Synthesis of α-glucuronic acid and amide derivatives in the presence of a participating 2-acyl protecting group

Article abstract of DOI:10.1021/ol026629j

(graph presented) Participating acyl groups located at C-2 in glucosyl and related donors generally promote formation of 1,2-trans-glycosides. Reactions of some glucuronic acid donors with TMSN₃/SnCl₄ or ROH/SnCl₄ gave only the 1,2-cis-glycoside. The stereoselectivity is consistent with participation of the C-6 group. The methodology was used for the synthesis of a Kdn2en mimetic with the α-configuration.

Full text of DOI:10.1021/ol026629j

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3675-3678
Synthesis of r-Glucuronic Acid and
Amide Derivatives in the Presence of a
Participating 2-Acyl Protecting Group
Manuela Tosin and Paul V. Murphy*
Department of Chemistry, Centre for Synthesis and Chemical Biology, Conway
Institute of Biomolecular and Biomedical Research, UniVersity College Dublin,
Belfield, Dublin 4, Ireland
paul.V.murphy@ucd.ie
Received July 29, 2002
ABSTRACT
Participating acyl groups located at C-2 in glucosyl and related donors generally promote formation of 1,2-trans-glycosides. Reactions of
some glucuronic acid donors with TMSN /SnCl4 or ROH/SnCl4 gave only the 1,2-cis-glycoside. The stereoselectivity is consistent with participation
3
of the C-6 group. The methodology was used for the synthesis of a Kdn2en mimetic with the r-configuration.
The preparation of glycosides in a stereoselective manner is
one of the most important goals for synthetic chemists. This
is a result of the biological and medical importance of
oligosaccharides, glycoproteins, and glycolipids,1 due to
interest in the synthesis of carbohydrate mimetics,2 carbo-
hydrate-based peptidomimetics,3 and carbohydrate-based
scaffolds for the synthesis of pharmacophore mapping
libraries.4 Such syntheses are challenging because of the
complexity and diversity of saccharides found in nature.
Much work has been carried out in development of strategies
for synthesis of O-glycosides. Widely used methods include
that of Koenigs and Knorr;5 halide-assisted glycosylation;6
the activation of thioglycosides,7 glycosylfluorides,8 trichoro-
acetimidates,9 pentenyl glycosides,10 glycosyl phosphites,11
and sulfoxides;12 the use of glycals13 or enzymes;14 and
donors without protecting groups.15 Recently research has
(5) Koenigs, W.; Knorr, E. Ber. Dtsch. Chem. Ges. 1901, 34, 957.
(6) Lemieux, R.; Hendricks, K. B., Stick, R. V.; James, K. J. Am. Chem.
Soc. 1975, 97, 4056.
(7) (a) Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N. Carbohydr. Res. 1973,
27, 55. (b) Oscarson, S. In Oligosaccharides in Chemistry and Biology: A
ComprehensiVe Handbook; Ernst, B., Hart, G., Sinay¨, P., Eds.; Wiley-
VCH: 2000; Vol. 1, pp 93-116. (c) Garegg. P. J. AdV. Carbohydr. Chem.
Biochem. 1997, 52, 179.
(1) Varki, A. Glycobiology 1993, 3, 97.
(8) Nicolaou, K. C.; Ueno, H. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker Inc.: New York, 1997; pp 313-338.
(9) Schmidt, R. R.; Jung, K.-H. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker Inc.: New York, 1997; pp 283-312.
(10) Fraser-Reid, B.; Madsen, R. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker Inc.: New York, 1997; pp 339-356.
(11) (a) Martin, T. J.; Schmidt, R. R. Tetrahedron Lett. 1992, 33, 6123.
(b) Kondo, H.; Ichikawa, Y.; Wong C.-H. J. Am. Chem. Soc. 1992, 114,
8748.
(2) (a) Wong, C.-H. Acc. Chem. Res. 1999, 32, 376. (b) Simanek, E. E.;
McGarvey, G. J.; Jablonski, J. A.; Wong, C.-H. Chem. ReV. 1998, 98, 833.
(3) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.; Leahy,
E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B., III; Strader, C. D.; Cascieri,
M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.; Maechler, L. J. Am.
Chem. Soc. 1992, 114, 9217.
(4) (a) Sofia, M. J.; Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina, R.;
Wang, H. M.; Gange, D. J. Org. Chem. 1998, 63, 2802. (b) Wunberg, T.;
Kallus, C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H. Angew. Chem.,
Int. Ed. 1998, 37, 2503.
(12) (a) Kim, S. H.; Augeri, D.; Yang, D.; Kahne, D. J. Am. Chem. Soc.
1994, 116, 1766. (b) Crich, D.; Sun, S. X. J. Org. Chem. 1997, 62, 1198.
10.1021/ol026629j CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002

been concerned with automated solid-phase16 and one-pot17
oligosaccharide synthesis. N-Glycosylation is also important,
particularly in relation to the synthesis of glycopeptides,
glycoproteins, and peptidomimetics; the synthesis of mol-
ecules of this type are often carried out via glycosyl azides.18
Protecting groups have been used to influence the stereo-
selectivity of reactions at the anomeric center. It is well-
established that participating acyl groups located at C-2 in
glucosyl and related donors generally promote formation of
â-glycosides (Scheme 1), whereas the use of nonparticipating
available D-glucuronic acid in the presence of iodine followed
by treatment with methanol in one pot gave the methyl ester
522 rather than the carboxylic acid (Scheme 3) as reported.21
Scheme 3a
Scheme 1. Participation of 2-Acyl Groups in Glycosylation
a Reagents and conditions: (a) Ac2O, I2, 70%; (b) H2O, 91%;
(c) PhNHMe (1.0 equiv), CH2Cl2, 15 h; (d) MeOH, 70%; (e) PhNH2
(1.2 equiv), CH2Cl2, 15 h, 70%; (f) iPrNH2 (1.2 equiv) CH2Cl2, 15
h, 55%.
groups (e.g., O-benzyl or azide) in solvents such as diethyl
ether facilitate preferential formation of the R-glycoside.19
We now describe highly stereoselective syntheses of R-gly-
cosides of glucuronic acid derivatives even though the donors
have participating O-acetate groups at C-2.
We found that isolation of the pure â-anhydride 4 was
possible after crystallization of the residue obtained from
the acetylation of glucuronic acid; this could be converted
into the desired acid by reaction with water. The reaction of
aniline and isopropylamine with 4 gave the amides 6 and 7,
respectively. Nucleophilic attack takes place at the carbonyl
group nearest the pyranose in these cases; the reaction of
the more hindered N-methylalanine gave 3 as a result of
nucleophilic attack at the less congested carbonyl group.
After having completed the synthesis of 3 and related
amides we next explored the introduction of a stable azide
at the anomeric center using SnCl4 and TMS-N3. However,
although the â-azide is, as expected, the major product from
ester 5,22 the R-azide was obtained from 3 (entry 3, Table
1).23 The reaction of other acid and amides derivatives
(entries 4-6, Table 1) under similar conditions also gave
the corresponding R-azide with no evidence of the â-azide
detectable by NMR; the â-azides were prepared from 9 as
outlined in Scheme 4 and used as standards in the analysis
of the products.
Our interest in the conformation of glycosylamides, in
particular for the design of scaffolds for restricted presenta-
tion of divalent and multivalent ligands,20 has prompted us
to begin an investigation of the conformational preferences
of amides such as 1. The synthesis of glycosylamides of this
type can in principle be achieved from carboxylic acids 2
and 3 (Scheme 2).
Scheme 2. Retrosynthetic Analysis of Glucuronyl Amides 1
When the reaction of the acetate 3 with SnCl4 was repeated
in the absence of trimethylsilyl azide, the 1,6-lactone 1724
was isolated (40-48%). Treatment of 17 with the Lewis acid
in the presence of TMS-N3 led only to formation of the
We could not reproduce the synthesis of 2 or 3 by the
published procedures.21 The acetylation of commercially
(13) Seeberger, P. H.; Bilodeau, M. T.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1380.
(18) Kunz, H.; Schulz M. In Glycopeptides and Related Compounds;
Large, D. G., Warren, C. D., Eds.; Marcel Dekker Inc.: New York, 1997;
pp 23-78.
(14) (a) Ichikawa, Y.; Look, G. Wong. C.-H. Anal. Biochem. 1991, 202,
215. (b) Tolborg, J. F.; Petersen, L.; Jensen, K. J.; Mayer, C.; Jakeman, D.
L.; Warren, R. A. J.; Withers, S. G. J. Org. Chem. 2002, 67, 4143.
(15) Lou, L.; Reddy, G. V.; Wang, H.; Hanessian, S. In PreparatiVe
Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker Inc.: New
York, 1997; pp 390-412.
(16) (a) Seeberger, P. H.; Haase, W.-C. Chem. ReV. 2000, 100, 4349.
(b) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
(17) (a) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734. (b) Douglas N. L.; Ley, S.
V.; Lucking, U.; Warriner S. L. J. Chem. Soc., Perkin Trans. 1 1998, 51.
(19) Lonn, H. J. Carbohydr. Chem. 1987, 6, 30.
(20) Bradley, H.; Fitzpatrick, G.; Glass, W. K.; Kunz, H.; Murphy, P.
V. Org. Lett. 2001, 3, 2629.
(21) Malkinson, J. P.; Falconer, R. A.; Toth, I. J. Org. Chem. 2000, 65,
5249.
(22) von Roedern, E. G.; Lohof, E.; Hessler, G.; Hoffmann, M.; Kessler,
H. J. Am. Chem. Soc. 1996, 118, 10156-10167.
(23) This constrasts with results reported in the literature. See ref 21.
(24) Takeda, Y.; Akimoto, T. Carbohydr. Res. 1982, 106, 175.
3676
Org. Lett., Vol. 4, No. 21, 2002

Table 1. Synthesis of Glycosyl Azides
entry
R1
R2
product
% yield
R or âc
1
2
3
4
5
6
OMe
OAc
OH
NHiPr
NHPh
NMePh
OMe
OH
OH
NHiPr
NHPh
NMePh
9
97a
97a
84b
45b
62b
51b
â22
R/âd
R
R
R
10
10
12
13
14
Preliminary investigations were carried out to assess the
potential for using the 1,6-lactone 17 in the synthesis of
O-glycosides (Scheme 5); its reaction with phenol proceeded
R
a Yield of crude product. b Yields after purification. c Determined by 1H
NMR analysis of crude product. d Variable ratios of products were obtained.
Scheme 5a
R-azide 10 in 85% yield. A similar reaction of amide 6 in
absence of TMS-N3 led to isolation of the R-chloride 18.
When 18 was treated with the Lewis acid in the presence of
Scheme 4a
a Reagents and conditions: (a) SnCl4 (0.5 equiv), TMSOTf (2.5
equiv), CH2Cl2 (dry), 15 h; (b) SnCl4 (0.5 equiv), CH2Cl2 (dry),
15 h. Ac2O, Py, DMAP (cat.) 72 h, then H2O, then LiOH.
a Reagents and conditions: (a) LiOH, THF, H2O, MeOH; (b)
NaOAc, Ac2O, then H2O; (c) (COCl)2 (1 equiv) CH2Cl2, DMF
(cat.), 0 °C, 2.5 h; (d) PhNHR (1 equiv), pyridine (2 equiv), CH2Cl2,
30 min.
in 64% yield26 to give only the R-glycoside 23. Reaction of
17 with 2-propanol gave the R-glycoside in 43% isolated
yield using a SnCl4/TMSOTf mixture; the use of either SnCl4
or TMSOTf on their own gave much lower yields. We find
in general that workup of the reactions involving SnCl4 is
complicated by formation of emulsions; we find that dilution
of the reaction mixture with dichloromethane followed by
filtration through Celite before the various washes are carried
out gives better yields and a more straightforward workup.
Although yields have not yet been optimized there are some
advantages: the lactone can be prepared in three steps in
35-40% overall yield from D-glucuronic acid without the
need for chromatographic separations at any stage and the
products from glycosylation could be extracted into aqueous
bicarbonate, which simplified their purification. Epimerisa-
tion of the â-O-glucuronide to the R-anomer is possible under
these conditions.27 However, the â-glycoside could not be
detected in the reaction mixtures in these two cases. We are
currently investigating alternative conditions and strategies
that may improve the recovery of product.
TMS-N3 this again gave 13 as the sole product. The â-azides
2 and 16 were exposed to the Lewis acid, and no significant
epimerization25 to the R-azide occurred, indicating that this
does not account for the observed stereoselectivity. These
results are consistent with the formation of intermediates 17
and 19/20 during the course of the reactions, which upon
further activation by the Lewis acid give the R-azide possibly
by an SN2 process. Intermediate 21 can similarly be used to
explain the formation of 14. Thus the stereoselectivity is
consistent with remote participation of the acid or amide
group; this is more important, under these conditions, than
participation of the acetate group at C-2.
(25) 1H NMR showed that <5% epimerization of the â-azide to the
R-azide had occurred after 15 h in CH2Cl2.
(26) Isolated yield after recrystallization.
(27) We found that 2,3,4-tri-O-acetyl-1-O-isopropyl-â-D-glucopyran-
uronic acid, methyl ester, prepared independently, gave significant amounts
of the R-anomer (∼50%) on treatment with SnCl4 in CH2Cl2 after 15 h.
The synthesis of 25 from 24 was carried out to illustrate
that this methodology could be useful in preparation of
Org. Lett., Vol. 4, No. 21, 2002
3677

molecules of biological interest; this molecule has structural
features similar to those found in sialidase inhibitors includ-
ing Kdn2en mimetics.28 Thus elimination of acetic acid and
concomitant introduction of an alkene between C-4 and C-5
was achieved by treatment of 24 with acetic anhydride and
pyridine for 72 h;29 this was followed by hydrolysis of the
anhydride and acetate protecting groups to give 25. Glucu-
ronic acid based mimetics of Kdn2en have been prepared
previously30 by von Itzstein and co-workers and have the
â-configuration; the chemistry described herein complements
this approach and facilitates the synthesis of the Kdn2en
mimetic 25, which has the R-configuration as a structural
probe for proteins that recognize sialic acid.
In summary, the synthesis of 1,2-cis-glucuronides31 can
be achieved even in the presence of 2-acyl participating
groups, and the stereoselectivity can be explained by
participation of remote acid or amide groups. The participa-
tion of remote groups might also account for the recent
observations by Hunt and Seeberger; they found that forma-
tion of ∼1:1 mixtures of R- and â-glycosides during some
solid-phase glycosylation reactions using a succinamyl linker
even in the presence of a 2-OPiv group.32 The results indicate
that this and related approaches may be worth investigating
more widely in synthesis of glycosides and for natural
products and other biologically interesting molecules with
similar structural features. We are currently exploring
synthesis of oligosaccharides and other glycosides where
participation of remote groups may influence stereoselectivity
and reactivity. Uronic acid donors have low reactivity in
carbohydrate chemistry, and their glycosylation reactions
often do not proceed efficiently.33 The possibility also exists
for enhancing or tuning the reactivity of these and other
donors using remote groups, and this is also being investi-
gated. The results of these studies and the solution structures
of amides 1 and related divalent compounds will be reported
in due course.
Acknowledgment. The authors thank Enterprise Ireland
(SC/00/182) and Dublin Corporation for financial support.
Supporting Information Available: 1H and 13C NMR
spectra of all compounds and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026629J
(28) (a) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason,
J. C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.;
Colman, P. M.; Varghese, J. N.; Ryan, D. M.; Woods, J. M.; Bethell, R.
C.; Hotham, V. J.; Cameron, J. M. Nature 1993, 363, 418. (b) Klefel, M.
J.; von Itzstein, M. Chem. ReV. 2002, 102, 471.
(29) Shorter reaction times lead to the recovery of 24.
(30) Florio, P.; Thomson, R. J.; von Itzstein, M. Carbohydr. Res. 2000,
328, 445.
(31) For some recently developed methods employing cyclic carbonates
and oxazolidinones for 1, 2-cis-glycoside synthesis, see: (a) Zhu, T.; Boons,
G.-J. Org. Lett. 2001, 3, 4201. (b) Benakli, K.; Zha, C.; Kerns, R. J. J. Am.
Chem. Soc. 2001, 123, 9461.
(32) Hunt, D. K.; Seeberger, P. H. Org. Lett. 2002, 4, 2751.
(33) Stachulski, A. V.; Jenkins, G. N. Nat. Prod. Rep. 1998, 15, 173.
3678
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