Straightforward total synthesis of 2-O-feruloyl-L-malate, 2-O-sinapoyl-L-malate and 2-O-5-hydroxyferuloyl-L-malate

Article abstract of DOI:10.1055/s-0029-1216983

A synthetic method for the preparation of 2-O-feruloylL-malic acid, 2-O-sinapoyl-L-malic acid and 2-O-5-hydroxyferuloyl-L-malic acid from malic acid and ferulic, sinapic, and hydroxyferulic acids, respectively, using Steglich esterification is described.

Full text of DOI:10.1055/s-0029-1216983

PAPER
A
Straightforward Total Synthesis of 2-O-Feruloyl-L-malate, 2-O-Sinapoyl-L-
malate and 2-O-5-Hydroxyferuloyl-L-malate
Synthesis of
O
l
-Esters
o
of
M
alic
A
c
r
id Relat
e
n
INRA, UMR206 Chimie Biologique, 78026 Versailles, France
Fax +33(1)30833119; E-mail: florent.allais@versailles.inra.fr; E-mail: ducrot@versailles.inra.fr
Received 29 May 2009; revised 30 June 2009
O
O
O
OH
Abstract: A synthetic method for the preparation of 2-O-feruloyl-
L-malic acid, 2-O-sinapoyl-L-malic acid and 2-O-5-hydroxy-
feruloyl-L-malic acid from malic acid and ferulic, sinapic, and
hydroxyferulic acids, respectively, using Steglich esterification is
described.
CO2H
CO2H
Steglich esterification
OMe
HO
CO2R2
CO2R2
+
R1
R1
OMe
Key words: isourea, cross-coupling, esterification, phenol, total
synthesis
OH
OH
7a R2 = H
1 R1 = H
4 R1 = H
7b R2 = Bn
7c R2 = t-Bu
2 R1 = OMe
3 R1 = OH
5 R1 = OMe
6 R1 = OH
Hydroxycinnamoyl-L-malic acids are natural products
(trans-phenylpropanoids) isolated from a variety of
plants; for example, 2-O-feruloyl-L-malic acid (1) from
radish (Raphanus sativus) (Figure 1).1a–c Interest in this
type of natural compounds (also referred in the literature
as ‘cinnamoyl malates’) has grown since it has been ob-
served that the severe decrease in sinapoyl malate (2) and
the appearance of 1 when plants, such as Arabidopsis,1d
have been downregulated in a crucial lignin biosynthetic-
pathway enzyme, COMT.1d,e
Scheme 1
We started with the synthesis of the malate moiety 7a, 7b,
and 7c. In order to efficiently and cleanly esterify ferulic
acid (4), malic acid has to be protected to avoid intramo-
lecular coupling. Benzyl esters, which would be cleanly
cleaved by hydrogenation reaction, happened to be our
first choice. Indeed, in the course of the synthesis of chic-
oric acid, Quideau used such dibenzyl malate ester, benzyl
groups being cleanly removed at the end of the synthesis
using catalytic hydrogen transfer [Pd(OAc)2, Et3N,
Et3SiH].3
4
O
O
2
3
CO2H
9
1CO2H
8'
7'
Benzyl malate ester 7b was synthesized in one step using
Steglich esterification of malic acid with benzyl alcohol in
the presence of DIC/DMAP in dichloromethane (72%)
(Scheme 2).
1 R = H
2 R = OMe sinapoyl malate
3 R = OH 5-hydroxyferuloyl malate
feruloyl malate
1'
2'
3'
6'
5'
R
OMe
4'
OH
BnOH
DIC, DMAP
Figure 1 Natural products related to malic acid
CH2Cl2, r.t.
(72%)
HO
HO
CO2H
CO2Bn
CO2Bn
7b
Though feruloyl malates and analogues proved to play a
crucial role in lignin biosynthesis1e,f and plant defense
against insects/pathogenic viruses/fungus,2 to the best of
our knowledge, no general synthesis of feruloyl malate
has been published.
CO2H
Scheme 2
Thereafter, compound 8 was synthesized via the Steglich
esterification of 4-O-benzyl-3-methoxycinnamic acid
with dibenzyl L-malate (7b) (85%). However, when it
came to cleave the benzyl groups in 8, we were not able to
saponify the benzyl esters without reducing the internal
double bond of the trans-phenylpropanoids moiety
(Scheme 3).
In the course of our research aimed at a better understand-
ing of the precise chemical mechanisms involved in the
biosynthesis of lignins and lignans, we devised an easy
and efficient access to 2-O-feruloyl-L-malate (1), 2-O-si-
napoyl-L-malate (2), and 2-O-5-hydroxyferuloyl-L-
malate (3) using carbodiimide-mediated Steglich esterifi-
cation starting from commercially available L-(–)-malic
acid and the corresponding cinnamic acids (Scheme 1).
We then turned to the protection of the carboxylic acids as
tert-butyl esters. Ralph and co-workers have already re-
ported a four-step synthesis of 7c, using this protection of
the carboxylic groups, but also involving a necessary pro-
SYNTHESIS 2009, No. x, pp 000A–000H
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Advanced online publication: xx.xx.2009
DOI: 10.1055/s-0029-1216983; Art ID: P07709SS
© Georg Thieme Verlag Stuttgart · New York

B
F. Allais et al.
PAPER
CO2H
CO2H
O
O
O
O
CO2H
CO2Bn
CO2Bn
CO2H
Pd(OAc)2
Ac2O, pyr, r.t.
(94%)
Et3N, Et3SiH
R
OMe
R
OMe
(95%)
OMe
OMe
OAc
10 R = H
11 R = OMe
OH
OH
OBn
4 R = H
5 R = OMe
8
Scheme 3
Scheme 5
tection/deprotection sequence of the hydroxyl group of obtained in 98% yield. Methylation (MeI, K2CO3, DMF)
malic acid.4 Though this route gave access to the desired of the remaining hydroxy group at C3, followed by hy-
malate, we preferred to design an alternative synthesis of drolysis of the orthoformate (HCl, MeOH) gave access to
7c avoiding such protection. Therefore, we decided to use ethyl 3,4-dihydroxy-5-methoxycinnamate (17) in 94%
isoureas as reactive intermediates to esterify malic acid yield (2 steps). Finally, saponification of 17 with a THF–
without prior protection of the hydroxyl group. Isoureas H2O solution of sodium hydroxide yielded 5-hydroxyfer-
offer two advantages : they may be purified prior to use, ulic acid (6) (98%, 49% overall yield, 7 steps).9 Peracety-
and, more importantly, they may be stored for extended lation of 6 with acetic anhydride–pyridine provided 4,5-
periods of time.5a N,N¢-Diisopropyl-O-tert-butylisourea diacetylferulic acid (18) in 95% yield.
(9) was then obtained, in 64% yield, by mixing diisopro-
pylcarbodiimide (DIC) and tert-butyl alcohol with a cata-
lytic amount of copper(I) chloride for 20 days (Scheme 4).
An alternative, shorter sequence was designed to synthe-
size intermediate 18 (Scheme 7). 3,4-Dihydroxy-5-meth-
oxybenzaldehyde (19) was peracylated (Ac2O, Et3N,
Malate 7c was thereafter obtained, in 63% yield, by add- 83%) to give intermediate 20, which underwent a Horner–
ing excess 9 to a solution of malic acid in dichloromethane Wadsworth–Emmons–Wittig olefination (n-BuLi, tert-
at room temperature (due to competitive loss of 2-methyl- butyl diethylphosphonoacetate, THF) and provided the
propene, formation of tert-butyl esters requires excess trans-a,b-unsaturated ester 21 (E/Z >98:2)6 in 89% yield.
isourea) (Scheme 4).5b
Removal of tert-butyl ester was then achieved via TFA-
mediated saponification to yield 18 (95%, 70% overall
yield from 19, 3 steps).
Prior to Steglich esterification of acids 4, 5, and 6 with 7c,
protection of the hydroxy group of acids 4, 5, 6 was nec-
essary to avoid intramolecular coupling. Acetylation of To synthesize large amounts of 18 rapidly, the shorter
commercially available ferulic acid (4) and sinapic acid synthetic sequence described above is undoubtedly the
(5) was achieved through acetylation with acetic anhy- best choice. However, in our quest of a versatile method-
dride in pyridine which gave, respectively, 4-O-acetylfer- ology for the regioselective functionalization of trihy-
ulic and sinapic acids 10 (94%) and 11 (94%) (Scheme 5).
droxylated aromatic rings, we intentionally focused our
efforts towards the design of the desymmetrization pro-
cess (15 → 17). Thereafter, DIC/DMAP coupling of 10,
11, 18 with 7c in dichloromethane allowed the formation
of the 2-O-cinnamoyl di-tert-butyl malates 22 (84%), 23
(84%), and 24 (70%) (Scheme 8).
Hydroxyferulic acid 6 was prepared as follows. Starting
from commercially available 3,4,5-trihydroxybenzalde-
hyde monohydrate (12), peracetylation with acetic anhy-
dride–pyridine provided intermediate 13 (73% yield),
which underwent a Horner–Wadsworth–Emmons–Wittig
olefination (n-BuLi, triethyl phosphonoacetate, THF) to Removal of protecting groups was achieved in a two-step
give the trans-a,b-unsaturated ester 14 (E/Z >98:2)6 in process involving TFA-mediated hydrolysis of tert-butyl
83% yield (Scheme 6). Finally, acetate removal with esters (93% yield after recrystallization) and acetate re-
aqueous 3 M HCl in acetone gave compound 15 in 89% moval (aq 3 M HCl–acetone, reflux), yielding the targeted
yield.7
compounds 1 (98%; 45% overall yield, 4 steps), 2 (98%;
72% overall yield, 4 steps), and 3 (92%; 28% overall yield
from 12, 11 steps).
At this stage of the synthesis, a desymmetrization process
had to be devised to differentiate the hydroxy groups at C4
and C5 from the one at C3. Desymmetrization was ob- For in vitro biological activity tests on oomycetes repro-
tained via orthoformate-protection of the C4 and C5 hy- duction,2e analytical samples of the malic acids 1, 2, and 3
droxy groups (Scheme 6).8 Orthoformate 16 was thus were required by our partner. Semipreparative HPLC pu-
(–)-malic acid
CH2Cl2
t-BuOH
CuCl
HO
HN
N
CO2t-Bu
CO2t-Bu
7c
N
C N
(63%)
(64%)
Ot-Bu
9
Scheme 4
Synthesis 2009, No. x, A–H © Thieme Stuttgart · New York

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Synthesis of O-Esters of Malic Acid Related to Natural Products
C
CO2Et
O
O
(EtO)2P(O)CH2CO2Et
THF, n-BuLi, –78 °C
E/Z >98:2
Ac2O, pyr, r.t.
(73%)
(83%)
AcO
OAc
AcO
OAc
HO
OH
OAc
14
OAc
13
OH
12
3 M HCl, acetone
(89%)
CO2Et
CO2Et
CO2Et
(EtO)3CH
1. MeI, K2CO3
Amberlyst 15-E
DMF, 70 °C
C6H6, Δ
2. 2 M HCl, MeOH
(98%)
(94%, 2 steps)
OH
HO
OH
O
HO
OMe
O
OH
OH
EtO
16
15
17
2 M NaOH
THF, r.t.
(98%)
CO2H
CO2H
Ac2O, pyr, r.t.
(94%)
HO
OH
6
OMe
AcO
OMe
OAc
18
Scheme 6
O
O
O
OH
CO2H
CO2t-Bu
CO2t-Bu
CO2t-Bu
O
(EtO)2P(O)CH2CO2t-Bu
THF, n-BuLi, –78 °C
E/Z >98:2
TFA, CH2Cl2, r.t.
(95%)
7c, DIC, DMAP
CH2Cl2, r.t.
(89%)
RO
OR
OMe
AcO
OMe
AcO
OMe
22/23 (84%)
24 (70%)
R
OMe
R
OMe
OAc
18
OAc
21
OAc
OAc
19 R = H
20 R = Ac
Ac2O, Et3N, r.t.
(83%)
10 R = H
11 R = OMe
18 R = OAc
22 R = H
23 R = OMe
24 R = OAc
Scheme 7
rifications of the synthetic malic acids on a C-18 column
were then effected and gave access to the analytical sam-
ples.
O
O
CO2H
CO2H
This convenient synthesis of trans-phenylpropanoids
proved itself valuable for studies aimed at elucidating and
exploiting the biological activity (e.g., in lignin biosyn-
thesis) of these ferulic acids based natural products as it
allows the formation of appreciable quantities of material
in a timely fashion. We also demonstrated that the use of
orthoformates to desymmetrize 3,4,5-trihydroxycinnam-
ate ester 15 is a powerful tool to segregate the C3, C4 and
C5 positions of trihydroxylated aromatic rings. Briefly,
this regioselective process offers new opportunities in
neolignans/polyphenols chemistry.
1. TFA, CH2Cl2, r.t.
2. 3 M HCl, acetone
1/2 (91%), 3 (85%)
R
OMe
OH
1 R = H
2 R = OMe
3 R = OH
Scheme 8
fied by distillation from sodium/benzoquinone under N2. Moisture
and O2-sensitive reactions were carried out in flame-dried glass-
ware under N2. Evaporations were conducted under reduced pres-
sure at temperature below 45 °C, unless otherwise noted. Column
chromatography (CC) was carried out under positive N2 pressure
with 40–63 mm silica gel (Merck®) and the indicated solvents. Melt-
CH2Cl2 (stabilized with amylene) was purified by distillation from
CaH2 under N2 immediately before use. THF and Et2O were puri-
Synthesis 2009, No. x, A–H © Thieme Stuttgart · New York

D
F. Allais et al.
PAPER
ing points are uncorrected. 1H NMR spectra of samples in the indi-
cated solvent were recorded at 300 MHz on a MercuryPlus 300
Varian instrument (1H NMR: CDCl3 residual signal at 7.26 ppm;
CD3OD residual signal at 3.31 ppm; acetone-d6 residual signal at
2.05 ppm). 13C NMR spectra of samples in the indicated solvent
were recorded at 75 MHz on a Varian instrument (13C NMR: CDCl3
residual signal at 77.26 ppm; CD3OD residual signal at 49.00 ppm;
acetone-d6 residual signal at 29.84 ppm). 13C multiplicities were de-
termined by DEPT135 experiments. Assignments are given as per the
labeling shown in Figure 1. IR spectra were recorded on a Nicolet
Avatar 320 FT-IR spectrometer. Optical rotations were measured
on a Bellingham+ ADP410 from Stanley. Electron impact (EI), and
low- and high-resolution MS analyses were obtained at the mass
spectrometry service of the ICSN-CNRS, Gif-sur-Yvette, Ver-
sailles, France. Elemental analyses were obtained from the ICSN-
CNRS, Gif-sur-Yvette, France. Chemicals were bought from
Sigma-Aldrich and Acros Organics and used without further purifi-
cation. All reported yields are uncorrected and refer to purified
products.
HRMS-EI: m/z [M + Na]+ calcd for C12H18O5 + Na: 269.1365;
found: 269.1374.
4-O-Acetylferulic Acid (10)
To ferulic acid (4; 10 g, 51.49 mmol, 1 equiv) were added pyridine
(15 mL) and Ac2O (13.6 mL, 14.72 g, 144.19 mmol, 2.8 equiv) at
r.t. The mixture was stirred for 3 h and then poured into an ice/water
solution (300 mL). The white precipitate was filtered, washed, and
dried to give pure 10 as a white powder (11.43 g, 94%); mp 195–
196 °C.
1H NMR (400 MHz, acetone-d6): d = 10.8 (br s, 1 H, CO2H), 7.66
(d, J = 15.9 Hz, 1 H, ArCH=CHCO2R), 7.47 (s, 1 H, H-2¢), 7.27 (d,
J = 7.8 Hz, H-5¢), 7.11 (d, J = 7.8 Hz, 1 H, H-6¢), 6.54 (d, J = 15.9
Hz, ArCH=CHCO2R), 3.91 (s, 3 H, CH3O-3¢), 2.25 (s, 3 H,
CH3CO2-4¢).
13C NMR (75 MHz, acetone-d6): d = 168.8 (s, CO2H), 167.7 (s,
CH3CO2-4¢), 152.8 (s, C-3¢), 144.9 (d, C-7¢), 134.4 (s, C-4¢), 124.2
(s, C-1¢), 122.1 (d, C-5¢), 119.5 (d, C-6¢), 116.5 (d, C-8¢), 112.6 (d,
C-2¢), 56.5 (q, CH3O-3¢), 20.5 (q, CH3CO2-4¢).
MS (EI, 50 eV): m/z (%) = 236 (7, [M+]), 194 (100), 179 (27), 133
(20), 77 (11), 51 (21), 43 (78).
HPLC: Semipreparative HPLC purification of 1, 2, and 3 was per-
formed on a Waters 600 delivery system with a C-18 Kromasil col-
umn (250 × 10.5 mm, 5 micron). The mobile phase was MeCN–
H2O–HCO2H (74.5:25:0.5) and gradient elution (0–30 min: 0 to
100% MeCN) was applied at a flow rate of 4 mL·min–1. Column ef-
fluent was monitored by UV detection at 313 nm with a Waters 990
Photodiode Array Detector.
HRMS-EI: m/z [M – H]+ calcd for C12H11O5: 235.0607; found:
235.0616.
2-O-(4-O-Acetylferuloyl)-di-tert-butyl Malate (22)
To a solution of 4-acetylferulic acid (10; 5 g, 21.16 mmol, 1 equiv)
and 7c (5.2 g, 21.16 mmol, 1 equiv) in CH2Cl2 (106 mL) at r.t. was
added DIC (3.33 mL, 2.67 g, 21.16 mmol, 1 equiv) and DMAP
(2.58 g, 10.58 mmol, 0.5 equiv). The mixture was stirred at r.t. for
1 day. The crude mixture was poured into hexane (200 mL) and the
resulting mixture was filtered over Celite®. The filtrate was concen-
trated in vacuo and the crude solid was purified by flash chromatog-
raphy (cyclohexane–EtOAc, 7:3) to yield ester 22 as a thick oil (8.2
g, 84%); [a]D25 +13.4 (c 0.01, CHCl3).
Method A: Analytical HPLC analyses of eluted fractions were car-
ried out on a Varian Prostar 240 pump system with a C-18 Varian
Res Elut (150 × 4.60 mm, 5 micron) column and dual UV detection
was performed at 200 and 313 nm with a Varian UV Prostar 335 de-
tector. The mobile phase was MeCN–H2O–HCO2H (74.5:25:0.5)
and gradient elution (0–20 min: 0 to 100% MeCN) was applied at a
flow rate of 1 mL·min–1. Retention times: 1 (tR = 3.44 min), 2
(tR = 3.46 min) and 3 (tR = 4.07 min).
Method B: Analytical HPLC analysis of eluted fractions was carried
out on a Waters System Controller 680 with two 510 pumps
equipped with an Inertsil 5ODS3 C-18 column (5 mm, 250 × 4.6
mm i.d.; Interchim, Montluçon, France). Samples were chromato-
graphed with the following gradient (flow rate l mL/min): 1 min iso-
cratic 15% solvent A (MeOH) and 85% solvent B (H2O, 0.5%
H3PO4), then within 29 min to 75% solvent A, then within 3 addi-
tional min to 100% solvent A, followed by a 3 min isocratic step in
100% solvent A. Compounds were detected by a Waters TM 996
Photodiode Array Detector (200 to 500 nm). Retention times: 1
(tR = 23.56 min), 2 (tR = 21.56 min), and 3 (tR = 20.10 min).
IR (neat): 2979, 2935, 1725, 1637, 1507, 1367, 1146 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.67 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2R), 7.10 (s, 1 H, H-2¢), 7.08 (d, J = 1.5 Hz, 2 H, H-
5¢, H-6¢), 6.42 (d, J = 15.9 Hz, 1 H, ArCH=CHCO2R), 5.42 (dd,
J = 5.4, 7.2 Hz, 1 H, H-2), 3.82 (s, 3 H, CH3O-3¢), 2.82 (m, 2 H, H-
3), 2.29 (s, 3 H, CH3CO2-4¢), 1.45 (s, 9 H, t-C4H9), 1.43 (s, 9 H, t-
C4H9).
13C NMR (75 MHz, CDCl3): d = 168.7 (s, CO2t-Bu), 168.5 (s, CO2t-
Bu), 168.1 (s, CH3CO2-4¢), 165.7 (s, C-9), 151.6 (s, C-3¢), 145.2 (d,
C-7¢), 141.8 (s, C-4¢), 133.4 (s, C-1¢), 123.4 (d, C-5¢), 121.5 (d, C-
6¢), 117.5 (d, C-8¢), 111.5 (d, C-2¢), 82.7 [s, CO2C(CH3)3], 81.6 [s,
CO2C(CH3)3], 69.3 (d, CO2CHCO2t-Bu), 56.1 (q, CH3O-3¢), 37.8 (t,
CH2CO2t-Bu), 28.2 [q, CO2C(CH3)3], 28.1 [q, CO2C(CH3)3], 20.7
(q, CH3CO2-4¢).
Di-tert-butyl Malate (7c)
To a suspension of malic acid (3.6 g, 29.0 mmol, 1 equiv) in CH2Cl2
(300 mL) at r.t. under argon was added N,N¢-diisopropyl-O-tert-bu-
tylisourea (9;5 38.8 g, 193.7 mmol, 6.7 equiv) and the mixture was
stirred for 2 days at r.t. The crude mixture was concentrated in vac-
uo and cyclohexane (400 mL) was added, and the resulting mixture
was filtered over Celite®. The filtrate was concentrated in vacuo and
the crude oil was purified by flash chromatography (cyclohexane–
MS (EI, 50 eV): m/z (%) = 464 (6, [M+]), 366 (65), 335 (46), 310
(61), 219 (12), 177 (57), 145 (36), 57 (100).
HRMS-EI: m/z [M + Na]+ calcd for C24H32O9 + Na: 487.1944;
found: 487.1930.
25
EtOAc, 5:5) to yield ester 7c as a yellow oil (4.49 g, 63%); [a]D
–6.4 (c 0.1036, CHCl3).
2-O-Feruloyl-L-Malate (1)
IR (neat): 3488, 2978, 2934, 2925, 1727, 1367, 1147 cm–1.
Ester 22 (410 mg, 0.88 mmol, 1 equiv) was dissolved in CH2Cl2 (4
mL) at r.t. and 99% TFA (1.3 mL, 2 g, 17.7 mmol, 20 equiv) was
added dropwise. The solution was stirred overnight and concentrat-
ed in vacuo to afford 4-acetoxyferuloyl malic acid as a crude oil,
which was used in the next step without further purification.
1H NMR (300 MHz, CDCl3): d = 4.30 (dd, J = 4.5, 5.7 Hz, 1 H,
CHCO2t-Bu), 2.73 (dd, J = 4.5, 16.2 Hz, 1 H, CH2CO2t-Bu), 2.64
(dd, J = 5.7, 16.2 Hz, 1 H, CH2CO2t-Bu), 1.49 (s, 9 H, t-C4H9), 1.46
(s, 9 H, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 172.7 (s, CO2t-Bu), 169.7 (s, CO2t-
Bu), 82.3 [s, CO2C(CH3)3], 81.1 [s, CO2C(CH3)3], 67.5 (d, CHOH),
39.9 (t, CH2CO2t-Bu), 28.0 [q, CO2C(CH3)3], 27.9 [q,
CO2C(CH3)3].
4-Acetoxyferuloyl Malic Acid
Yield: 287.1 mg, 93%; [a]D24 +19. 2 (c 0.112, CHCl3).
IR (neat): 3021, 2981, 1720, 1637, 1214 cm–1.
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Synthesis of O-Esters of Malic Acid Related to Natural Products
E
1H NMR (300 MHz, CDCl3): d = 7.67 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2R), 7.31 (s, 1 H, H-2¢), 7.14 (d, J = 7.8 Hz, 1 H, H-
5¢), 7.02 (d, J = 7.8 Hz, 1 H, H-6¢), 6.54 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2R), 5.54 (dd, J = 3.6, 8.1 Hz, 1 H, H-2), 3.79 (s, 3 H,
CH3O-3), 2.94 (m, 2 H, H-3), 2.25 (s, 3 H, CH3CO2-4¢).
13C NMR (75 MHz, CDCl3): d = 172.8 (s, CO2CH), 172.3 (s,
CO2H), 170.4 (s, CH3CO2-4¢), 167.3 (s, C-9) 152.9 (s, C-3¢), 146.5
(d, C-4¢), 143.0 (s, C-7¢), 134.5 (s, C-1¢), 124.2 (d, C-5¢), 122.5 (d,
C-6¢), 118.2 (d, C-8¢), 112.7 (d, C-2¢), 70.0 (d, CO2CHCO2H), 56.5
(q, CH3O-3¢), 36.9 (t, CH2CO2H), 20.5 (q, CH3CO2-4¢).
hexane (20 mL) and the resulting mixture was filtered over Celite®.
The filtrate was concentrated in vacuo and the crude solid was pu-
rified by flash chromatography (cyclohexane–EtOAc, 7:3) to yield
23
ester 23 as a thick oil (629.4 mg, 84%); [a]D +19.2 (c 0.0156,
CHCl3).
IR (neat): 2975, 2939, 1724, 1596, 1264, 1144 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2R), 6.75 (s, 2 H, H-2¢, H-6¢), 6.43 (d, J = 15.9 Hz, 1
H, ArCH=CHCO2R), 5.43 (dd, J = 5.4, 7.2 Hz, 1 H, H-2), 3.82 (s, 6
H, CH3O-3¢, CH3O-5¢), 2.82 (m, 2 H, H-3), 2.32 (s, 3 H, CH3CO2-
4¢), 1.46 (s, 9 H, t-C4H9), 1.44 (s, 9 H, t-C4H9).
MS (EI, 50 eV): m/z (%) = 351 (25, [M – H]+), 235 (100), 171 (45).
HRMS-EI: m/z [M – H]+ calcd for C16H15O9: 351.0716; found:
351.0706.
13C NMR (75 MHz, CDCl3): d = 168.6 (s, CO2t-Bu), 168.5 (s, CO2t-
Bu), 168.1 (s, CH3CO2-4¢), 165.7 (s, C-9), 152.7 (s, C-3¢, C-5¢),
145.7 (d, C-7¢), 132.7 (s, C-1¢), 130.9 (s, C-4¢), 117.7 (d, C-8¢),
105.1 (d, C-2¢, C-6¢), 82.8 [s, CO2C(CH3)3], 81.7 [s, CO2C(CH3)3],
69.4 [d, CO2CHCO2t-Bu], 56.4 (q, CH3O-3¢, CH3O-5¢), 37.8 (t,
CH2CO2t-Bu), 28.2 [q, CO2C(CH3)3], 28.1 [q, CO2C(CH3)3], 20.5
(q, CH3CO2-4¢).
To a mixture of 4-acetylferuloyl malic acid (309 mg, 0.88 mmol, 1
equiv) in acetone (30 mL) was added aq 3 M HCl (9 mL). The re-
sulting solution was refluxed for 3 h, cooled to r.t., and diluted with
EtOAc (200 mL). The EtOAc layer was then washed with brine (50
mL), dried (MgSO4), and concentrated in vacuo to afford 110 as a
crude oil.
MS (EI, 50 eV): m/z (%) = 494 (6, [M+]), 452 (5), 396 (10), 365
(29), 40 (100), 207 (19), 57 (40).
1
HRMS-EI: m/z [M + Na]+ calcd for C25H34O10 + Na: 517.2050;
found: 517.2040.
Yield: 266.5 mg (98%); [a]D26 +10.0 (c 0.002, MeOH).
IR (neat): 3314, 2974, 1708, 1046 cm–1.
Sinapoyl-L-malate (2)
1H NMR (300 MHz, CD3OD): d = 7.63 (d, J = 15.9 Hz, 1 H, H-7¢),
7.20 (s, 1 H, H-2¢), 7.05 (d, J = 8.1 Hz, 2 H, H-6¢), 6.79 (d, J = 8.1
Hz, 1 H, H-5¢), 6.38 (d, J = 15.9 Hz, 1 H, H-8¢), 5.49 (dd, J = 3.6,
8.1 Hz, 1 H, H-2), 3.86 (s, 3 H, CH3O-3¢), 3.01 (dd, J = 3.6, 15.9 Hz,
1 H, H-3), 2.89 (dd, J = 8.1, 15.9 Hz, 1 H, H-3).
13C NMR (75 MHz, CD3OD): d = 172.9 (s, C-1), 172.5 (s, C-4),
168.0 (s, C-9), 150.7 (s, C-4¢), 149.3 (s, C-3¢), 147.8 (d, C-7¢), 127.5
(s, C-1¢), 124.3 (d, C-6¢), 116.4 (d, C-5¢), 114.5 (d, C-8¢), 111.7 (d,
C-2¢), 69.9 (d, C-2), 56.4 (q, CH3O-3¢), 37.0 (t, C-3).
MS (EI, 50 eV): m/z (%) = 309 (40, [M – H]+), 258 (5), 251 (7), 193
(100), 154 (7), 129 (7).
HRMS-EI: m/z [M – H]+ calcd for C14H13O8: 309.0610; found:
309.0609.
Ester 23 (200 mg, 0.4 mmol, 1 equiv) was dissolved in CH2Cl2 (1.8
mL) at r.t. and TFA (0.6 mL, 925 mg, 8.1 mmol, 20 equiv) was add-
ed dropwise. The solution was stirred overnight and concentrated in
vacuo. The crude oil was purified by flash chromatography (cyclo-
hexane–EtOAc, 7:3) to provide the free dicarboxylic acid as a thick
oil.
Intermediate Dicarboxylic Acid
Yield: 141.7 mg (93%); [a]D23 +3.8 (c 0.008, EtOAc).
IR (neat): 2987, 2942, 1721, 1597, 1129 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2R), 6.85 (s, 2 H, H-2¢, H-6¢), 6.51 (d, J = 15.9 Hz, 1
H, ArCH=CHCO2R), 5.47 (dd, J = 3.6, 8.1 Hz, 1 H, H-2), 3.82 (s, 6
H, CH3O-3¢, CH3O-5¢), 2.88 (m, 2 H, H-3), 2.22 (s, 3 H, CH3CO2-
4¢).
13C NMR (75 MHz, CDCl3): d = 172.9 (s, CO2H), 172.4 (s, CO2H),
170.2 (s, CH3CO2-4¢), 167.4 (s, CO2CH), 153.8 (s, C-3¢, C-5¢),
147.0 (d, C-7¢), 134.0 (s, C-1¢), 129.3 (s, C-4¢), 118.3 (d, C-8¢),
106.1 (d, C-2¢, C-6¢), 70.1 (d, CO2CHCO2H), 56.7 (q, CH3O-3¢,
CH3O-5¢), 37.0 (t, CH2CO2H), 20.2 (q, CH3CO2-4¢).
MS (EI, 50 eV): m/z (%) = 405 (100, [M + Na]+), 363 (18), 311 (15),
283 (43), 207 (10).
HRMS-EI: m/z [M + Na]+ calcd for C17H18O10 + Na: 405.0798;
found: 405.0795.
4-Acetyl-3,5-dimethoxycinnamic Acid (11)
To sinapic acid (5; 1 g, 3.76 mmol, 1 equiv) were added pyridine (1
mL) and Ac2O (0.99 mL, 1.07 g, 10.53 mmol, 2.8 equiv) at r.t. The
mixture was stirred for 3 h and then poured into an ice/water mix-
ture. The white precipitate was filtered, washed with H2O (10 mL),
and dried to give pure 11 as a white solid (940 mg, 94%); mp 192–
193 °C.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2H), 6.80 (s, 2 H, H-2¢, H-6¢), 6.40 (d, J = 15.9 Hz, 1
H, ArCH=CHCO2H), 3.86 (s, 6 H, CH3O-3¢, CH3O-5¢), 2.35 (s, 3 H,
CH3CO2-4¢).
13C NMR (75 MHz, CDCl3): d = 171.6 (s, CO2H), 168.6 (s,
CH3CO2-3¢), 152.9 (s, C-3¢, C-5¢), 147.0 (d, C-7¢), 132.6 (s, C-1¢),
129.9 (s, C-4¢), 117.8 (d, C-8¢), 105.3 (d, C-2¢, C-6¢), 56.5 (q, CH3O-
3¢, CH3O-5¢), 20.6 (q, CH3CO2-4¢).
MS (EI, 50 eV): m/z (%) = 266 (15, [M+]), 224 (100), 209 (17), 181
(10), 43 (54).
To a solution of the free dicarboxylic acid (140 mg, 0.37 mmol, 1
equiv) in acetone (24.4 mL) was added aq 3 M HCl (7.4 mL). The
resulting solution was refluxed for 3 h, cooled to r.t. and diluted
with EtOAc (160 mL). The organic layer was then washed with
brine (40 mL), dried (MgSO4), and concentrated in vacuo to afford
2
10 as a crude oil.
HRMS-EI: m/z [M – H]+ calcd for C13H13O6: 265.0712; found:
265.0720.
2
Yield: 122 mg (98%); [a]D26 +40.0 (c 0.002, MeOH).
IR (neat): 3340, 2975, 1718, 1044, 879 cm–1.
4-Acetyl-3,5-dimethoxycinnamoyl-di-tert-butyl Malate (23)
To a solution of 11 (405 mg, 1.52 mmol, 1 equiv) and 7c (373 mg,
1.52 mmol, 1 equiv) in CH2Cl2 (8 mL) at r.t. was added DIC (0.24
mL, 192.1 mg, 1.52 mmol, 1 equiv) and DMAP (93 mg, 0.76 mmol,
0.5 equiv). The mixture was stirred at r.t. for 1 day, then poured into
1H NMR (300 MHz, CD3OD): d = 7.60 (d, J = 15.9 Hz, 1 H, H-7¢),
6.86 (s, 2 H, H-2¢, H-6¢), 6.40 (d, J = 15.9 Hz, 1 H, H-8¢), 5.49 (dd,
J = 3.6, 8.1 Hz, 1 H, H-2), 3.83 (s, 6 H, CH3O-3¢, CH3O-5¢), 3.01
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F. Allais et al.
PAPER
(dd, J = 3.6, 15.9 Hz, 1 H, H-3), 2.89 (dd, J = 8.1, 15.9 Hz, 1 H, H-
3).
13C NMR (75 MHz, CD3OD): d = 172.9 (s, C-1), 172.5 (s, C-4),
168.0 (s, C-9), 149.3 (s, C-3¢, C-5¢), 148.0 (d, C-7¢), 139.6 (s, C-4¢),
126.4 (s, C-1¢), 115.0 (d, C-8¢), 107.0 (d, C-2¢, C-6¢), 69.9 (d, C-2),
56.8 (s, CH3O-3¢, CH3O-5¢), 37.0 (t, C-3).
layer was dried (MgSO4), filtered, and concentrated in vacuo to af-
ford a crude pink oil, which can be purified by flash chromatogra-
phy (cyclohexane–EtOAc, 5:5) to give 15 as a white solid (322 mg,
83%); mp 176–179 °C.
IR (neat): 3339, 2973, 2896, 1687, 1608, 1266 cm–1.
1H NMR (300 MHz, acetone-d6): d = 8.07 (br s, 3 H, OH), 7.45 (d,
J = 15.6 Hz, 1 H, ArCH=CHCO2Et), 6.73 (s, 2 H, H-2, H-5), 6.22
(d, J = 15.6 Hz, 1 H, ArCH=CHCO2Et), 4.17 (q, J = 6.3 Hz, 2 H,
CO2CH2CH3), 1.25 (t, J = 6.3 Hz, 3 H, CO2CH2CH3).
HRMS-EI: m/z [M – H]+ calcd for C15H15O9: 339.0716; found:
339.0708.
3,4,5-Triacetoxybenzaldehyde (13)
13C NMR (75 MHz, acetone-d6): d = 167.4 (s, CO2Et), 146.7 (d, C-
7¢), 145.8 (s, C-3¢, C-5¢), 136.6 (s, C-4¢), 126.8 (s, C-1¢), 116.1 (d,
C-8¢), 108.6 (d, C-2¢, C-6¢), 60.5 (t, CO2CH2CH3), 14.7 (q,
CO2CH2CH3).
MS (EI, 50 eV): m/z = 223 (100%, [M – H]+).
HRMS-EI: m/z [M – H]+ calcd for C11H11O5: 223.0606; found:
3,4,5-Trihydroxybenzaldehyde monohydrate 12 (1 g, 5.8 mmol, 1
equiv) was dissolved in a mixture of Ac2O (4.4 mL, 4.75 g, 46.5
mmol, 8 equiv) and pyridine (2 mL) at r.t. under argon. The mixture
was stirred overnight at r.t. and then poured into an ice/water mix-
ture (20 mL). The white solid was filtered, washed with aq 1 M HCl
(10 mL) and sat. aq NaHCO3 (10 mL). After drying, 13 was ob-
tained as a white solid (1.18 g, 73%); mp 107–108 °C.
223.0599.
IR (neat): 3027, 1780, 1703, 1369, 1314, 1180, 754 cm–1.
Ethyl 3-Hydroxy-4,5-(ethoxymethylenedioxy)cinnamate (16)
A mixture of compound 15 (322 mg, 1.44 mmol, 1 equiv),
(EtO)3CH (0.72 mL, 639.1 mg, 4.31 mmol, 3 equiv), and Am-
berlyst® 15-E (7.2 mg) in benzene (14.4 mL) was refluxed for 16–
20 h with azeotropic removal of the EtOH–benzene mixture by us-
ing a Dean–Stark apparatus. After completion, the mixture was fil-
tered over Celite® and the solvent was removed in vacuo and
directly purified by flash chromatography (cyclohexane–
EtOAc, 5:5) to give 16 as a thick yellow oil (394.5 mg, 98%).
1H NMR (300 MHz, CDCl3): d = 9.90 (s, 1 H, CHO), 7.64 (s, 2 H,
H-2¢, H-6¢), 2.30 (s, 9 H, CH3CO2-3¢, CH3CO2-4¢, CH3CO2-5¢).
13C NMR (75 MHz, CDCl3): d = 189.5 (s, CHO), 167.7 (s,
CH3CO2-3¢, CH3CO2-5¢), 166.5 (s, CH3CO2-4¢), 144.5 (s, C-3¢),
134.3 (s, C-4¢), 121.9 (d, C-2¢, C-6¢), 20.8 (q, CH3CO2-3¢, CH3CO2-
5¢), 20.3 (q, CH3CO2-4¢).
MS (EI, 50 eV): m/z (%) = 280 (7, [M+]), 238 (6), 196 (18), 154
(14), 43 (100).
HRMS-EI: m/z [M + Na]+ calcd for C13H12O7 + Na: 303.0481;
IR (neat): 2985, 2940, 2256, 1741, 1373 cm–1.
found: 303.0486.
1H NMR (300 MHz, CDCl3): d = 7.55 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2Et), 6.90 (s, CHOCH2CH3), 6.76 (s, 1 H, H-5), 6.71
(s, 1 H, H-6), 6.25 (dt, J = 15.9 Hz, 1 H, ArCH=CHCO2Et), 4.24 (q,
J = 7.0 Hz, 2 H, CO2CH2CH3), 3.73 (q, J = 7.0 Hz, 2 H,
CHOCH2CH3), 2.01 (br s, 1 H, HO-3¢), 1.30 (t, J = 7.0 Hz, 3 H,
CO2CH2CH3), 1.23 (q, J = 7.0 Hz, 3 H, CHOCH2CH3).
13C NMR (75 MHz, CDCl3): d = 167.4 (s, CO2Et), 148.0 (s, C-3¢),
144.6 (s, C-5¢), 139.1 (d, C-7¢), 135.0 (s, C-4¢), 129.7 (s, C-1¢), 120.2
(d, C-8¢), 117.3 (d, C-2¢), 112.6 (d, C-6¢), 100.6 [s, CH(OEt)], 60.8
(t, CO2CH2CH3), 60.0 (t, CHOCH2CH3), 15.1 (q, CHOCH2CH3),
14.6 (q, CO2CH2CH3).
MS (EI, 50 eV): m/z (%) = 303 (22, [M + Na]+), 277 (10), 235 (15),
167 (19).
HRMS-EI: m/z [M + Na]+ calcd for C14H16O6 + Na: 303.0845;
found: 303.0845.
Ethyl 3,4,5-Triacetoxycinnamate (14)
To a solution of triethyl phosphonate (1.61 mL, 1.82 g, 8.12 mmol,
1.4 equiv) in freshly distilled THF (6 mL) at –78 °C under argon
was added dropwise a solution of BuLi in THF (1.6 M, 5.1 mL, 8.12
mmol, 1.4 equiv). The mixture was stirred at –65 °C for 1 h and
cooled to –78 °C. A solution of 13 (1.9 g, 5.8 mmol, 1 equiv) in THF
(6 mL) was then added dropwise and the mixture was stirred over-
night at r.t. The crude mixture was diluted with EtOAc (100 mL)
and the EtOAc layer was washed with brine (20 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo to afford a
crude yellow oil, which was purified by flash chromatography (cy-
clohexane–EtOAc, 6:4) to afford 14 as white needles (1.68 g, 83%);
mp 59–63 °C.
IR (neat): 3022, 2984, 1776, 1707, 1642, 1214, 1179, 754 cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.37 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2Et), 7.26 (s, 2 H, H-2¢, H-6¢), 6.30 (d, J = 15.9 Hz, 1
H, ArCH=CHCO2Et), 3.96 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 2.03
(s, 9 H, CH3O-3¢, CH3O-4¢, CH3O-5¢), 1.03 (t, J = 7.2 Hz, 3 H,
CO2CH2CH3).
13C NMR (75 MHz, CDCl3): d = 167.8 (s, CH3CO2-3¢, CH3CO2-5¢),
166.9 (s, CH3CO2-4¢), 166.5 (s, CO2CH2CH3), 144.1 (d, C-7¢),
142.3 (s, C-3¢, C-5¢), 136.0 (s, C-4¢), 133.3 (s, C-1¢), 120.7 (d, C-8¢),
120.3 (d, C-2¢, C-6¢), 60.9 (t, CO2CH2CH3), 20.8 (q, CH3CO2-3¢,
CH3CO2-5¢), 20.4 (q, CH3CO2-4¢), 14.5 (q, CO2CH2CH3).
Ethyl 3-Methoxy-4,5-dihydroxycinnamate (17)
To a solution of 16 (250 mg, 0.89 mmol, 1 equiv) in DMF (4.5 mL)
was added K2CO3 (308.5 mg, 2.23 mmol, 2.5 equiv) and MeI (0.14
mL, 317 mg, 2.23 mmol, 2.5 equiv). The mixture was warmed to
70 °C overnight and then cooled to r.t. The reaction was quenched
with the addition of H2O (5 mL) and extracted with Et2O (3 × 10
mL). The combined organic layers were washed with brine (5 mL),
dried (MgSO4), and concentrated in vacuo to afford a crude oil,
which was purified by flash chromatography (cyclohexane–
EtOAc, 5:5) to give ethyl 3-methoxy-4,5-(ethoxymethylene-
dioxy)cinnamate (259.3 mg, 99%).
MS (EI, 50 eV): m/z (%) = 350 (3, [M+]), 308 (6), 206 (12), 224
(48), 178 (19), 152 (8), 72 (8), 59 (26), 43 (100).
HRMS-EI: m/z [M + Na]+ calcd for C17H18O8 + Na: 373.0899;
found: 373.0882.
Ethyl 3-Methoxy-4,5-(ethoxymethylenedioxy)cinnamate
IR (neat): 2981, 1704, 1625, 1509, 1270, 1026, 830 cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.53 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2Et), 6.89 (s, CHOCH2CH3), 6.75 (s, 1 H, H-5), 6.69
(s, 1 H, H-6), 6.25 (t, J = 15.9 Hz, 1 H, ArCH=CHCO2Et), 4.22 (q,
J = 7.0 Hz, 2 H, CO2CH2CH3), 3.90 (s, 3 H, CH3O-3), 3.73 (q,
J = 7.0 Hz, 2 H, CHOCH2CH3), 1.30 (t, J = 7.0 Hz, 3 H,
CO2CH2CH3), 1.23 (q, J = 7.0 Hz, 3 H, CHOCH2CH3).
Ethyl 3,4,5-Trihydroxycinnamate (15)
To a solution of 14 (980 mg, 2.28 mmol, 1 equiv) in acetone (17
mL) was added aq 3 M HCl (17 mL) and the solution was refluxed
for 3 h. The solution was cooled to r.t., diluted with EtOAc (80 mL),
and the organic layer was washed with brine (20 mL). The organic
Synthesis 2009, No. x, A–H © Thieme Stuttgart · New York

PAPER
Synthesis of O-Esters of Malic Acid Related to Natural Products
G
13C NMR (75 MHz, acetone-d6): d = 167.1 (s, CO2Et), 148.0 (s, C-
3¢), 144.5 (s, C-5¢), 143.3 (s, C-4¢), 144.6 (d, C-7¢), 136.0 (s, C-4¢),
129.3 (s, C-1¢), 120.1 (d, C-8¢), 117.1 (d, C-2¢), 109.1 (d, C-6¢),
101.2 [s, CH(OEt)], 60.6 (t, CO2CH2CH3), 59.8 (t, CHOCH2CH3),
56.8 (q, CH3O-3¢), 15.0 (q, CHOCH2CH3), 14.5 (q, CO2CH2CH3).
MS (EI, 50 eV): m/z (%) = 317 (100, [M + Na]+), 295 (3), 249 (18).
HRMS-EI: m/z [M + Na]+ calcd for C15H18O6 + Na: 317.1001;
ArCH=CHCO2H), 4.00 (s, 3 H, CH3O-3¢), 2.36 (s, 3 H, CH3CO2-
4¢), 2.35 (s, 3 H, CH3CO2-5¢).12
13C NMR (75 MHz, acetone-d6): d = 171.0 (s, CO2H), 168.6 (s,
CH3CO2-4¢), 167.9 (s, CH3CO2-5¢), 153.8 (s, C-5¢), 144.9 (s, C-3¢),
144.3 (d, C-7¢), 134.6 (s, C-4¢), 133.7 (s, C-1¢), 120.2 (d, C-2¢),
116.2 (d, C-8¢), 110.1 (d, C-6¢), 56.8 (q, CH3O-3¢), 20.4 (q,
CH3CO2-4¢), 20.1 (q, CH3CO2-5¢).12
found: 317.0999.
MS (EI, 50 eV): m/z = 317 (100%, [M + Na]+).
To a solution of ethyl 3-methoxy-4,5-(ethoxymethylenedioxy)cin-
namate (259.3 mg, 0.88 mmol, 1 equiv) in MeOH (4.4 mL) was
added aq 2 M HCl (4.4 mL) and the mixture was stirred for 2 h at
r.t. The resulting solution was diluted with EtOAc (30 mL). The or-
ganic layer was then washed with brine (5 mL), dried (MgSO4), and
concentrated in vacuo to afford a crude oil, which was purified by
flash chromatography (cyclohexane–EtOAc, 5:5) to give 17 (187.5
mg, 95%).
HRMS-EI: m/z [M + Na]+ calcd for C14H14O7 + Na: 317.0638;
found: 317.0623.
3,4-Diacetoxy-5-methoxycinnamoyl-di-tert-butyl Malate Ester
(24)
To a solution of 18 (1.23 g, 4.18 mmol, 1 equiv) and 7c (1.02 g, 4.18
mmol, 1 equiv) in CH2Cl2 (8 mL) at r.t. was added DIC (0.65 mL,
528.0 mg, 4.18 mmol, 1 equiv) and DMAP (255.6 mg, 2.09 mmol,
0.5 equiv). The mixture was stirred at r.t. for 1 day, then the filtrate
was concentrated in vacuo and the crude solid was purified by flash
chromatography (cyclohexane–EtOAc, 7:3) to yield ester 24 as an
oil (1.52 g, 70%); [a]D25 +11.1 (c 0.0072, CHCl3).
17
IR (neat): 3388, 2985, 1687, 1515, 1264, 1090, 732 cm–1.
1H NMR (300 MHz, acetone-d6): d = 8.00 (s, 1 H, OH), 7.84 (s, 1
H, OH), 7.52 (d, J = 15.9 Hz, 1 H, ArCH=CHCO2Et), 6.90 (s, 1 H,
H-5), 6.83 (s, 1 H, H-6), 6.34 (t, J = 15.9 Hz, ArCH=CHCO2Et),
4.18 (q, J = 7.0 Hz, 2 H, CO2CH2CH3), 3.88 (s, 3 H, CH3O-3), 1.26
(t, J = 7.0 Hz, 2 H, CO2CH2CH3).
13C NMR (75 MHz, acetone-d6): d = 167.4 (s, CO2Et), 149.2 (s, C-
3¢), 146.5 (s, C-5¢), 145.9 (d, C-7¢), 137.5 (s, C-4¢), 126.7 (s, C-1¢),
116.3 (d, C-8¢), 110.5 (d, C-6¢), 104.5 (d, C-2¢), 60.5 (t,
CO2CH2CH3), 56.6 (q, CH3O-3¢), 14.7 (q, CO2CH2CH3).
IR (neat): 2981, 2935, 1774, 1728, 1369, 1143 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2R), 6.98 (s, 1 H, H-6¢), 6.96 (s, 1 H, H-2¢), 6.42 (d,
J = 15.9 Hz, 1 H, ArCH=CHCO2R), 5.43 (dd, J = 5.1, 7.2 Hz, 1 H,
H-2), 3.86 (s, 3 H, CH3O-3¢), 2.82 (m, 2 H, H-3), 2.30 (s, 3 H,
CH3CO2-4¢), 2.29 (s, 3 H, CH3CO2-5¢), 1.47 (s, 9 H, t-C4H9), 1.45
(s, 9 H, t-C4H9).12
13C NMR (75 MHz, CDCl3): d = 168.6 (s, CO2t-Bu), 168.2 (s, CO2t-
Bu), 167.7 (s, CH3CO2-4¢, CH3CO2-5¢), 165.6 (s, C-9¢), 153.0 (s, C-
5¢), 144.6 (s, C-3¢), 143.9 (d, C-7¢), 133.9 (s, C-4¢), 133.0 (s, C-1¢),
118.6 (d, C-8¢), 115.5 (d, C-2¢), 109.2 (d, C-6¢), 82.9 [s,
CO2C(CH3)3], 81.8 [s, CO2C(CH3)3], 69.5 (d, CO2CHCO2t-Bu),
56.5 (q, CH3O-3¢), 37.8 (t, CH2CO2t-Bu), 28.3 [q, CO2C(CH3)3],
28.2 [q, CO2C(CH3)3], 20.8 (q, CH3CO2-4¢), 20.5 (q, CH3CO2-5¢).12
MS (EI, 50 eV): m/z (%) = 237 (100, [M – H]+), 223 (5), 165 (4).
HRMS-EI: m/z [M – H]+ calcd for C12H13O5: 237.0763; found:
237.0765.
3-Methoxy-4,5-dihydroxycinnamic Acid (6)
Aq 2 M NaOH (80 mL) was added to a solution of compound 17
(850 mg, 3.57 mmol, 1 equiv) in THF (32 mL). The mixture was
stirred at r.t. for 8 h and then made acidic with concd HCl to pH 5.
The suspension was extracted with EtOAc (3 × 300 mL). The com-
bined organic layers were washed with brine (200 mL), and dried
(MgSO4). Concentration in vacuo afforded 6 (685.7 mg, 97%). All
spectral data were in full agreement with those reported in the liter-
ature.11
MS (EI, 50 eV): m/z (%) = 545 (62, [M + Na]+), 489 (66), 433 (100).
HRMS-EI: m/z [M + Na]+ calcd for C26H34O11 + Na: 545.1999;
found: 545.2017.
5-Hydroxyferuloyl-L-malate (3)
Ester 24 (310 mg, 0.59 mmol, 1 equiv) was dissolved in CH2Cl2 (2.7
mL) at r.t. and TFA (0.88 mL, 1.35 g, mmol, 20 equiv) was added
dropwise. The solution was stirred overnight and concentrated in
vacuo to afford the free dicarboxylic acid as a crude oil, which was
used in the next step without further purification.
3,4-Diacetoxy-5-methoxycinnamic Acid (18)
From Compound 6: Compound 6 (1 g, 4.76 mmol, 1 equiv) was dis-
solved in a mixture of Ac2O (3.6 mL, 3.88 g, 38.1 mmol, 8 equiv)
and pyridine (1.6 mL) at r.t. under argon. The mixture was stirred
overnight at r.t. and poured into an ice/water mixture (32 mL). The
white solid was filtered, washed with aq 1 M HCl (10 mL) and sat.
aq NaHCO3 (15 mL). After drying, 18 was obtained as a white solid
(1.33 g, 95%).
Intermediate Dicarboxylic Acid
Yield: 226.8 mg (94%); [a]D26 +13.8 (c 0.026, CHCl3).
IR (neat): 2975, 1726, 1264, 1171, 1095 cm–1.
1H NMR (300 MHz, acetone-d6): d = 9.69 (br s, 2 H, 2 × CO2H),
7.65 (d, J = 15.9 Hz, 1 H, ArCH=CHCO2R), 7.35 (s, 1 H, H-6¢),
7.12 (s, 1 H, H-2¢), 6.61 (d, J = 15.9 Hz, 1 H, ArCH=CHCO2R),
5.43 (dd, J = 3.6, 8.1 Hz, 1 H, H-2), 3.86 (s, 3 H, CH3O-3¢), 3.02
(dd, J = 3.6, 16.8 Hz, 1 H, H-3), 2.92 (dd, J = 8.1, 16.8 Hz, 1 H, H-
3), 2.23 (s, 6 H, CH3CO2-4¢, CH3CO2-5¢).12
13C NMR (75 MHz, CDCl3): d = 171.0 (s, CO2H), 170.6 (s, CO2H),
168.7 (s, CH3CO2-4¢), 167.9 (s, CH3CO2-5¢), 166.1 (s, C-9), 153.8
(s, C-3¢), 145.2 (s, C-5¢), 144.9 (d, C-7¢), 134.8 (s, C-4¢), 133.4 (s,
C-1¢), 119.1 (d, C-8¢), 116.6 (d, C-6¢), 110.0 (d, C-2¢), 69.4 (d,
CO2CHCO2H), 56.8 (q, CH3O-3¢), 36.4 (t, CH2CO2H), 20.4 (q,
CH3CO2-4¢), 20.1 (q, CH3CO2-5¢).12
From Compound 21: Ester 21 (2.0 g, 5.71 mmol, 1 equiv) was dis-
solved in CH2Cl2 (60 mL) at r.t. and 99% TFA (20.0 mL, 13.03 g,
114.28 mmol, 20 equiv) was added dropwise. The solution was
stirred overnight and concentrated in vacuo to afford a crude oil,
which was used in the next step without further purification. Re-
crystallization from acetone–hexane provided 18 as a white solid
(1.59 g, 95%); mp 161–163 °C.
IR (neat): 3020, 2979, 1770, 1689, 1636, 1504, 1212, 1097, 754
cm–1.
1H NMR (300 MHz, acetone-d6): d = 9.14 (br s, 1 H, CO2H), 7.72
(d, J = 15.9 Hz, 1 H, ArCH=CHCO2H), 7.44 (d, J = 1.5 Hz, 1 H, H-
6¢), 7.24 (d, J = 1.5 Hz, 1 H, H-2¢), 6.65 (d, J = 15.9 Hz, 1 H,
To a mixture of the above free dicarboxylic acid (233 mg, 0.57
mmol, 1 equiv) in acetone (38 mL) was added aq 3 M HCl (8.76
mL). The resulting solution was refluxed for 3 h, cooled to r.t., and
Synthesis 2009, No. x, A–H © Thieme Stuttgart · New York

H
F. Allais et al.
PAPER
diluted with EtOAc (100 mL). The organic layer was then washed
with brine (20 mL), dried (MgSO4), and concentrated in vacuo to af-
ford 310 as a thick oil.
142.2 (d, C-7¢), 133.2 (s, C-4¢), 121.5 (s, C-1¢), 115.1 (d, C-8¢),
108.9 (d, C-2¢, C-6¢), 80.8 [s, CO2C(CH3)3], 56.3 (q, CH3O-3¢), 28.3
[q, CO2C(CH3)3], 20.6 (q, CH3CO2-4¢), 20.3 (q, CH3CO2-5¢).12
MS (EI, 50 eV): m/z = 373 (100%, [M + Na]+).
HRMS-EI: m/z [M + Na]+ calcd for C18H22O7 + Na: 373.1263;
3
Yield: 181.4 mg (98%); [a]D26 +55.0 (c 0.002, MeOH).
found: 373.1251.
IR (neat): 3348, 2979, 1705, 1600, 1143 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.56 (d, J = 15.9 Hz, 1 H, H-7¢),
6.77 (s, 1 H, H-6¢), 6.74 (s, 1 H, H-2¢), 6.33 (d, J = 15.9 Hz, 1 H, H-
8¢), 5.49 (dd, J = 3.6, 8.1 Hz, 1 H, H-2), 3.82 (s, 3 H, CH3O-3¢), 3.01
(dd, J = 3.6, 15.9 Hz, 1 H, H-3), 2.89 (dd, J = 8.1, 15.9 Hz, 1 H, H-
3).12
Acknowledgment
The authors would like to acknowledge Albert Kohlmann for his
precious help in HPLC purification of the targeted compounds.
13C NMR (75 MHz, CD3OD): d = 172.9 (s, C-1), 172.5 (s, C-4),
168.0 (s, C-9), 146.7 (s, C-3¢, C-5¢), 148.1 (d, C-7¢), 138.5 (s, C-4¢),
126.5 (s, C-1¢), 114.6 (d, C-8¢), 110.4 (d, C-2¢, C-6¢), 69.9 (d, C-2),
56.7 (s, CH3OC-3¢), 37.0 (t, C-3).12
HRMS-EI: m/z [M – H]+ calcd for C14H13O9: 325.0560; found:
325.0547.
References
(1) (a) Nielsen, J. K.; Olsen, O.; Pedersen, H.; Sorensen, H.
Phytochemistry 1984, 23, 1741. (b) Pedras, M. S. C.; Zheng,
Q.-A.; Gadaji, R. S.; Rimmer, S. R. Phytochemistry 2008,
69, 894. (c) Liang, Y.-S.; Choi, Y. H.; Kim, H. K.; Linthorst,
H. J. M.; Verpoorte, R. Phytochemistry 2006, 67, 2503.
(d) Chapple, C. C. S.; Vogt, T.; Ellis, B. E.; Sommerville, C.
R. Plant Cell 1992, 4 , 1413. (e) Gujon, T.; Sibout, R.;
Pollet, B.; Mabra, B.; Nussaume, L.; Bechtold, N.; Lu, F.;
Ralph, J.; Mila, I.; Barrière, Y.; Lapierre, C.; Jouanin, L.
Plant Mol. Biol. 2003, 51, 973. (f) Lapierre, C.; Pollet, B.;
Mila, I.; Gujon, T.; Sibout, R.; Buffard, D.; Lu, F.; Schatz, P.
F.; Ralph, J.; Barrière, Y.; Jouanin, L. 12th International
Symposium on Wood and Pulping Chemistry; Madison:
Wisconsin, 2003.
(2) (a) Jack, E.; Dumas, B.; Geoffroy, P.; Favet, N.; Inzé, D.;
Van Nontagu, M.; Fritig, B.; Legrand, M. Mol. Plant-
Microbe Interact. 1992, 5, 294. (b) Pellegrini, L.; Geoffroy,
P.; Fritig, B.; Legrand, M. Plant Physiol. 1993, 103, 509.
(c) Pellegrini, L.; Rohfritsch, O.; Fritig, B.; Legrand, M.
Plant Physiol. 1994, 106, 877. (d) Igarashi, K.; Itoh, M.;
Harada, T. Agric. Biol. Chem. 1990, 54, 1053. (e) Quentin,
M.; Pegard, A.; Allasia, V.; Allais, F.; Ducrot, P.-H.; Favery,
B.; Levis, C.; Martinet, S.; Masur, C.; Ponchet, M.; Roby,
D.; Schlaich, N.; Jouanin, L.; Keller, H. PLoS Pathogens
2009, 5, 1.
3,4-Diacetoxy-5-methoxybenzaldehyde (20)
3,4-Dihydroxy-5-methoxybenzaldehyde (19; 2 g, 11.89 mmol, 1
equiv) was dissolved in a mixture of Ac2O (15 mL) and Et3N (11.6
mL, 8.42 g, 83.25 mmol, 7 equiv) at 0 °C. The mixture was then
stirred at r.t. for 2 h. The excess of Ac2O was destroyed by careful
addition of EtOH (7.5 mL) at 0 °C. The mixture was diluted with
H2O (200 mL) and extracted with EtOAc (3 × 200 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo to afford 20 as
a crude oil. Purification by flash chromatography (cyclohexane–
EtOAc, 7:3) yielded 20 as a thick yellow oil (2.48 g, 83%).
IR (neat): 3021, 1774, 1701, 1600, 1215, 1176, 754 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.78 (s, 1 H, CHO), 7.30 (s, 1 H,
H-6¢), 7.24 (s, 1 H, H-2¢), 3.8 (s, 3 H, CH3O-3), 2.24 (s, 3 H,
CH3CO2-4¢), 2.22 (s, 3 H, CH3CO2-5¢).12
13C NMR (75 MHz, CDCl3): d = 190.2 (s, CHO), 167.8 (s,
CH3CO2-5¢), 167.0 (s, CH3CO2-4¢), 153.2 (s, C-3¢), 144.0 (s, C-5¢),
137.1 (s, C-4¢), 134.3 (s, C-1¢), 117.8 (d, C-6¢), 108.9 (d, C-2¢), 56.4
(q, CH3O-3), 20.4 (q, CH3CO2-4¢), 20.0 (q, CH3CO2-5¢).12
MS (EI, 50 eV): m/z = 275 (100%, [M + Na]+).
HRMS-EI: m/z [M + Na]+ calcd for C12H12O6 + Na: 275.0532;
(3) Lamidey, A.-M.; Fernon, L.; Pouységu, L.; Delattre, C.;
Quideau, S. Helv. Chim. Acta 2002, 85, 2328.
found: 275.0533.
(4) Schatz, P. F.; Lapierre, C.; Ralph, J. 12th International
Symposium on Wood and Pulping Chemistry; Madison:
Wisconsin, 2003.
tert-Butyl 3,4-Diacetoxy-5-methoxycinnamate (21)
To a solution of tert-butyl diethylphosphonate (2.79 mL, 3.0 g, 11.9
mmol, 1.2 equiv) in freshly distilled THF (20 mL) at –78 °C under
argon was added dropwise a solution of n-BuLi in THF (1.6 M, 7.46
mL, 11.9 mmol, 1.2 equiv). The mixture was stirred at –65 °C for 1
h and then cooled to –78 °C. A solution of 20 (2.5 g, 9.92 mmol, 1
equiv) in THF (10 mL) was then added dropwise and the mixture
was stirred overnight at r.t. The crude mixture was diluted with
EtOAc (100 mL) and the EtOAc layer was washed with brine (30
mL). The organic layer was dried (MgSO4) and concentrated in vac-
uo to afford a crude yellow oil, which was purified by flash chroma-
tography (cyclohexane–EtOAc, 5:5) to afford 21 as a thick yellow
oil (1.68 g, 89%).
(5) (a) Mathias, L. J. Synthesis 1979, 561. (b) Amer, M. F. A.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Heterocycles
2007, 72, 181.
(6) E/Z ratios were determined from the corresponding 1H NMR
spectra.
(7) (a) Ester 15 was also obtained from 3,4,5-trimethoxy-
benzaldehyde using a Horner–Wadsworth–Emmons
coupling reaction (98%, E/Z >98:2)6 followed by
demethylation of the three methoxy groups with AlCl3/
EtSH/CH2Cl2 (61%) (b) Node, M.; Nishide, K.; Fuji, K.;
Fujita, E. J. Org. Chem. 1980, 45, 4275.
(8) Alam, A.; Takaguchi, Y.; Ito, H.; Yoshida, T.; Tsuboi, S.
Tetrahedron 2005, 61, 1909.
(9) (a) Jakobs, A. E.; Christiaens, L. J. Org. Chem. 1996, 61,
4842. (b) Xing, X.; Ho, P.; Bourquin, G.; Yeh, L.-A.; Cuny,
G. D. Tetrahedron 2003, 59, 9961.
(10) Harbaum, B.; Hubbermann, E. M.; Wolff, C.; Herges, R.;
Zhu, Z.; Schwarz, K. J. Agric. Food Chem. 2007, 55, 8251.
(11) Nakamura, T. Chem. Pharm. Bull. 1962, 10, 281.
(12) In order to remain consistent throughout the paper, all
labeling positions refer to Figure 1. Therefore, OCH3 is
always at C-3¢ regardless of IUPAC numbering rules.
IR (neat): 3018, 2979, 2939, 1770, 1703, 1639, 1203, 1140, 749
cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.45 (d, J = 15.9 Hz, 1 H,
ArCH=CHCO2Et), 6.93 (s, 1 H, H-6¢), 6.91 (s, 1 H, H-2¢), 6.27 (d,
J = 15.9 Hz, 1 H, ArCH=CHCO2Et), 3.80 (s, 3 H, CH3O-3¢), 2.26
(s, 3 H, CH3CO2-4¢), 2.25 (s, 3 H, CH3CO2-5¢), 1.50 (s, 9 H, t-
C4H9).12
13C NMR (75 MHz, CDCl3): d = 168.1 (s, CH3CO2-5¢), 167.6 (s,
CH3CO2-4¢), 165.9 (s, CO2t-Bu), 152.7 (s, C-3¢), 143.7 (s, C-5¢),
Synthesis 2009, No. x, A–H © Thieme Stuttgart · New York