Simple synthesis of phenylpropenoid β-D-glucopyranoside congeners based on Mizoroki-Heck type reaction of organoboron reagents

Article abstract of DOI:10.1016/j.tetlet.2005.04.023

Palladium(II)-catalyzed carbon-carbon bond formation between allyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (3) and phenylboronic acid congeners gave the phenylpropenoid 2,3,4,6-tetra-O-acetyl-β-d- glucopyranoside (4a-f) in good yield. Among them, compounds 4a-c were converted to the naturally occurring phenylpropenoid β-d-glucopyranoside analogues (1a-c).

Full text of DOI:10.1016/j.tetlet.2005.04.023

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4123–4125
Simple synthesis of phenylpropenoid b-D-glucopyranoside
congeners based on Mizoroki–Heck type reaction
of organoboron reagents
Masashi Kishidaa,b and Hiroyuki Akitaa,*
aSchool of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
bTsukuba Research Institute, Novartis Pharma. K.K., 8, Ohkubo, Tsukuba-shi, Ibaraki 300-2611, Japan
Received 23 February 2005; revised 22 March 2005; accepted 1 April2005
Available online 22 April 2005
Abstract—Palladium(II)-catalyzed carbon–carbon bond formation between allyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (3) and
phenylboronic acid congeners gave the phenylpropenoid 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (4a–f) in good yield. Among
them, compounds 4a–c were converted to the naturally occurring phenylpropenoid b-D-glucopyranoside analogues (1a–c).
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
glucopyranoside (1c).4 This process was usefulfor the
synthesis of a variety of b-D-glucopyranoside analogues
because a metalcatayl st and protection of the hydroxyl
groups on the glucose unit were not needed. However, in
the case of the enzymatic glucosidation using hydropho-
bic alcohol, such as 4-methoxy-cinnamyl alcohol, excess
amount of alcohol was needed (4 equiv) and chemical
yield was poor (11%).4b Moreover, for the purpose of
the diverse phenylpropenoid glucoside analogues using
existing glucosidation methods, many kinds of the
substituted cinnamyl alcohols should be synthesized.
Now, we report a simple total synthesis of rosin (1a),
Golden root (Roseroot, Rhodiola rosea L., Crassula-
ceae) has been used for a long time as a resource in Chi-
1
nese traditionalmedicine. Phenylpropenoid glucoside,
such as rosin (cinnamyl O-b-D-glucopyranoside; 1a),
was isolated from R. rosea as one of the major active
ingredients and reported to be pharmacologically active
as antioxidants and neurostimulants.2 Moreover, some
other phenylpropenoid glucoside analogues have been
isolated as bioactive substances. For instance, sachal-
iside 1 (4-hydroxycinnamyl O-b-D-glucopyranoside; 1b)
and 4-methoxy-cinnamyl O-b-D-glucopyranoside (1c)
have been isolated from the callus cultures of the plant
(Scheme 1).3
sachaliside
1 (1b) and 4-methoxy-cinnamyl-O-b-D-
glucopyranoside (1c) using the Mizoroki–Heck (MH)
type reaction between the substituted arylboronic acid
and allyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (3)
under Pd(II) condition as the key reaction (Scheme 2,
step (iii)). The MH type reaction of phenylboronic acid
and olefin under Pd(0)-catalyzed condition was shown
by Cho and Uemura.5a On the other hand, organobo-
ron-mediated MH type reaction via a Pd(II)-catalyzed
To investigate their pharmacological activities, we have
recently reported that the coupling of cinnamyl alcohol
derivatives and 4-nitrophenyl b-D-glucopyranoside
using b-glucosidase (EC 3.2.1.21) in phosphate buffer
(pH 5) gave rosin (1a) and 4-methoxy-cinnamyl O-b-D-
OH
OMe
OH
Ar =
O
HO
HO
O
Ar
OH
Rosin (1a)
Sachaliside 1 (1b)
1c
Scheme 1.
*
Corresponding author. Tel.: +81 474 72 1805; fax: +81 474 76 6195; e-mail: akita@phar.toho-u-ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.023

4124
M. Kishida, H. Akita / Tetrahedron Letters 46 (2005) 4123–4125
OH
OAc
O
O
a
HO
HO
AcO
AcO
b
O
O
O
O
D-Glucose
OH
OAc
3
2
OAc
O
OH
O
d
AcO
AcO
HO
HO
c
Ar
Ar
OAc
OH
4
1
Scheme 2. Reagents and conditions: (a) ally alcohol/H2O/immobilized b-glucosidase with ENTP-4000, 50 °C, 72 h, 60%; (b) Ac2O/cat. DMAP/
pyridine, rt overnight, 95%; (c) ArB(OH)2/cat. Pd(OAc)2/Cu(OAc)2/LiOAc/DMF, 60–100 °C, 1–2 h, 45–75%; (d) K2CO3/MeOH, rt 1 h or NaOMe/
MeOH, rt 1 h, 63–99%.
condition had been also reported by Du et al.5b How-
ever, the reaction of allyl ether with phenyl boronic acid
was examined only one example in this literature5b and
no other examples have been reported in the field of
carbohydrate chemistry. Furthermore, we synthesized
non-natural phenylpropenoid analogues to investigate
the limitation of this strategy.
using LiOAc, Cu(OAc)2, a catalytic amount of
Pd(OAc)2 in DMF at 100 °C for 1.5 h to give cinnamyl
2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (4a) in 71%
yield (entry 1). As summarized in Table 1, phenylbo-
ronic acid having an electron-donating group (entry 3),
an electron-withdrawing group (entries 4–6) and a non-
protected hydroxylgroup (entry 2) underwent MH type
reactions smoothly in reasonable yield. After deprotec-
tion of coupling products (4a–f) using NaOMe/MeOH
or K2CO3/MeOH, the desired phenylpropenoid b-D-
glucoside analogues (1a–f)9 were obtained rapidly. The
spectroscopic data (1H and 13C NMR) and specific rota-
tion {[a]D} of synthetic natural-type phenylpropenoid
b-D-glucoside analogues (1a–c) were fully identical
with those of naturalproducts.
2. Synthesis of substrate for MH type reaction
Some synthesis of allyl 2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranoside (3)6 and the direct glucosidation of D-glucose
using b-glucosidase (EC 3.2.1.21) from almonds have
been reported.7 Meanwhile, we had reported direct
b-glucosidation between D-glucose and primary alcohol
using the immobilized b-glucosidase (EC 3.2.1.21) from
almonds with the synthetic prepolymer ENTP-4000
giving mono-b-D-glucopyranoside in moderate yield.8
As in the previous method, allyl b-D-glucopyranoside
(2) could be prepared from D-glucose and allyl alcohol
using the immobilized b-glucosidase in 60% yield. Acet-
ylation of allyl b-D-glucopyranoside (2) with acetic acid
anhydride in pyridine afforded allyl 2,3,4,6-tetra-O-
acetyl-b-D-glucopyranoside (3) as a key substrate for
MH type reaction.
4. Discussion
The MH type reaction of silanols and organotin com-
pounds with olefins via a Pd(II)-mediated pathway has
been reported by Hiyama and co-workers.10 Based on
this pathway, a plausible MH type reaction mechanism
with arylboronic acid was presented in Scheme 3.
According to this mechanism, the arylunit migrated
to the palladium centre from arylboronic acid to furnish
an aryl palladium species first, and this reactive aryl pal-
ladium species was added to an olefin of allyl 2,3,4,6-
tetra-O-acetyl-b-D-glucopyranoside (3) to afford an
intermediate A. After reductive b-elimination of the
intermediate A occurred, the desired product was ob-
tained along with the release of palladium(0). Finally,
3. Results
The reaction of phenylboronic acid with allyl 2,3,4,6-
tetra-O-acetyl-b-D-glucopyranoside (3) was carried out
Table 1. Reaction of phenylboronic acid with 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosidea and deprotection
Entry
Ar–B(OH)2
Deprotectionc
OAc
O
OH
O
A: K2CO3/MeOH;
B: NaOMe/MeOH
(%)
(%)
AcO
AcO
HO
HO
O
Ar
O
Ar
OAc
OH
1 : Ar@Ph (95)
Ar@4-(OH)Ph (95) b:
1 : Ar@4-(OMe)Ph (69)c
1 : Ar@4-CI–Ph (85)
1 : Ar@4-(CN)Ph (99)
1
2
3
4
5
6
Ph–B(OH)2
4-(OH)Ph–B(OH)2
4a: Ar@Ph (71)
A
B
A
B
B
A
a
b
4b: Ar@4-(OH)Ph (57)
4c: Ar@4-(OMe)Ph (72)
4d: Ar@4-Cl–Ph (75)
4e: Ar@4-(CN)Ph (75)
4f: Ar@4-(CF3)Ph (45)
1
4-(OMe)Ph–B(OH)2
4-Cl–Ph–B(OH)2
d
4-(CN)Ph–B(OH)2
4-(CF3)Ph–B(OH)2
e
1 : Ar@4-(CF3)Ph (63) f
a Unless otherwise noted, all coupling reactions were carried out in DMF (4 mL), using 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (1.0 mmol),
Ar–B(OH)2 (1.2 mmol), Pd(OAc)2 (0.1 mmol), Cu(OAc)2 (2 mmol) and LiOAc (3 mmol) at 100 °C for 1.5 h.
b The amount of 4-hydroxyphenylboronic acid used was 3.0 mmol.
c Method A: K2CO3 (1.0 equiv based on 4a–f) in MeOH, method B: 25% NaOMe in MeOH (1.0 equiv based on 4a–f) in MeOH.

M. Kishida, H. Akita / Tetrahedron Letters 46 (2005) 4123–4125
4125
Ar-B(OH)2
5. Conclusion
Pd(OAc)2
[O]
In conclusion, a variety of natural and non-natural type
phenylpropenoid glucopyranoside analogues have been
synthesized based on the MH type reaction. Therefore,
structurally diverse phenylpropenoid b-D-glucopyrano-
side analogues could be prepared using a number of
commercially available substituted phenylboronic acids.
AcOB(OH)2
Pd(0)
ArPd(OAc)
O
Glu
PdOAc
Ar
HOAc
3
O
Glu
O
Ar
References and notes
Glu
Intermediate A
4a-f
1. Saratikov, A. S.; Krasnov, E. A.; Duvidson, L. M.;
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9. Satisfactory analytical data were obtained for all new
compounds.
Scheme 3. The plausible MH type reaction mechanism with arylbo-
ronic acid.
the palladium(0) species was oxidized by a combination
of copper(II) acetate and lithium acetate to regenerate
palladium(II) as the key species of this catalytic reaction.
Indeed, the treatment of allyl 2,3,4,6-tetra-O-acetyl-b-D-
glucopyranoside (3) and phenylboronic acid in the pres-
ence of tetrakistriphenylphosphine palladium(0) affected
removal of the allyl group instead of the desired MH
type reaction. In addition, non-protected allyl b-D-
glucopyranoside (2) could be reacted with arylboronic
acid under the same conditions. However, the chemical
yield was poor due to a low conversion. For instance,
when allyl b-D-glucopyranoside (2) was treated with
phenylboronic acid in the presence of LiOAc,
Cu(OAc)2, a catalytic amount of Pd(OAc)2 in DMF at
100 °C for 5 h, the desired cinnamyl b-D-glucopyrano-
side (1a) could be obtained in only 11% along with a
large amount of the starting material. This phenomenon
might be explained by the deactivation of arylboronic
acid due to the formation of arylboronic ester from aryl-
boronic acid and allyl b-D-glucopyranoside (2). In fact,
4,4,5,5-tetramethyl-2-(4-hydroxyphenyl)-1,3-dioxaborane
could not be reacted with allyl 2,3,4,6-tetra-O-acetyl-
b-D-glucopyranoside (3) under the same conditions
and it was suggested that a boronic ester was less reac-
tive than a boronic acid to react with an allyl ether in
this case.
10. Hirabayashi, K.; Ando, J.; Kawashima, J.; Nishihara, Y.;
Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73,
1409–1417.