Catalytic synthesis of novel 4-C-glycosyl coumarins using a domino Heck reaction/lactonization process

Article abstract of DOI:10.1016/j.tetlet.2009.04.134

A catalytic synthesis of novel 4-linked C-glycosyl coumarins was achieved using a domino Heck reaction/lactonization process. Methyl 3-glycosyl cinnamates were prepared from methyl 4-glycosyl-but-2-enoates using a panel of aryl iodides under Heck conditio

Full text of DOI:10.1016/j.tetlet.2009.04.134

Tetrahedron Letters 50 (2009) 4254–4257
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic synthesis of novel 4-C-glycosyl coumarins using a domino Heck
reaction/lactonization process
*
Denis Giguère, Ramesh Patnam, Juan M. Juarez-Ruiz, Mathieu Neault, René Roy
Department of Chemistry, Université du Québec à Montréal, PO Box 8888, Suc. Centre-Ville, Montréal, Que, Canada H3C 3P8
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic synthesis of novel 4-linked C-glycosyl coumarins was achieved using a domino Heck reaction/
lactonization process. Methyl 3-glycosyl cinnamates were prepared from methyl 4-glycosyl-but-2-eno-
ates using a panel of aryl iodides under Heck conditions. A direct application of this new methodology
was made toward preliminary hemagglutination inhibition assays against galectins-1 and -3. C-Galacto-
Received 25 February 2009
Revised 28 April 2009
Accepted 29 April 2009
Available online 5 May 2009
side 30 had an IC50 of 313
l
M against galectin-1.
Ó 2009 Elsevier Ltd. All rights reserved.
Coumarins exhibit a wide range of functions including varied
biological activities.1 When coupled to carbohydrate residues, cou-
marins have shown application as antibacterial,2 anticoagulant,3
anticancer agents4 and as a fluorescent probe for ultrafast DNA
dynamics.5 Joining carbohydrates to coumarins via C–C bond,
could provide more valuable and glycosidically stable analogs for
various biological investigations. A large number of glycosyl cou-
marin derivatives, including some with O- or C-glycosidic linkages,
occur naturally.6 Figure 1 shows natural products such as Dauro-
side D,7 C6 coumarinyl glycoside8 and the family presented in this
study. Coumarins can be classically synthesized by the Perkin,1a,9
Pechmann,1a,10 Knoevenagel,8 Wittig,11 and Kostanecki-Robin-
son,12 Reformatsky,13 and more recently cross-metathesis14 and
palladium coupling reactions.15 Most methods lack generality
and efficiency, therefore the use of a mild catalytic methodology
to create the coumarin backbone in presence of sensitive func-
tional groups is thus required. The first synthesis of C-glycosyl cou-
marin derivatives was made by Mahling et al.16 and since then,
most of the reports presented the synthesis of C-aryl coumarin gly-
cosidic linkages having the aryl of the coumarins attached at the
anomeric position of the carbohydrate residues.17 However, to
the best of our knowledge, no report on the anomerically 4-C-
linked glycocoumarins is known. To this end, we used a domino
Heck reaction/lactonization process.15a Transition metal-catalyzed
cross-couplings have proven to be powerful tools for mild and
highly efficient carbon–carbon bond formations. Among these pro-
cesses, those involving palladium (Heck) catalysis are particularly
powerful for the synthesis of complex molecules, owing to their
excellent level of selectivity and high functional group tolerance.18
Consequently and on the basis of previous expertise in our group,19
the palladium(0)-catalyzed Heck reaction was used to synthesize
C-linked glycomimetics bearing a panel of substituted methyl cin-
(a)
(b)
HO
O
OH
O
O
O
HO
O
HO
HO
O
HO
HO
HO
HO
OH
Dauroside D
C-6 Coumarinyl glycoside
(c)
Cross-
metathesis
O
O
RO
RO
CO2Me
O
O
O
Pd(0)
RO
RO
CO2Me
OH
I
O
OH
Figure 1. Various coumarin C-glycosides: (a) Dauroside D;7 (b) C-5 coumarinyl
glycoside,8 and (c) this work.
namate or coumarin derivatives. When carbohydrates are con-
nected with such varied decorations, a large number of diverse
and novel biologically useful glycoconjugates can be generated.20
In continuation of our interest in the applications of organometallic
catalysis toward the synthesis of carbohydrate analogs,19 we report
herein a convenient synthesis of various C-glycosyl coumarins
using the Heck reaction.
The syntheses were initiated with the known C-allyl mannopy-
ranosides 1,21 2,22 and C-allyl galactopyranosides 3,21 423 which
were subjected to a cross-metathesis reaction, using Grubbs’ sec-
ond generation catalyst and methyl acrylate to provide unsatu-
rated esters 5–8, respectively, in yields ranging from 68% to 94%
(Table 1).19
The next step involved Heck couplings onto unsaturated esters
5–8. The reaction was optimized with respect to the catalyst, base,
phase transfer catalyst, ligand, solvent, temperature, and reaction
* Corresponding author. Tel.: +1 514 987 3000x2546; fax: +1 514 987 4054.
E-mail address: roy.rene@uqam.ca (R. Roy).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.134

D. Giguère et al. / Tetrahedron Letters 50 (2009) 4254–4257
4255
Table 1
Table 2
Synthesis of unsaturated esters 5–8 from a cross-metathesis reaction catalyzed by
Grubbs’ second generation catalyst starting with C-allyl glycosides 1–4
Heck reaction on mannosides 5 and 6 with various aryl iodides 9–12 to provide
methyl cinnamate mannosyls 13–17
Entry
Substrates
Products
Yieldsa (%)
Entry
1
Substrates
Aryl halides
Products
Yielda (%)
OBn
O
OBn
O
I
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
5
1
82
70
9
CO2Me
H
1
MeO2C
H
5
nOe
13
OAc
O
OAc
O
AcO
AcO
AcO
AcO
AcO
AcO
OAc
O
AcO
AcO
2
92
AcO
2
6
9
68
CO2Me
2
6
MeO2C
14
BnO
BnO
BnO
BnO
OBn
O
OBn
O
I
OBn
O
BnO
BnO
BnO
BnO
3
68
OMe
BnO
3
4
5
5
51
CO2Me
3
OMe
10
7
MeO2C
15
AcO
AcO
AcO
AcO
OAc
OAc
O
O
I
OBn
BnO
BnO
CO2Me
O
AcO
AcO
4
94
OH
BnO
4
8
81b
OH
11
a
MeO2C
Yields refer to isolated pure products using methyl acrylate, Grubbs’ second
generation catalyst in refluxing dichloromethane for 3 h.
16
time. The optimal conditions were found to be Pd(OAc)2
(10 mol %), NaHCO3 (3 equiv), Bu4NBr (1 equiv) in DMF (0.16 M)
at 85 °C for 12 h. Having glycosides 5–8 with a diversity of protect-
ing groups and anomeric configurations in hand, we performed the
Heck coupling18 under optimized conditions with a panel of substi-
tuted aryl iodides. Table 2 shows the synthesis of various methyl 3-
mannosylcinnamates 13–17 from unsaturated esters 5 and 6 using
aryl iodides 9–12. C-Mannosides 13–17 were isolated from good to
excellent yields (42–81%). The E-isomers of the double bond were
isolated for all cinnamates except when 4-iodophenol (entry 4)
was used (E/Z ratio of 7:1 as determined by 1H NMR). The stereo-
chemistry of the double bond in mannoside 13 was confirmed by
NOE experiments. The allylic proton and ortho protons from the
phenyl group showed a strong interaction (10%), thus indicating
that the double bond had the E-configuration (entry 1).
Table 3 shows the Heck reaction on C-galactosides 7 and 8 with
aryl iodides 9, 11, and 18. Methyl C-galactosyl cinnamates 19–23
were isolated in 56 to 84% yields. The E-isomers were usually ob-
tained except, again when 4-iodophenol (entry 2) and 3-iodoben-
zyl alcohol (entry 3) were used as aryl partners. In both cases a
2:1 stereoisomeric ratio was obtained in favor of the E-isomers.
When 2-iodophenol 24 and 2-iodophenyl acetate 25 were used
as aryl partners, 4-linked glycosyl coumarins were directly isolated
obviously originating from a Heck reaction followed in situ by a
lactonization process (Table 4). Under standard Heck conditions,
unsaturated esters 5, 7, and 8 were transformed into C-glycosyl
coumarins 26–28 in very good (75%) to good yields (43%). The C-
glycosyl coumarins likely resulted from the standard Heck reaction
with the usual syn b-elimination of the palladium to get the E-iso-
mer, then isomerization of the double bond, under basic reaction
conditions, followed by lactonization.24
I
OBn
O
BnO
BnO
BnO
5
5
42
Br
Br
12
MeO2C
17
a
Yields refer to isolated pure products using Pd(OAc)2, TBABr, NaHCO3, ArI 9–12
in DMF at 85 °C for 12 h.
b
E/Z ratio (7:1).
To illustrate the potential usefulness of these new compounds,
some of the above-mentioned unprotected galactosides were eval-
uated as ligands against galectin-1 and -3 (Gal-1 and -3).25 Galec-
tins26 are a family of cytosolic b-
D-galactoside binding proteins.
The roles of the galectins family are numerous, but a striking com-
mon feature of all galectins is the strong modulation of their
expression during development, differentiation stages, and under
different physiological or pathological conditions.27 Studies have
demonstrated that Gal-3 is involved in cancer and tumor progres-
sion,28 and can regulate apoptotic process29 together with Gal-130
which can additionally act as a soluble host factor that promotes
HIV-1 infectivity through stabilization of virus attachment to host
cells.31 Unprotection of acylated galactosides 8, 22, 23, and 28 with
methanolic sodium methoxide afforded free alcohols 29–32,
respectively, in excellent yield.
All compounds and control
inhibition of hemagglutination assay at a concentration of 1
of both galectins. Hemagglutination assays were performed using
(D-galactose) were tested by
l
M

4256
D. Giguère et al. / Tetrahedron Letters 50 (2009) 4254–4257
Table 3
Table 4
Heck reaction on C-galactosides 7, 8 with aryl iodides 9, 11, and 18 to provide methyl
3-galactosyl cinnamates 19–23
Synthesis of 4-linked coumarin C-glycosyls 26–28 using a domino Heck reaction/
lactonization process
Entry Substrates Aryl halides
Products
BnO
Yielda (%)
Entry
Substrates
Aryl halides
Products
Yielda (%)
I
OBn
O
OBn
O
BnO
BnO
OR
BnO
BnO
BnO
1
2
3
7
7
7
9
64
1
2
5
52
24 R = OH
25 R = OAc
O
MeO2C
O
19
26
43
75
48
BnO
BnO
OBn
O
BnO
BnO
OBn
O
OH
11
84b
BnO
BnO
3
4
7
24
25
O
MeO2C
20
O
27
I
BnO
BnO
OBn
O
AcO
AcO
OAc
O
73b
OH
BnO
OH
18
AcO
5
8
24
25
75
48
O
MeO2C
O
21
28
6
AcO
AcO
OAc
CO2Me
a
Yields refer to isolated pure products using Pd(OAc)2, TBABr, NaHCO3, ArI 24
and 25 in DMF at 85 °C for 12 h.
O
AcO
4
8
9
74
application was made toward evaluation of various unprotected
galactosides against Gal-1 and -3. Galactoside precursor 30 had
22
IC50 of 313 lM against Gal-1.
AcO
AcO
OAc
O
CO2Me
Acknowledgments
AcO
5
8
11
56
This work was supported from Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) for a Canadian Research
Chair in Therapeutic Chemistry to R.R. D.G. thanks FQRNT (Québec)
for a postgraduate fellowship. Finally, the authors thank Prof. Sac-
hiko Sato (U. Laval, QC, Canada) for the hemagglutination inhibi-
tion assays.
OH
23
a
Yields refer to isolated pure products using Pd(OAc)2, TBABr, NaHCO3, ArI 9, 11,
18 in DMF at 85 °C for 12 h.
b
Supplementary data
E/Z ratio (2:1).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.134.
red blood cells, type O, fixed with 3% glutaraldehyde–0.0025%
NaN3 in PBS31 to confer both lectins equal relative affinities. Galac-
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