A novel and effective procedure for the preparation of glucuronides.

Article abstract of DOI:10.1021/ol0062143

6-Phenylthio-6-deoxy-D-glucopyranosides were easily prepared from 6-hydroxy-D-glucopyranosides and employed as effective glycosyl donors or acceptors. And the resulting coupling products were then readily converted into the corresponding D-glucuronide-con

Full text of DOI:10.1021/ol0062143

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2539-2541
A Novel and Effective Procedure for the
Preparation of Glucuronides
Biao Yu,* Xiangming Zhu, and Yongzheng Hui*
State Key Laboratory of Bio-organic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
byu@pub.sioc.ac.cn
Received June 15, 2000
ABSTRACT
6-Phenylthio-6-deoxy-D-glucopyranosides were easily prepared from 6-hydroxy-D-glucopyranosides and employed as effective glycosyl donors
or acceptors. And the resulting coupling products were then readily converted into the corresponding D-glucuronide-containing compounds.
Glucuronide is an integral component in proteoglycans which
play essential roles in many cellular processes, including cell
growth and cell-cell interactions.1 Glucuronide exists also
as an important structural unit in a number of bacterial
capsular polysaccharides and plant glycosides which show
promising biological activities.2,3 Furthermore, glucuronide
is frequently the final form of a drug or xenobiotic eliminated
from the body, often performing a detoxification role.4 As a
consequence of these biological rationales, development of
synthetic schemes for glucuronides has been targeted by
many investigators.4,5 Although most of the methods em-
ployed for glucuronide synthesis have their parallel in
glucopyranoside synthesis, glucuronide donors or acceptors
have been found to be more sluggish than the corresponding
glucopyranoside counterparts. Schmidt and co-workers have
in fact classified glycuronide donors as the type of glycosyl
donor with the lowest reactivity.6 The distinctive chemistry
of glucuronides has been attributed to the electron-withdraw-
ing 5-carboxyl group, which remarkably decreases the
nucleophilicity of the hydroxy groups on glucuronide ac-
ceptors, or exerts a destabilizing effect on the incipient C-1
cation leading to the low reactivity of glucuronide donors.
Consequently, coupling with glucuronide donors or acceptors
usually gives low yields of the products.4 Oscarson et al.
therefore have recently developed ethyl thio-glucuronide
donors with activating protective groups (benzyl or silyl) at
O-3 and O-4 and a neighboring participating group at O-2.7
Alternatively, glucuronides, glucuronide-containing oligosac-
charides in particular, are often synthesized by introduction
of the carboxyl group at a later oxidation step after coupling
with a glucopyranoside moiety.5 However, this approach
requires extensive protective group manipulations for selec-
tively generating a free 6-OH at a later stage.
(1) (a) Bhavanandan, V. P.; Davidson, E. A. In Glycoconjugates; Allen,
H. J., Kisailus, E. C., Eds.; Marcel Dekker: New York, 1992; pp 167. (b)
Kjellen, L.; Lindahl, U. Annu. ReV. Biochem. 1991, 60, 443.
(2) (a) Lindberg, B.; Kenne, L. The Polysaccharides; Academic Press:
New York, 1985; Vol. 2, p 287. (b) Lindberg, B. AdV. Carbohydr. Chem.
Biochem. 1990, 48, 279.
(3) Hostettmann, K.; Marston, A. Saponins; Cambridge University
Press: Cambridge, UK, 1995.
(4) For a comprehensive review on glucuronide synthesis, see: Stachul-
ski, A. V.; Jenkins, A. N. Nat. Prod. Rep. 1998, 173.
(5) For synthesis of glucuronide-containing oligosaccharides by oxidation
at a later stage, see for examples: (a) Yeung, B. K. S.; Hill, D. C.; Janicka,
M.; Petillo, P. A. Org. Lett. 2000, 2, 1279. (b) Nilsson, M.; Svahn, C. M.;
Westman, J. Carbohydr. Res. 1993, 246, 161. (c) Slaghek, T. M.; Hypponen,
T. K.; Ogawa, T.; Kamerling, J. P.; Vliegenhart, J. F. G. Tetrahedron Lett.
1993, 34, 7939. (d) Slaghek, T. M.; Nakahara, Y.; Ogawa, T. Tetrahedron
Lett. 1992, 33, 4971. (e) Ichikawa, Y.; Ichikawa, K.; Kuzuhara, H.
Carbohydr. Res. 1985, 141, 273.
(6) Mueller, T.; Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1994,
35, 4763.
(7) (a) Garegg, P. J.; Olsson, L.; Oscarson, S. J. Org. Chem. 1995, 60,
2200. (b) Krog-Jensen, C.; Oscarson, S. Carbohydr. Res. 1998, 308,
287.
10.1021/ol0062143 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000

To circumvent the problems in glucuronide synthesis, we
envisioned developing a glucuronide precursor, which could
behave as a normal glycosyl donor or acceptor, while could
be readily converted into the glucuronide residue after
assembling of the whole molecule. This paper reports that
6-phenylthio-glucopyranosides serves nicely for these pur-
poses.
Scheme 2a
To test the feasibility of using 6-phenylthio-glucopyrano-
sides as glucuronide precursors, we first examined the
substitution of 6-OH with phenylthio group and then the
conversion of the resulting 6-SPh to carboxyl group on a
simple glucopyranoside 1 (Scheme 1). Treatment of methyl
Scheme 1a
a (a) (PhS)2, n-Bu3P, pyridine, rt, 24 h; (b) (1) Ac2O, pyridine,
rt, overnight; (2) TBAF, HOAc, THF, rt, 10 h; (3) CNCCl3, DBU,
CH2Cl2, rt, 1 h, 81% (for three steps).
a (a) (PhS)2, n-Bu3P, pyridine, rt, 24 h, 94%; (b) SO2Cl2/pyridine
(2.0 equiv), CCl4, 0 °C; (c) HgCl2 (10.0 equiv), pyridine (2 equiv),
MeOH/H2O/CH2Cl2 (2:1:1), rt, 90% (for two steps).
The use of 6-phenylthio-glucopyranose derivatives as
glycosyl donors or acceptors for preparation of glycosides
or disaccharides was examined. The results are listed in
Figure 1 and Table 1. Glycosylation of sugar alcohol 1 and
2,3,4-tri-O-benzoyl-R-D-glucopyranoside (1) with phenyl
disulfide and tri-n-butylphosphine in pyridine8 at room
temperature gave 6-phenyl sulfide 2 in 94% yield, which
was then subjected to sulfuryl chloride and pyridine in carbon
tetrachloride at 0 °C, the conditions developed by Fortes et
al.,9 to provide the R,R-dichloro-phenyl sulfide 3. Compound
3 was found to be unstable upon silica gel column chroma-
tography, and consequently was directly treated with mer-
cury(II) chloride in methanol/water/dichloromethane at room
temperature, affording the desired methyl ester 4 in 90%
yield.
Encouraged by the ready transformation from gluco-
pyranoside 1 to glucuronide 4 under mild conditions, we
prepared 6-phenylthio-substituted ethylthio-glucopyranoside
donor 6, trichloroacetimidate donor 11, and acceptor 8 with
a free 4-OH from the corresponding 6-OH glucopyranosides
(5, 7, and 9) (Scheme 2). It should be noted that the
6-phenylsulfenylation of glucopyranoside derivatives was
achieved in excellent yields and in a regioselective manner
(for diols 7 and 9).
Figure 1. Selected donors and acceptors.
cholesterol (15) with ethyl 2,3,4-tri-O-benzoyl-6-phenylthio-
6-deoxy-1-thio-â-D-glucopyranoside (6) under the promotion
of MeOTf10 provided the corresponding products (17 and
18) in 60% and 56% yields, respectively (entries 1 and 2).
The moderate yields were conceivably resulted from the
interference of the 6-phenylthio substitution on the activation
of the anomeric ethylthio group of donor 6. Stronger
promotion conditions,11 e.g., NIS/AgOTf as promoter, gave
a complicated mixture of the products. Fortunately, using
trichloroacetimidate 11 as donor, under the promotion of
TMSOTf,12 led to high yields of the coupling products (19
and 20, entries 3 and 4). Glycosylation of 6-phenylthio-
(8) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 17, 1409.
(9) (a) Fortes, C. C.; Fortes, H. C.; Goncalves, D. C. R. G. J. Chem.
Soc. Chem. Commun. 1982, 857. (b) Fortes, C. C.; Souto, C. R. O.; Okino,
E. A. Synth. Commun. 1991, 21, 2045.
(10) (a) Lonn, H. Carbohydr. Res. 1985, 139, 105; 115. (b) Lonn, H. J.
Carbohydr. Chem. 1987, 6, 301.
(11) (a) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1995, 52, 170.
(b) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(12) (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(b) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994, 50,
21.
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Org. Lett., Vol. 2, No. 16, 2000

Table 1a
entry
donor
acceptor
conditions
product
yield,b %
1
2
3
4
5
6
7
6
6
1
15
15
16
8
A
A
B
B
C
C
C
17
18
19
20
21
22
23
60
56
82
85
70
81
92
11
11
12
13
14
8
8
a Conditions A: donor (2.0 equiv), acceptor (1.0 equiv), 4 Å MS, CH2Cl2,
MeOTf (5.0 equiv). Conditions B: donor (1.0 equiv), acceptor (1.5-2.0
equiv), 4 Å MS, CH2Cl2, TMSOTf (0.2 equiv). Conditions C: donor (2.0
equiv), acceptor (1.0 equiv), 4 Å MS, CH2Cl2, TMSOTf (0.2 equiv).
b Isolated yields.
substituted glucopyranoside 8 (as an acceptor) with tri-
chloroacetimidate donors 12-14, provided the corresponding
coupling products in good to excellent yields (70-92%)
(entries 5-7). All the glycosidic linkages produced were
1
proved by H NMR analysis to be 1,2-trans configurations
due to the donors used possessing neighboring participating
groups.
Figure 2. Methyl glucuronates prepared from 6-phenylthio sub-
stituted precursors. Experimental conditions are as follows: (1)
SO2Cl2 (2.0 equiv), pyridine (2.0 equiv), CCl4, 0 °C; (2) HgCl2
(10.0 equiv), pyridine (2.0 equiv), MeOH/H2O/CH2Cl2 (2:1:1), or
MeOH/H2O/CHCl3 (2:1:1), rt. The numbers enclosed in parentheses
are isolated yields for two steps.
Glycosides and disaccharides which contained the 6-phen-
ylthio-substituted glucopyranose residue were demonstrated
to be ready precursors of the corresponding methyl glu-
curonates (Figure 2). The transformations were realized in
two steps under the conditions developed by Fortes et al.9
Thus, treatment of 17 or 19-23 with sulfuryl chloride in
the presence of pyridine in carbon tetrachloride provided the
corresponding R,R-dichloro-phenyl sulfides cleanly (on
TLC), which after a usual workup, was directly subjected
to hydrolysis (HgCl2/MeOH/H2O) to give the corresponding
methyl glucuronates (24-29). Hydrolysis of disaccharide
derivatives (17, 21-23) was carried out in a mixture solvent
of MeOH/H2O/CH2Cl2, providing the corresponding methyl
glucuronates (24, 27-29) in high yields (85-89% for two
steps). Because of the poor solubility in the above mixture
solvent, steroidal glycosides 19 and 20 were subjected to
hydrolysis in MeOH/H2O/CHCl3, generating methyl glu-
curonates 25 and 26 in lower yields (71% and 68%,
respectively, for two steps). It should be noted that the acyl
protective groups (acetyl and benzoyl groups), the glycosidic
bonds, and the carbon-carbon double bonds containing in
the substrates were unaffected under these transformation
conditions.
In conclusion, we have developed an effective alternative
to the preparation of glucuronides by using 6-phenylthio-
substituted glucopyranosides as precursors. The present
strategy should be applicable to the synthesis of other
uronides as well. Application of this method to the synthesis
of biologically active uronide-containing compounds is our
current interest and will be reported in due course.
Acknowledgment. We thank the Ministry of Science and
Technology of China and the National Natural Science
Foundation of China (29925203) for financial support.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for 6-phenyl sulfides (2, 6,
8 10 11), coupling products (17-23), and final methyl
glucuronates (24-29). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0062143
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