Towards the synthesis of the skeleton of salvianolic acid D

Article abstract of DOI:10.1055/s-2006-926332

A successful synthesis of the acid part of salvianolic acid D is described (eight steps from isovanillin, 22% overall yield). The benzaldehyde key intermediate was obtained in six steps in 52% overall yield and was converted into the trimethylated precurs

Full text of DOI:10.1055/s-2006-926332

768
SHORT PAPER
Towards the Synthesis of the Skeleton of Salvianolic Acid D
T
owards the Skel
l
eton of
é
Salvianolic
m
A
cid D ence Queffélec, Fabrice Bailly, Philippe Cotelle*
Laboratoire de Chimie Organique et Macromoléculaire, UMR CNRS 8009, Université de Lille 1, 59655 Villeneuve d’Ascq, France
Fax +33(320)336309; E-mail: Philippe.Cotelle@univ-lille1.fr
Received 23 September 2005; revised 10 October 2005
Salvianolic acid D was isolated from Salvia miltiorrhiza
Abstract: A successful synthesis of the acid part of salvianolic acid
and the synthesis of the dimethylated acid part of salvian-
D is described (eight steps from isovanillin, 22% overall yield). The
benzaldehyde key intermediate was obtained in six steps in 52%
overall yield and was converted into the trimethylated precursor
olic acid D (2) was described.9 The prerequisite for the
elaboration of the target polyphenol needs the building of
molecule using the Knoevenagel procedure. Finally, the acid part of the intermediate 5, which can be considered a milestone in
salvianolic acid D was obtained by the exhaustive deprotection of
the synthesis of various natural dimers of caffeic acid.
the methyl groups with boron tribromide.
Compound 5 can be obtained either from isovanillin or
2,3-dimethoxybenzaldehyde.
Key words: natural polyphenols, antivirals, boron tribromide
Ai and Li reported the synthesis of 5 starting from isova-
nillin 3 (Scheme 1). Using the same procedure, we were
able to obtain compound 4 in 28% overall yield but the
cleavage of the lactone previously described in 20% yield,
was unsuccessful in our hands.
Salvia is an important genus widely cultivated and used in
traditional medicines. It is a rich source of polyphenols
and the water-soluble extracts of Salvia are of great im-
portance due to their bioactivities (antioxidant, antiplate-
let, antitumor, and antiviral activities).1 Some of them
exhibit potent effects against HIV-1 enzymes.2–4 Due to
our convergent interests in the total synthesis of natural
polyphenols5–6 and the discovery of new HIV-1 integrase
inhibitors,7–8 we decided to systematically synthesize acid
moieties of salvianolic acids and related compounds
(Figure 1).
O
O
CHO
CHO
COOCH3
OCH3
2 steps
7 steps
15%
OH
OCH3
28%
OCH3
OCH3
OCH3
overall yield
5
3
4
COOH
This work deals with the elaboration of a key intermediate
in the synthesis of a series of dimers of caffeic acid and
with the total synthesis of the acid part of salvianolic acid
D (1).
2 steps
63%
COOH
OCH3
OCH3
COOH
COOX
2
Scheme 1 Ai and Li procedure9
HO2C
HO
COOH
During the course of this work, 5 was also obtained in
61% yield by another method10 using 2,3-dimethoxybenz-
aldehyde 6 as starting material (Scheme 2). Since the sixth
step of this procedure requires purification by column
chromatography of two regioisomers and we had the need
for a multigram-scale synthesis of 5 in mind, we decided
to explore an alternative strategy (Scheme 3).
O
HO
OH
OH
OH
COOX
salvianolic acid D
przewalskinic acid A
COOX
COOX
HO
HO
OH
COOX
OH
We started, as in the Ai and Li procedure, and in a short
communication dealing with the total synthesis of hep-
tamethyl lithospermate,11 by the O-allylation of isovanil-
lin followed by the Claisen rearrangement of O-
allylisovanillin in dimethylacetamide. After methylation
of the phenol groups, the protection of the formyl group
was required, which was perfectly achieved by its trans-
formation into the acetal derivative 9 with trimethyl ortho-
formate. A Lemieux–Rudloff oxidation led to the acid 10.
The dimethylacetal was hydrolyzed during the work-up.
Finally 10 was converted into its methyl ester to give 5.
OH
OH
HO
OH
salvianolic acid E
salvianolic acid L
OH
COOH
X =
OH
Figure 1 Structures of salvianolic acids and related compounds
SYNTHESIS 2006, No. 5, pp 0768–0770
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926332; Art ID: Z17705SS
x
x
.
x
x
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0
0
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© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Towards the Skeleton of Salvianolic Acid D
769
SiO2, 200–400 mesh (Merck) was used for column chromatogra-
phy. Melting points were obtained on a Reichert Thermopan melt-
ing point apparatus, equipped with a microscope. NMR spectra
were obtained with a AC 200 Bruker spectrometer in the appropri-
ate solvent with TMS as internal reference. J values are given in Hz.
Mass spectra were recorded on a Thermo-Finnigan PolarisQ mass
spectrometer (70 eV, Electronic Impact). Elemental analyses were
performed by CNRS laboratories (Vernaison) and were within 0.4%
of the theoretical values.
OCH3
OCH3
H3CO
CHO
7 steps
H3CO
COOCH3
CHO
61%
6
5
OCH3
2 steps
H3CO
COOH
COOH
59%
3-Allyloxy-4-methoxybenzaldehyde
2
To isovanillin (3) (5.00 g, 32.9 mmol) in anhyd acetone (20 mL), al-
lyl bromide (5.00 g, 3.6 mL, 41.3 mmol) and K2CO3 (5.00 g, 36.2
mmol) were added. Then the mixture was refluxed for 3 h. The re-
moval of K2CO3 by filtration and the evaporation of acetone gave
the desired compound (6.32 g, 99%) as a yellow oil.
Scheme 2 Detterbeck and Hesse procedure10
Two steps were necessary to obtain the acid part of salvi-
anolic acid D from 5. First, a Knoevenagel condensation
was required and the a,b-unsaturated acid side-chain was
received in good yield. Secondly, treatment with boron
tribromide as deprotecting reagent afforded the desired
product 1 in moderate yield.
1H NMR (200 MHz, CDCl3): d = 3.80 (s, 3 H, OMe), 4.55 (dt, 2 H,
3
2
4J = 1.45 Hz, J = 5.4 Hz, CH2), 5.17 (dq, 1 H, J = 4J = 1.45 Hz,
3Jcis = 10.2 Hz), 5.29 (dq, 1 H, 2J = 4J = 1.45 Hz, 3Jtrans = 17.9 Hz),
3
3
3
5.99 (m, 1 H, Jcis = 10.2 Hz, Jtrans = 17.9 Hz, J = 5.4 Hz, =CH),
6.83 (d, 1 H, 3J = 8.3 Hz), 7.25 (d, 1 H, 4J = 1.9 Hz), 7.31 (dd, 1 H,
3J = 8.3 Hz, 4J = 1.9 Hz), 9.61 (s, 1 H, CHO).
2-Allyl-3-hydroxy-4-methoxybenzaldehyde (7)
CHO
CHO
CHO
A solution of 3-allyloxy-4-methoxybenzaldehyde (6.316 g, 32.90
mmol) in dimethylacetamide (9.2 mL) was stirred at 180 °C for 10
h. The cold solution was poured into aq 2 N NaOH soln (4 × 30 mL)
and washed with Et2O (2 × 20 mL). The aq layer was acidified with
conc HCl soln and was extracted with EtOAc. Evaporation gave 7
as a brown oil (5.68 g, 90%).
i)
ii)
iii)
OH
OCH3
OH
OCH3
OCH3
OCH3
8
3
7
H3CO
OCH3
3
1H NMR (200 MHz, CDCl3): d = 3.80 (d, 2 H, J = 5.9 Hz, CH2),
CHO
3.95 (s, 3 H, OMe), 5.00 (m, 2 H), 5.81 (br s, 1 H), 6.05 (m, 1 H,
3Jcis = 10.5 Hz, Jtrans = 16.5 Hz, J = 6.0 Hz, =CH), 6.83 (d, 1 H,
3
3
COOH
iv)
v)
vi)
3J = 8.3 Hz), 7.41 (d, 1 H, 3J = 8.3 Hz), 10.05 (s, 1 H, CHO).
OCH3
OCH3
OCH3
OCH3
10
2-Allyl-3,4-dimethoxybenzaldehyde (8)
9
To 7 (6.00 g, 31.2 mmol) in DMF (34 mL), K2CO3 (8.65 g, 62.7
mmol) and MeI (6.61 g, 2.9 mL, 46.6 mmol) were added. The mix-
ture was stirred at r.t. for 10 h, then taken up in H2O (20 mL) and
extracted with Et2O (3 × 20 mL). Washing the organic phase with
aq 2 N NaOH soln and evaporation gave 8 (5.85 g, 91%) as a brown
oil.
COOH
COOH
CHO
COOCH3
COOH
COOCH3
vii)
viii)
1H NMR (200 MHz, CDCl3): d = 3.80 (s, 3 H, OMe), 3.82 (dt, 2H,
OCH3
OH
OCH3
3J = 3.5 Hz, CH2), 3.95 (s, 3 H, OMe), 5.00 (m, 2 H), 6.05 (m, 1 H,
OCH3
OH
1
OCH3
11
3
3
3Jcis = 10.5 Hz, Jtrans = 16.5 Hz, J = 6.0 Hz, =CH), 6.90 (d, 1 H,
5
3J = 8.6 Hz), 7.61 (d, 1 H, 3J = 8.6 Hz), 10.05 (s, 1 H, CHO).
13C NMR (50 MHz, CDCl3): d = 28.4 (t), 55.9 (q), 60.5 (q), 109.7
(d), 115.2 (d), 127.7 (s), 129 (d), 135.7 (s), 137 (d), 147 (s), 157.2
(s), 190.5 (d).
MS (EI, 70 eV): m/z (%) = 206 (50) [M+], 191 (100), 190 (15), 175
(32), 115 (16), 91 (27).
Scheme 3 Reagents and conditions: i) Allyl bromide, K2CO3, ace-
tone, reflux, 3 h, 99%; ii) Dimethylacetamide, reflux, 10 h, 90%; iii)
MeI, K2CO3, DMF, r.t., 10 h, 91%; iv) HC(OMe)3, MeOH, NH4Cl, re-
flux, 2 h, 86%; v) KMnO4, NaIO4, K2CO3, t-BuOH–H2O, r.t., 4 h,
77%; vi) SOCl2, MeOH, 0 °C, 1.5 h, 96%; vii) Malonic acid, py, pipe-
ridine, 60 °C, 10 h, 94%; viii) BBr3, CH2Cl2, r.t., 10 h, then H2O, 48
h, 45%.
Anal. Calc for C12H14O3: C, 69.88; H, 6.84; O, 23.27. Found: C,
69.44; H, 6.96; O, 23.39.
Herein, we have described an efficient synthesis of the
benzaldehyde 5 in a slightly lower overall yield (52%)
than in a previous work (61%) but in a more convenient
manner for a multigram scale. This key intermediate 5 is
2-Allyl-1-(dimethoxymethyl)-3,4-dimethoxybenzene (9)
A mixture of 8 (5.85 g, 28.4 mmol), trimethyl orthoformate (6.05 g,
6.2 mL, 56.8 mmol), and a cat. amount of NH4Cl (ca 0.1 g) in
MeOH (54 mL) was refluxed for 2 h. After cooling to r.t., the mix-
expected to allow for the total synthesis of przewalskinic ture was poured into ice-cooled aq 2 N NaOH soln (10 mL) and ex-
tracted quickly with Et2O (3 × 20 mL). Evaporation gave 9 (6.15 g,
86%) as a brown oil.
1H NMR (200 MHz, CDCl3): d = 3.26 (s, 6 H, OMe), 3.5 (dt, 2 H,
CH2), 3.76 (s, 3 H, OMe), 3.83 (s, 3 H, OMe), 4.95 (m, 2 H), 5.35
(s, 1 H), 5.95 (m, 1 H, =CH), 6.77 (d, 1 H, 3J = 8.6 Hz), 7.25 (d, 1
H, 3J = 8.6 Hz).
acid A and the acid parts of salvianolic acid L and salvi-
anolic acid E (Figure 1). As a first example, 5 was con-
verted into the skeleton of salvianolic acid D (1) in a
satisfactory 22% overall yield.
Synthesis 2006, No. 5, 768–770 © Thieme Stuttgart · New York

770
C. Queffélec et al.
SHORT PAPER
13C NMR (50 MHz, CDCl3): d = 23.4 (t), 47 (q, 2OCH3), 49.3 (q),
54.4 (q), 95.2 (d), 103.4 (d), 108.6 (d), 116.1 (d), 122.8 (s), 125.7
(s), 131 (d), 141 (s), 146.5 (s).
1H NMR (200 MHz, CDCl3): d = 3.7 (s, 3 H), 3.82 (s, 3 H), 3.88 (s,
2 H), 3.91 (s, 3 H), 6.29 (d, 1 H, 3J = 15.6 Hz), 6.9 (d, 1 H, 3J = 8.9
Hz), 7.42 (d, 1 H, 3J = 8.9 Hz), 7.92 (d, 1 H, 3J = 15.6 Hz).
MS (EI, 70 eV): m/z (%) = 252 (6) [M+], 221 (33) [M+ – OCH3],
206 (36), 191 (82), 189 (100), 188 (32), 175 (36), 174 (77), 149
(38).
Acid Part of Salvianolic Acid D (1)
To a solution of 11 (4.88 g, 17.4 mmol) in CH2Cl2 (20 mL), a 1 M
BBr3 soln in CH2Cl2 (69.5 mL) was added dropwise at 20 °C. After
24 h of stirring, the reaction was carefully quenched with H2O (40
mL). A brown solid precipitated rapidly and filtration of this gave 1
(1.87 g, 45%) as a brown solid.
Anal. Calc for C14H20O4: C, 66.65; H, 7.99; O, 25.37. Found: C,
66.45; H, 7.57; O, 25.20.
(6-Formyl-2,3-dimethoxyphenyl)acetic Acid (10)
1H NMR (200 MHz, CD3COCD3): d = 4.09 (s, 2 H), 6.29 (d, 1 H,
To 9 (6.15 g, 24.4 mmol) in t-BuOH (40 mL) was added a solution
of K2CO3 (10.1 g, 73.1 mmol) in H2O (79 mL). To the resulting sus-
pension were added NaIO4 (21.6 g, 101 mmol) and KMnO4 (3.15 g,
19.5 mmol). The mixture started to warm and was stirred for 4 h at
r.t. The mixture was washed with EtOAc (10 mL) and this organic
layer discarded. The aq layer was acidified with concd HCl soln and
again exhaustively extracted with EtOAc. Evaporation yielded 10
(4.2 g, 77%) as a brown oil.
3
3J = 16.13 Hz), 6.96 (d, 1 H, J = 8.51 Hz), 7.38 (d, 1 H, 3J = 8.51
Hz), 7.58 (d, 1 H, 3J = 16.0 Hz).
13C NMR (50 MHz, CDCl3): d = 32.9 (t), 116.4 (d), 117.9 (d), 121.5
(s), 124.7 (d), 125.7 (s), 140.9 (d), 141.4 (s), 142.9 (s), 167.6 (s),
173.9 (s).
MS (EI, 70 eV): m/z (%) = 220 (46) [M – H2O]+, 176 (100) [M –
H2O – CO2]+, 148 (45), 147 (50), 146 (20), 119 (31), 91 (46).
1H NMR (200 MHz, CDCl3): d = 3.75 (s, 3 H, OMe), 3.88 (s, 3 H,
Anal. Calc for C11H10O6: C, 55.47; H, 4.23; O, 40.30. Found: C,
55.87; H, 4.61; O, 40.57.
3
OMe), 4.12 (s, 2 H, CH2), 6.85 (d, 1 H, J = 8.3 Hz), 7.5 (d, 1 H,
3J = 8.3 Hz), 9.8 (s, 1 H, CHO).
13C NMR (50 MHz, CDCl3): d = 31.3 (t), 56.1 (q), 61.1 (q), 110.7
Acknowledgment
(d), 128.3 (s), 129.3 (s), 132.9 (d), 148.3 (s), 157.6 (s), 177 (s), 192.2
(d).
This work was financially supported by grants from Centre National
de la Recherche Scientifique (CNRS) and Agence Nationale de la
Recherche contre le Sida (ANRS).
MS (EI, 70 eV): m/z (%) = 194 (38) [M+ – CH2O], 180 (20), 179
(100), 91 (15).
Anal. Calc for C11H12O5: C, 58.93; H, 5.39; O, 35.68. Found: C,
58.67; H, 5.25; O, 35.90.
References
Methyl (6-Formyl-2,3-dimethoxyphenyl)acetate (5)
To an ice-cooled solution of 10 (4.20 g, 18.8 mmol) in MeOH (31
mL), SOCl2 (3.72 g, 2.3 mL, 31.3 mmol) was slowly added drop-
wise. After 1.5 h stirring, evaporation yielded 5 (4.28 g, 96%) as a
brown oil.
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1H NMR (200 MHz, CDCl3): d = 3.67 (s, 3 H, CO2Me), 3.8 (s, 3 H,
OMe), 3.95 (s, 3 H, OMe), 4.18 (s, 2 H, CH2), 7.00 (d, 1 H, 3J = 8.6
Hz), 7.58 (d, 1 H, 3J = 8.6 Hz), 9.90 (s, 1 H, CHO).
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3-[3,4-Dimethoxy-2-(2-methoxy-2-oxoethyl)phenyl]acrylic
Acid (11)
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To a solution of 5 (1.10 g, 4.62 mmol) in pyridine (136 mL) were
added malonic acid (979 mg, 9.41 mmol) and two drops of piperi-
dine. The mixture was refluxed for 10 h and then poured into an ex-
cess of concd HCl soln. Extraction with EtOAc and evaporation
gave 11 (1.216 g, 94%) as a brown solid.
Synthesis 2006, No. 5, 768–770 © Thieme Stuttgart · New York