those used in the literature. Prof. Ishikawa is thanked for the
kind confirmation of the wavelength ranges of their ORD data
(ref.[2]). Prof. Xuefeng Mei and Ms. Kailei Lin of Shanghai Institute
of Materia Medica, Chinese Academy of Sciences, are thanked for
providing access to the Rudolph Autopol VI polarimeter.
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Received: February 18, 2014
Published Online: April 10, 2014
Eur. J. Org. Chem. 2014, 3451–3459
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3459