A Stereoselective Synthesis of (+)-Piscidic Acid and Cimicifugic Acid L

Article abstract of DOI:10.1002/ejoc.201501002

Alkylation of the lithium enolate of (2S,3S,5S,6S)-dimethoxy-2,3-dimethyl-1,4-dioxane-5,6-dithiocarboxylate using 4-benzyloxybenzyl bromide stereoselectively gave two new stereogenic centres with the carboxylate groups in a cis relationship. Hydrolytic de

Full text of DOI:10.1002/ejoc.201501002

FULL PAPER
DOI: 10.1002/ejoc.201501002
A Stereoselective Synthesis of (+)-Piscidic Acid and Cimicifugic Acid L
[a]
[a,b]
and M. Rita Ventura*[a]
Vanessa Miranda, Christopher D. Maycock,
Keywords: Total synthesis / Asymmetric synthesis / Chiral pool / Alkylation / Natural products
Alkylation of the lithium enolate of (2S,3S,5S,6S)-dimethoxy-
,3-dimethyl-1,4-dioxane-5,6-dithiocarboxylate using 4-
benzyloxybenzyl bromide stereoselectively gave two new
duced the natural product (+)-piscidic acid. Installation of a
2
cinnamic acid ester at the secondary hydroxy group was fol-
lowed by selective deprotection to give a mixture of cis/trans
cinnamates in a 3:1 ratio. Finally, the natural product cimici-
stereogenic centres with the carboxylate groups in a cis rela-
tionship. Hydrolytic deprotection of this intermediate pro- fugic acid L was obtained.
Introduction
(+)-Piscidic acid (1) is one of the constituents of hypnotic
and narcotic extracts from Piscidea erythrina L. (Jamaica
[
1]
dogwood), and is also an active constituent of Dioscorea
nippoinica, a medicinal plant used to treat chronic bronchi-
tis[
2,3]
(Figure 1). Piscidic acid has also been isolated from
[
4]
[5]
Cimicifuga simplex and Narcissus poeticus. It has been
identified in the cactus Opuntia,[ which comprises about
6,7]
200–300 cactus species that grow in arid and semi-arid
zones. Traditionally, Opuntia cactus plants serve as sources
of fruit and vegetables, and are also used for medicinal and
cosmetic purposes. Additionally, piscidic acid (1) and O-
methylpiscidic acid have been shown to be linked to phos-
phorus uptake in pigeon peas, Cajanus cajan L. Millsp., an
important crop in India.[
3,8,9]
Closely related cimicifugic acids have been isolated from
several Cimicifuga species.[
10,11]
Cimicifugic acid L (2),
which consists of a piscidic acid moiety esterified with 3,4-
dimethoxycinnamic acid at the secondary alcohol, was iso-
lated from the aerial parts of Cimicifuga simplex and
Cimicifuga japonica.[ Cimicifugic acid G (3) was isolated
12]
from an extract of the rhizomes and roots of black cohosh
(
Actaea racemosa L. or Cimicifuga racemosa),[ which is a
13]
Figure 1. Piscidic acid (1) and cimicifugic acids L (2), G (3), and
N (4).
native North American plant belonging to the Ranuncula-
ceae family. The rhizomes and roots of this plant have been
used by Native Americans to treat malaise, gynecological
disorders, diarrhoea, sore throats, and rheumatism. It is
also used as a botanical supplement for the treatment of
menopausal symptoms in the US and Europe. C. racemosa
extracts have shown anticancer, anti-inflammatory, and
[
13]
antioxidant activities.
been isolated from a prepared mixture of the rhizomes of
Cimicifugic acid G (3) has also
[
a] Instituto de Tecnologia Química e Biológica António Xavier,
Universidade Nova de Lisboa, EAN,
[
14]
C. dahurica and C. heracleifolia (ratio about 1:9).
These
2
780-157 Oeiras, Portugal
E-mail: rventura@itqb.unl.pt
http://www.itqb.unl.pt/
two Cimicifuga species and C. simplex are described as
source plants of “Cimicifugae rhizome” in the Japanese and
Chinese Pharmacopoeia. “Cimicifugae rhizome” is used for
its anti-inflammatory, analgesic, and antipyretic properties
in Chinese and Japanese traditional medicine. The cis iso-
mer of cimicifugic acid G, known as cimicifugic acid N (4),
[b] Faculdade de Ciências da Universidade de Lisboa,
Departamento de Química e Bioquímica,
1
749-016 Lisboa, Portugal
Supporting information and ORCID(s) from the author(s) for
this article are available on the WWW under http://dx.doi.org/
1
0.1002/ejoc.201501002.
Eur. J. Org. Chem. 2015, 7529–7533
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7529

V. Miranda, C. D. Maycock, M. R. Ventura
FULL PAPER
was isolated from the aerial parts of C. simplex and C. ja-
[
12]
ponica along with 2 (Figure 1).
Results and Discussion
(+)-Piscidic acid (1) can be regarded as an alkylated tar-
taric acid derivative, and several syntheses of this com-
[
3,8,15]
pound have been reported.
Seebach reported an ap-
proach that is notable for its conciseness,[ but the piscidic
acid (1) obtained did not have the correct stereochemistry
for the natural compound. Previously, we have described
the synthesis of (+)-O-methylpiscidic acid dimethyl ester,
and the formal synthesis of natural analogues, starting from
d-tartaric acid. The natural abundance of tartaric acid in
both of its enantiomeric forms is an advantage, and it is
often used as a small chiral building block for the asymmet-
15]
[
16]
[17,18]
ric synthesis of other natural products.
In our previous
work, the lithium enolate of dithioester 5, readily available
[
18–20]
from tartaric acid,
underwent stereoselective mono-
Scheme 2. Synthesis of cimicifugic acid L (2). (a) 3,4-Dimeth-
oxycinnamoyl chloride, Et N, CH Cl , 0 °C to room temp., 95%;
3 2 2
and dialkylations to form new stereogenic centres, where
the acetal provided a chiral memory. The alkylation reac- (b) FeCl , CH Cl , 0 °C, 53%, trans/cis = 3:1; (c) LiI, pyridine,
3
2
2
125 °C, without light, 60%, trans/cis = 3:1.
tion of 5, derived from d-tartaric acid, with 4-meth-
oxybenzyl bromide was the key step in a short synthesis of
4
Ј-O-methylpiscidic acid dimethyl ester.[16] In this paper, we
hydrogenation, compound 9 was obtained quantitatively.
Hydrolysis of the methyl esters gave piscidic acid (1) in 81%
describe the use of the same efficient strategy to create the
stereochemistry necessary to synthesise natural piscidic acid
20
[21]
yield, [α]D = +45.5 (c = 1.16, MeOH) {ref. [α]D = +42.8
(
1; Scheme 1). Cimicifugic acid L (2) was obtained by fur-
ther esterification of the secondary alcohol of tartrate inter-
mediate with 3,4-dimethoxycinnamoyl chloride
Scheme 2). To the best of our knowledge, none of the cim-
icifugic acids have been previously synthesised.
[5]
28
(
c = 0.80, MeOH); ref. [α] = +48.88 (c = 2.6, H O);
D 2
[1]
20
[3]
22
ref. [α] = +41.03 (c = 2.6, H O); ref. [α] = +32.3 (c
D
2
D
8
=
1.35, H O)}. From 4-benzyloxypiscidic acid dimethyl es-
2
(
ter (8), cimicifugic acid L (2) was synthesised in three steps
(Scheme 2).
Cinnamate ester 10 was obtained in excellent yield (95%)
by selective esterification of the secondary hydroxy group
of diol 8 with 3,4-dimethoxycinnamoyl chloride and Et N.
3
In order to preserve the double bond of the cinnamate, the
benzyl group could not be removed using catalytic
hydrogenolysis. Acid-catalysed removal of the this group
[
22,23]
with FeCl3
gave the desired compound 11 in 53%
yield; however, a 3:1 mixture of the trans/cis isomers was
obtained. The same reaction was carried out with cinna-
mate ester 12, and, interestingly, only the trans product,
phenol 13, was obtained (Scheme 3). We believe that, al-
though the FeCl probably facilitated this isomerisation,
3
without the necessary methoxy groups the stabilising
hydrogen bond does not form. Optimised 3D structures of
trans-11 and cis-11 (Figure 2) indicated that a hydrogen
Scheme 1. Synthesis of (+)-piscidic acid (1). (a) LDA (lithium diiso- bond could be established between the free phenolic
propylamide), 4-benzyloxybenzyl bromide, HMPA (hexameth- hydroxy group and the 3-OMe group of the cinnamic acid
ylphosphoramide), THF, –78 °C, 86%; (b) TFA (trifluoroacetic
moiety in both cases. However, in the trans isomer, the two
acid), CH
8%; (d) H
2 m), reflux, 81%.
2
Cl
2
, H
2
O, reflux, 92%; (c) NaOMe, MeOH, room temp.,
aromatic rings are perpendicular, while in the cis isomer
these rings are parallel. In the formation of 11, the trans
isomer was the major isomer of the product; this shows that
8
2
, Pd/C (10%), EtOAc, 50 psi, 100%. (e) H
2
O, KOH
(
Alkylation of the lithium dienolate of 5 with 4-benzyl- it is the more stable isomer, and the fact that the trans/cis
oxybenzyl bromide gave monoalkylated product 6 exclu- isomers were formed in a 3:1 ratio shows that there is not
sively in 86% yield.[ Removal of the dioxane acetal with a significant energy difference between the two isomers. The
TFA in dichloromethane/water gave diol 7 in excellent yield presence of the energetically favourable hydrogen bond
16]
(92%). Transesterification gave dimethyl ester 8, and, after helps to decrease the expected energy difference.
7530
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Eur. J. Org. Chem. 2015, 7529–7533

Synthesis of (+)-Piscidic Acid and Cimicifugic Acid L
THF (3 mL) was added to the LDA solution, and the mixture was
stirred at –78 °C for 45 min. A solution of bromide 4 (0.472 g,
1
.70 mmol) in HMPA (1.17 mL) was then added to the dienolate
solution. The reaction mixture was stirred at –78 °C for 1 h, and
then the reaction was quenched with saturated aqueous NH Cl
solution. The aqueous phase was extracted with ethyl acetate (3ϫ
0 mL), then the combined organic phases were dried with MgSO
4
2
4
,
and concentrated. Purification of the residue by flash column
chromatography (hexane/ethyl acetate, 95:5 and 90:10) gave 6
2
0
(
0.520 g, 83%) as a viscous colourless oil. [α]
D
= +35.9 (c = 1.35,
1
CH Cl ). H NMR (CDCl ): δ = 7.37 (m, 7 H), 6.87 (d, J = 8.7 Hz,
2 2 3
2
1
1
7
1
7
H), 5.05 (s, 2 H), 3.99 (s, 1 H), 3.32 (s, 3 H), 3.32 (d, J = 14.3 Hz,
H), 3.19 (d, J = 14.3 Hz, 1 H), 2.95–2.74 (m, 4 H), 2.85 (s, 3 H),
.33 (s, 3 H), 1.30 (s, 3 H), 1.27 (t, J = 7.4 Hz, 3 H), 1.26 (t, J =
Scheme 3. Synthesis of compound 13. (a) Cinnamoyl chloride,
Et N, CH Cl , 0 °C, 74%; (b) FeCl , CH Cl , 0 °C, 37%.
3 2 2 3 2 2
1
3
3
.5 Hz, 3 H) ppm. C NMR (CDCl ): δ = 199.3, 198.9, 157.7,
37.2, 132.0, 128.5, 128.4, 127.9, 127.4, 114.1, 100.3, 99.6, 83.0,
3.2, 69.9, 51.7, 48.0, 42.5, 22.9, 22.1, 17.6, 17.5, 14.5, 14.1 ppm.
–
1
FTIR: ν˜ = 1679 (C=O) cm . C28
36 7 2
H O S (548.71124): calcd. C
61.29, H 6.61, S 11.69; found C 61.29, H 6.61, S 11.69.
S,S-Diethyl (2R,3S)-2-[4-(Benzyloxy)benzyl]-2,3-dihydroxybutane-
bis(thioate) (7): Trifluoroacetic acid (0.35 mL, 4.50 mmol) and a
catalytic amount of H
.64 mmol) in CH Cl
for 3 h, then it was concentrated. The residue was purified by flash
column chromatography (hexane/ethyl acetate, 80:20) to give diol
2
O were added to a solution of 6 (0.350 g,
(3 mL). The mixture was heated at reflux
Figure 2. 3D structures of trans-11 (left) and cis-11 (right)
0
2
2
[
PBE1PBE/6-311G(d,p) optimisation method].
2
0
Selective cleavage of the methyl esters in the presence of 7 (0.254 g, 92%) as a white solid. [α]
D
= –23.7 (c = 0.9, CH
2 2
Cl ).
[
24]
1
the cinnamate group was accomplished using LiI,
and m.p. 82–83 °C. H NMR (CDCl
3
): δ = 7.37 (m, 5 H), 7.12 (d, J =
8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.02 (s, 2 H), 4.43 (s, 1 H),
cimicifugic acid L (2) was obtained in 60% yield as a mix-
ture of trans/cis isomers (3:1). Cimicifugic acid L (2) was
isolated as the trans isomer. However, cimicifugic acid N
3.21 (d, J = 13.9 Hz, 1 H), 3.13 (d, J = 13.9 Hz, 1 H), 2.88 (m, 2
H), 2.80 (m, 2 H), 1.24 (t, J = 7.4 Hz, 3 H), 1.17 (t, J = 7.4 Hz, 3
1
3
H) ppm. C NMR (CDCl
3
): δ = 204.2, 201.5, 158.1, 137.0, 131.8,
28.6, 128.0, 127.5, 126.1, 114.1, 84.3, 79.7, 69.9, 40.6, 23.3, 23.2,
4.3, 14.1 ppm. FTIR (neat): ν˜ = 3440–3241 (OH), 1668 (C=O)
(
(
4), which is the cis isomer of 3, has already been identified
Figure 1); thus, cis isomers of the other cimicifugic acids
1
1
may also be present in natural sources.
–1
26 5 2
cm . C22H O S (434.56884): calcd. C 60.80, H 6.03, S 14.76;
found C 60.80, H 6.02, S 14.65.
Dimethyl (2R,3S)-2-[4-(Benzyloxy)benzyl]-2,3-dihydroxysuccinate
Conclusions
(
8): Sodium methoxide (0.020 g, 0.366 mmol) was added to a solu-
An efficient and rapid route has been developed for the tion of 7 (0.053 g, 0.12 mmol) in dry methanol (3 mL) at 0 °C, and
synthesis of piscidic acid (1) and cimicifugic acid L. This the reaction mixture was stirred for 30 min. The reaction was then
quenched with saturated aqueous NH
phase was extracted with ethyl acetate (3ϫ 10 mL), and the com-
bined organic phases were dried with MgSO , and concentrated.
Purification of the residue by preparative chromatography (hexane/
4
Cl solution. The aqueous
synthetic strategy could be useful for the synthesis of other
cimicifugic acids by varying the aryl alkylating reagent and
the substituents on the cinnamoyl chloride.
4
2
0
ethyl acetate, 50:50) gave 8 (0.040 g, 88%) as a white solid. [α]
D
=
1
+
=
47.5 (c = 0.125, CH
2 2 3
Cl ). m.p. 101–102 °C. H NMR (CDCl ): δ
Experimental Section
7.38 (m, 5 H), 7.08 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2
1
H), 5.02 (s, 2 H), 4.55 (d, J = 8.5 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s,
General Methods: H NMR spectra were obtained at 400 MHz in
3
H), 3.29 (d, J = 13.9 Hz, 1 H), 3.05 (d, J = 13.9 Hz, 1 H) ppm.
CDCl
tetramethylsilane. C NMR spectra were obtained at 100.61 MHz
in CDCl . Assignments are supported by 2D correlation NMR
3
; chemical shift values (δ) are given in ppm downfield from
1
3
13
C NMR (CDCl ): δ = 173.3, 171.7, 158.0, 137.0, 131.1, 128.6,
3
1
28.0, 127.5, 127.2, 114.7, 80.1, 75.1, 69.9, 52.9, 52.8, 40.6 ppm.
3
–
1
FTIR (neat): ν˜ = 3488–3374 (OH), 1639 (C=O) cm . C20
374.38448): calcd. C 64.16, H 5.92; found C 64.40, H 5.85.
22 7
H O
spectroscopic studies. Medium-pressure preparative column
chromatography: silica gel Merck 60 H. Analytical TLC: alumin-
(
ium-backed silica gel Merck 60 F254. Reagents and solvents were
Dimethyl (2R,3S)-2,3-Dihydroxy-2-(4-hydroxybenzyl)succinate (9):
Diol 8 (0.040 g, 0.110 mmol) in ethyl acetate (5 mL) was hydroge-
nated at 50 psi in the presence of Pd/C (10%; 0.25 equiv.). After
purified and dried according to ref.[25] Specific rotations ([α]
20
) were
D
measured with a Perkin–Elmer D241 automatic polarimeter. All
reactions were carried out under argon.
4
h, the reaction mixture was filtered, and the solvent was evapo-
2
0
S,S-Diethyl (2R,3S,5S,6S)-2-[4-(Benzyloxy)benzyl]-5,6-dimethoxy-
rated to give diol 9 (0.030 g, 100%) as a white solid. [α]
D
= +52.0
1
5,6-dimethyl-1,4-dioxan-2,3-dicarbothioate (6): LDA was prepared
(c = 0.25, CH
2
Cl
2
). m.p. 64–65 °C. H NMR (CDCl
3
): δ = 7.00 (d,
by adding BuLi (1.6 m in hexane; 1.56 mL, 2.50 mmol) to a solu-
tion of diisopropylamine (0.42 mL, 2.95 mmol) in dry THF (4 mL)
at 0 °C. The solution was stirred at 0 °C for 15 min, and then it
was cooled to –78 °C. A solution of 5 (0.400 g, 1.13 mmol) in dry
J = 8.5 Hz, 2 H), 6.69 (d, J = 8.5 Hz, 2 H), 4.56 (s, 1 H), 3.74 (s,
3 H), 3.73 (s, 3 H), 3.26 (d, J = 14.0 Hz, 1 H), 3.04 (d, J = 14.0 Hz,
1
3
1 H) ppm. C NMR (CDCl
3
): δ = 173.4, 171.7, 155.0, 131.2, 126.6,
115.3, 80.3, 75.2, 52.9, 40.6 ppm. FTIR (neat): ν˜ = 3440–3262
Eur. J. Org. Chem. 2015, 7529–7533
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7531

V. Miranda, C. D. Maycock, M. R. Ventura
FULL PAPER
–
1
(OH), 1739 (C=O) cm . C13
H
16
O
7
(284.27): calcd. C 54.93, H 5.67;
ppm. FTIR (neat): ν˜ = 1715 and 1742 (C=O), 1628 (C=C alkene)
–
1
found C 55.10, H 5.64.
cm .
(
+)-Piscidic Acid (1): Diol 9 (0.053 g, 0.120 mmol) was dissolved
in H O (3 mL), and an aqueous solution of KOH (2 m; 0.11 mL,
.210 mmol) was added. The mixture was heated at reflux for 12 h,
Cimicifugic Acid L (2): Compound 11 (0.011 g, 0.023 mmol) was
dissolved in pyridine (2 mL), and LiI (0.012 g, 0.093 mmol) was
added. The reaction mixture was stirred at 125 °C for 6 h while
2
0
after which time all of the starting material had been consumed. protected from light. After 6 h, the pyridine was removed under
+
The pH was adjusted to 1–2 by the addition of Dowex-H . The
reaction mixture was filtered, and the solvent was evaporated to
give (+)-piscidic acid (1; 0.026 g, 91%) as a yellowish viscous oil.
vacuum. The residue was partitioned between HCl (10%) and ethyl
acetate. The combined organic phases were dried with anhydrous
MgSO and concentrated. The residue was dissolved in water. The
4
20
[21]
[
α]
D
= +45.5 (c = 1.16, MeOH) {ref.
[α]
O); ref.[1] [α]
O)}. 1H NMR
D
= +42.8 (c = 0.80,
aqueous solution was then washed with chloroform. The aqueous
[
5]
28
20
MeOH); ref. [α]
(
D
= +48.88 (c = 2.6, H
2
D
= +41.03
phase was concentrated to give 2 (0.006 g, 60%, trans/cis = 3:1) as
[
3]
22
1
c = 2.6, H
CDCl
.55 (s, 1 H), 2.98 (d, J = 14.0 Hz, 1 H), 2.93 (d, J = 14.0 Hz, 1 H) (d, J = 16.1 Hz, trans isomer), 6.02 (d, J = 12.2 Hz, cis isomer),
2
O); ref. [α]
D
= +32.3 (c = 1.35, H
2
a colourless viscous oil. H NMR (D
2
O): δ = 7.68 (d, J = 16.1 Hz,
(
3
): δ = 6.99 (d, J = 8.6 Hz, 2 H), 6.67 (d, J = 8.6 Hz, 2 H), cis isomer), 7.66 (d, J = 16.0 Hz, trans isomer), 7.17–6.70 (m), 6.42
4
13
3
ppm. C NMR (CDCl ): δ = 175.6, 174.2, 154.5, 131.5, 126.9, 5.54 (s, trans isomer), 5.39 (s, cis isomer), 3.79 (s, cis isomer), 3.76
1
1
2
15.1, 80.6, 74.7, 40.4 ppm. FTIR (neat): ν˜ = 3424–3262 (OH),
(s, trans isomer), 3.75 (s, trans isomer), 3.71 (s, cis isomer), 3.00 (d,
–1
Na [M + Na]+ J = 13.7 Hz, trans isomer), 2.91 (d, J = 13.5 Hz, trans isomer), 2.68
+
725 (C=O) cm . HRMS: calcd. for C11
79.0475; found 279.0478.
12 7
H O
(d, J = 15.2 Hz, cis isomer), 2.53 (d, J = 13.8 Hz, cis isomer) ppm.
1
3
C NMR (D
51.7 (cis isomer), 148.2 (trans isomer), 147.3 (cis isomer), 131.6
trans isomer), 127.0 (trans isomer), 126.7 (trans isomer), 123.7 (cis
2
O): δ = 168.1 (trans isomer), 154.5 (trans isomer),
Dimethyl (2R,3R)-2-[4-(Benzyloxy)benzyl]-3-{[trans-3-(3,4-dimeth-
oxyphenyl)acryloyl]oxy}-2-hydroxysuccinate (10): Triethylamine
1
(
(24 μL, 0.176 mmol) and 3,4-dimethoxycinnamoyl chloride (40 mg,
isomer), 115.0 (trans isomer), 113.4 (trans isomer), 111.4 (trans iso-
mer), 110.3 (cis isomer), 55.6 (trans isomer), 55.5 (trans isomer),
0
0
3
.176 mmol) were added to a solution of compound 8 (0.044 g,
.118 mmol) in dry CH Cl (2 mL) at 0 °C. After 1.5 h at 0 °C and
0 min at room temperature, the reaction was quenched with satu-
Cl solution (5 mL). The aqueous phase was ex-
tracted with ethyl acetate (3ϫ 10 mL), and the combined organic
phases were dried with MgSO and concentrated. Purification of
2
2
5
5.5 (cis isomer), 40.5 (trans isomer) ppm. FTIR (neat): ν˜ = 3357
–1
(
OH), 1645 (C=O) cm .
rated aqueous NH
4
Dimethyl (2R,3R)-2-[4-(Benzyloxy)benzyl]-3-(cinnamoyloxy)-2-
hydroxysuccinate (12): Triethylamine (22 μL, 0.16 mmol) and cin-
4
the residue by preparative chromatography (ethyl acetate/hexane/
namoyl chloride (27 mg, 0.16 mmol) were added to a solution of
dichloromethane, 10:20:20) gave 10 (0.070 g, 95%) as a colourless
compound 8 (0.040 g, 0.107 mmol) in dry CH
After 2 h at 0 °C, the reaction was quenched with saturated aque-
7.79 (d, J = 15.9 Hz, 1 H), 7.42–7.34 (m, 5 H), 7.16–7.09 (m, 4 ous NH Cl solution (5 mL). The aqueous phase was extracted with
H), 6.89–6.87 (m, 3 H), 6.54 (d, J = 15.9 Hz, 1 H), 5.84 (s, 1 H), CH Cl (3ϫ 10 mL), and the combined organic phases were dried
with MgSO and concentrated. Purification of the residue by pre-
parative chromatography (hexane/ethyl acetate, 70:30) gave 12
2 2
Cl (2 mL) at 0 °C.
viscous oil. [α]2
0
= +37.9 (c = 1.09, CH Cl ). H NMR (CDCl ): δ
D 2 2 3
1
=
4
2
2
5
.02 (s, 2 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.80 (s, 3 H), 3.75 (s, 3
4
1
3
H), 3.20 (d, J = 13.8 Hz, 1 H), 2.97 (d, J = 13.7 Hz, 1 H) ppm.
C
2
0
NMR (CDCl
3
): δ = 172.6, 167.7, 166.2, 158.1, 151.6, 149.4, 148.5,
(0.040 g, 74%) as a colourless viscous oil. [α]
2 2 3
CH Cl ). H NMR (CDCl ): δ = 7.85 (d, J = 16.0 Hz, 1 H), 7.58
D
= +37.3 (c = 0.88,
1
1
1
37.0, 131.1, 128.6, 128.0, 127.5, 127.1, 126.6, 123.3, 114.7, 114.1,
11.0, 109.5, 78.9, 75.6, 70.0, 56.0, 55.9, 53.2, 52.7, 40.6 ppm. FTIR
(m, 2 H), 7.43–7.32 (m, 8 H), 7.10 (d, J = 8.7 Hz, 2 H), 6.88 (d, J
= 8.7 Hz, 2 H), 6.66 (d, J = 16.0 Hz, 1 H), 5.83 (s, 1 H), 5.02 (s, 2
–
1
(neat): ν˜ = 1715 and 1742 (C=O), 1628 (C=C alkene) cm .
H), 3.80 (s, 3 H), 3.75 (s, 3 H), 3.20 (d, J = 13.7 Hz, 1 H), 2.97 (d,
J = 13.7 Hz, 1 H) ppm. C NMR (CDCl ): δ = 172.6, 167.6, 166.0,
3
Dimethyl (2R,3R)-3-{[trans/cis-3-(3,4-Dimethoxyphenyl)acryloyl]-
13
oxy}-2-hydroxy-2-(4-hydroxybenzyl)succinate (11): FeCl (0.017 g,
solution of ester 10 (0.020 g,
3
1
1
58.1, 147.0, 137.0, 134.1, 131.1, 130.8, 129.0, 128.6, 128.4, 128.0,
27.5, 126.6, 116.5, 114.7, 78.9, 75.8, 70.0, 53.2, 52.8, 40.6 ppm.
0
0
.11 mmol) was added to
a
[23]
.035 mmol) in dry CH Cl (2 mL) at 0 °C. After 25 min at 0 °C,
2
2
–1
FTIR (neat): ν˜ = 1742 (C=O), 1637 (C=C alkene) cm . HRMS:
the reaction was quenched with water (5 mL), and the aqueous
phase was extracted with CH Cl (3ϫ 10 mL). The combined or-
ganic phases were dried with anhydrous MgSO and concentrated.
Purification of the residue by preparative chromatography (hexane/
ethyl acetate, 50:50) gave 11 (0.009 g, 53%, trans/cis = 3:1) as a tion of ester 12 (0.020 mg, 0.04 mmol) in dry CH
Na [M + Na]+ 527.1676; found 527.1670.
+
calcd. for C29H O
28 8
2
2
4
Dimethyl (2R,3R)-3-(Cinnamoyloxy)-2-hydroxy-2-(4-hydroxybenz-
yl)succinate (13): FeCl (0.019 g, 0.12 mmol) was added to a solu-
Cl (2 mL) at
0 °C. After 25 min at 0 °C, the reaction was quenched with water
(5 mL), and the aqueous phase was extracted with CH Cl (3ϫ
10 mL). The combined organic phases were dried with anhydrous
MgSO and concentrated. Purification of the residue by preparative
isomer), 3.93 (s, 3 H, trans isomer), 3.92 (s, cis isomer), 3.90 (s, cis chromatography (hexane/ethyl acetate, 60:40) gave 13 (0.006 g,
3
2
2
1
colourless viscous oil. H NMR (CDCl
trans isomer), 7.72 (d, J = 2.0 Hz, cis isomer), 7.16–6.71 (m), 6.53
d, J = 16.0 Hz, trans isomer), 6.40 (d, J = 15.8 Hz, cis isomer),
.84 (s, 1 H, trans isomer), 5.70 (s, cis isomer), 3.94 (s, 3 H, trans
3
): δ = 7.79 (d, J = 15.6 Hz,
2
2
(
5
4
2
0
isomer), 3.80 (s, 3 H, trans isomer), 3.77 (s, cis isomer), 3.75 (s, 3
H, trans isomer), 3.73 (s, cis isomer), 3.56 (s, 1 H, trans isomer),
37%) as a colourless viscous oil. [α]
D
= +103.9 (c = 0.31, CH
2 2
Cl ).
1
H NMR (CDCl
3
): δ = 7.85 (d, J = 16.0 Hz, 1 H), 7.58 (m, 2 H),
3.19 (d, J = 13.8 Hz, 1 H, trans isomer), 3.08 (d, J = 13.8 Hz, cis
7.41 (m, 3 H), 7.05 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 8.4 Hz, 2 H),
isomer), 2.95 (d, J = 13.8 Hz, 1 H, trans isomer), 2.88 (d, J =
6.66 (d, J = 16.0 Hz, 1 H), 5.83 (s, 1 H), 3.80 (s, 3 H), 3.75 (s, 3
3.8 Hz, cis isomer) ppm. 13C NMR (CDCl
67.6 (cis isomer), 166.3, 154.9, 151.6, 149.3, 146.9, 146.6 (cis iso-
): δ = 172.6, 167.7,
H), 3.19 (d, J = 13.8 Hz, 1 H), 2.95 (d, J = 13.8 Hz, 1 H) ppm.
NMR (CDCl
13
C
1
1
3
3
): δ = 172.6, 167.6, 166.1, 154.9, 147.0, 134.1, 131.3,
mer), 131.3, 127.1, 126.4, 125.2 (cis isomer), 123.3, 115.3, 115.2 (cis 130.8, 129.0, 128.4, 126.3, 116.5, 115.3, 78.9, 75.8, 53.2, 52.8,
isomer), 114.1, 113.5 (cis isomer), 111.0, 110.3 (cis isomer), 109.5, 40.5 ppm. FTIR (neat): ν˜ = 3432–3351 (OH), 1720 (C=O), 1635
–
1
+
+
7
5
8.9, 78.8 (cis isomer), 75.6, 56.0, 55.9, 55.8 (cis isomer), 53.2,
3.1 (cis isomer), 52.7, 52.6 (cis isomer), 40.5, 40.4 (cis isomer)
(C=C alkene) cm . HRMS: calcd. for C22
437.1207; found 437.1210.
22 8
H O Na [M + Na]
7532
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Eur. J. Org. Chem. 2015, 7529–7533

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Received: July 30, 2015
Published Online: October 23, 2015
[
Eur. J. Org. Chem. 2015, 7529–7533
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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