Synthesis of 2-C-branched oligo(glyco-amino acid)s (OGAAs) by ring opening of 1,2-cvclopropanecarboxylated sugar donors

Article abstract of DOI:10.1002/chem.200901022

A study was conducted to demonstrate the N-idosuccinimide (NIS)-mediated ring opening of 1,2-cyclopropanecarboxylated glycosyl donors with carbohydrate O-nucleophilic glycosyl bond acceptors. The study used 1,5-anhydro-2,6-dideoxy- 1,2-C-(exo-carbomethoxy

Full text of DOI:10.1002/chem.200901022

DOI: 10.1002/chem.200901022
Synthesis of 2-C-Branched Oligo(glyco–amino acid)s (OGAAs) by Ring
Opening of 1,2-Cyclopropanecarboxylated Sugar Donors
Perali Ramu Sridhar,* Patteti Venu Kumar, Kalapati Seshadri, and Rayala Satyavathi[a]
Dedicated to Professor S. Chandrasekaran
Carbohydrates decorated with amino acids are becoming
an important area of glyco-chemistry research.[1] Possessing
the architecture of a sugar and an amino acid in a single
molecule, these glyco–amino acids (GAAs)[2] are expected
to exhibit the characteristics of both carbohydrates and
amino acids, which are both biological polymer precursors.
C-branched glyco–a-amino acid moieties are found in a
developed for the direct synthesis of 2-C-branched carbohy-
drate derivatives from glucals.[7a,12] These branched glyco-
sides were further derivatised to bicyclic carbohydrate 1,2-
lactones.[13] Glucal-derived donor–acceptor cyclopropanes
have also been used as 1,3-dipoles under acidic conditions,
which result in (3+2) cycloaddition reactions in presence of
dipolarophiles.[14] By using the ability of 1,2-cyclopropane-
carboxylated sugars to undergo electrophilic ring opening
assisted by the adjacent oxygen in presence of an electro-
phile,[15] we herein present the N-iodosuccinimide (NIS)-
mediated ring opening of 1,2-cyclopropanecarboxylated gly-
cosyl donors with carbohydrate O-nucleophilic glycosyl
bond acceptors.
ACHTUNGTRENNUNG
variety of nucleoside antibiotics, such as polyoxins,[3] mihara-
mycins,[4] nikkomycin[5] and amipuramycin.[6] Very few meth-
ods are available in the literature for the synthesis of mono-
saccharide-derived C-branched GAA derivatives.[7] Linking
À
an a-amino acid at C-2 or C-4 through a C C bond has
been found to be very difficult. For this reason, the biologi-
cal importance of these GAAs is not yet fully understood. It
has been shown that unnatural 2-C-acetonylsugars serve as
metabolic substrates for cell surface engineering by mimick-
To achieve this novel glycosylation reaction, we began by
using
1,5-anhydro-2,6-dideoxy-1,2-C-(exo-carbomethoxy-
methylene)-3,4-di-O-benzyl-a-l-rhamnal 1[7b] as the donor
and 1,2-3,4-diisopropylidine-a-d-galactose 2 as the acceptor
with NIS as the electrophile at 08C in acetonitrile. However,
no expected disaccharide was observed under these reaction
conditions, even with an excess of acceptor 2 (>3 equiv).
Similar reaction conditions with dichloromethane as the
ing 2-N-acetylsugars.[8] Similarly, a 2-C-N-hydroxy
ACTHUNTGRENNGaU cetamide
mimic of GlcNAc was synthesised and shown to be an inhib-
itor of the biosynthesis of lipid A.[9] Herein, we report the
first stereoselective synthesis of 2-C-branched oligo(glyco–
amino acid)s (OGAAs) by ring opening of 1,2-cyclopropa-
necarboxylated sugar donors.
The high reactivity and regioselectivity of donor–acceptor
cyclopropanes has been well documented in the literature.[10]
1,2-cyclopropanecarboxylated sugars have been used as
donor–acceptor cyclopropanes in the synthesis of 2-C-
branched monosaccharides through electrophilic C1–C7
ACHTUNGTRENNUNGcyclopropane ring opening or by transition-metal-catalysed
glycosylation.[11] Recently, a four-component Pavarov reac-
tion and a transition-metal-mediated radical reaction were
[a] Dr. P. R. Sridhar, P. V. Kumar, K. Seshadri, R. Satyavathi
School of Chemistry
University of Hyderabad
Hyderabad, 500 046 (India)
Fax : (+91)040-23012460
E-mail: prssc@uohyd.ernet.in
Scheme 1. Synthesis of 2-C-branched GAA disaccharides. i) NIS,
TMSOTf, CH2Cl2, 08C–RT, 74% yield; ii) NaN3, DMF, 96% yield;
iii) Ph3P, THF; iv) H2O, reflux, 91% yield.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901022.
7526
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7526 – 7529

COMMUNICATION
ACHTUNGTRENNUNGsolvent did not improve the gly-
cosylation reaction. We then
looked for promoters and after
several attempts found that tri-
methylsilyl trifluoromethanesul-
fonate (TMSOTf; 15 mol%) is
the best promoter for this gly-
cosylation reaction.[16] Treat-
ment of 1 and 2 with NIS/
TMSOTf in dichloromethane
(0–288C, 8 h) afforded 2’-C-
Scheme 2. Proposed mechanism for the NIS-mediated ring opening of 1,2-cyclopropanecarboxylated sugar de-
rivatives.
branched disaccharide
3
in
74% yield as a single diastereo-
mer[17] in which two new stereo-
centers were introduced at C1’
and C7’ in a single reaction. It
is worth noting that only
1.1 equivalents of acceptor,
with respect to the donor, were
used for this glycosylation reac-
tion. Substitution of a-iodocar-
Table 1. Ring opening of 1,2-cyclopropanecarboxylated carbohydrate donors with sugar acceptors; synthesis
of 2-C-branched GAA disaccharides.
Entry
Donor cyclopro-
pane
Acceptor
Iodide
([%])
Azide
([%])
GAA derivative
Yield[a]
[%]
boxylate
3 with NaN3/DMF
(288C, 24 h; DMF=N,N-dime-
thylformamide) afforded azido-
carboxylate 4 in 96% yield. Re-
duction of the azide under
Staudinger reaction conditions
(Ph3P/THF/H2O) produced dis-
accharide GAA derivative 5 in
91% isolated yield (Scheme 1).
The proposed mechanism of
NIS-mediated ring opening in-
1
7 (75)
8 (95)
92
90
2
3
11 (72)
12 (96)
2
15 (72)
16 (92)
89
volves
a stereospecific “edge
attack” of iodine on 1,2-cyclo-
propanecarboxylate 1 to gener-
ate an oxocarbenium ion that is
immediately trapped with tri-
flate. The triflate is released by
neighbouring-group participa-
tion of the C7-carboxylate to
generate a second oxocarbeni-
um ion intermediate, which is
sufficiently long lived that it
can be intercepted with a nucle-
ophile. Nucleophilic attack by a
glycosyl acceptor oxygen at the
anomeric carbon gives disac-
charide product 3 (Scheme 2).
The generality of this method
has been proved by successfully
applying it to a number of 1,2-
20 (95)
4
5
6
14
1
19 (70)
24 (67)
28 (63)
85
94
92
21[b] (98)
26 (92)
25[c] (96)
10
23
29 (90)
33 (93)
7
8
9
1
32 (70)
36 (69)
39 (65)
97
90
88
34[d] (97)
10
14
31
31
37 (92)
40 (88)
cyclopropanated
glycosyl
donors and differentially pro-
tected sugar acceptors. Thus,
the reaction of cyclopropane-
carboxylates 1, 10 and 14 with
[a] Yield of GAA derivative. Only b-glycosides were formed, and no trace of a product was observed. [b] The
free hydroxyl group of azide 20 was acetylated. [c] The free hydroxyl group of iodide 24 was acetylated.
acceptors 6 and 2 gave the ring- [d] The free hydroxyl group of azide 33 was acetylated.
Chem. Eur. J. 2009, 15, 7526 – 7529
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7527

P. R. Sridhar et al.
opened 2-C-branched GAA disaccharide derivatives 9, 13
and 17, respectively, in good yields with very high diastereo-
selectivity at the newly formed C1’ and C7’ stereocenters
(Table 1, entries 1, 2 and 3). The stereochemistry at C1’ was
confirmed by observing
a large coupling constant (J
ꢀ8.8 Hz) for the C1’ proton, which indicates a 1,2-trans con-
figuration for all the ring-opened disaccharide derivatives.
The stereochemistry at C2’ was defined on the basis of the
stereochemistry present in the 1,2-cyclopropanecarboxylated
sugar precursor. The stereochemistry at C7’ was assigned
based on the proposed mechanism and on one of the GAA
derivative crystal structures we reported previously.[7b]
Our next investigations focused on regioselective glycosyl-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
O-benzyl-a-d-glucopyranoside 18 in the presence of NIS/
TMSOTf in dichloromethane at 08C. The reaction produced
a single product, 19, that was converted to azide 20. The re-
gioselectivity at the 6-O position was assigned by acetylating
the free hydroxyl group in 20 with Ac2O/pyridine and ob-
serving a downfield shift in the signal of the C4 proton in
acetylated disaccharide 21. Similarly, reactivity-based glyco-
sylation of 1,2-cyclopropanecarboxylates 1 and 10 with
methyl-4,6-O-benzylidine-a-d-glucopyranoside 23 produced
the 2-C-branched disaccharide derivatives 24 and 28, respec-
Scheme 3. Synthesis of 2-C-branched OGAA derivatives. i) p-TsOH·H2O,
MeOH, 92% yield; ii) 1, NIS, TMSOTf, CH2Cl2, 08C–RT, 62% yield;
iii) NaN3, DMF, 85% yield; iv) Ac2O, pyridine, 93% yield; v) Ph3P, THF;
vi) H2O, reflux, 80% yield.
À
tively, in good yield. Interestingly, C3 OH was involved in
the glycosylation step of these reactions.[18]
The aforementioned acceptor-reactivity-based glycosyl-
ACHTUNGTRENNUNGation of 1,2-cyclopropanecarboxylated sugar donors could
edge, this method is the first report of the use of 1,2-cyclo-
propanecarboxylated sugars in traditional oligosaccharide
synthesis. The novel glycosidation method was successfully
applied to the synthesis of a number of 2-C-branched GAA
disaccharides and to the preparation of an OGAA deriva-
tive. Mimicking natural glycosides with carbon-branched
GAAs and determining the biological importance of these
hybrid biomolecules are in progress.
also be extended to the other sugar derivatives. Thus, treat-
ment of cyclopropanecarboxylated donors 1, 10 and 14 with
methyl-2,6-di-O-benzyl-b-d-galactopyranoside 31 gave disac-
charide derivatives 32, 36 and 39, respectively, in good
yields. All the disaccharide a-iodocarboxylates (24, 28, 32,
36 and 39) were converted to the corresponding azides (26,
29, 33, 37 and 40, respectively) by using NaN3/DMF to give
excellent yields (ꢀ90%). All these azides were further con-
verted to the corresponding 2-C-branched GAA derivatives
27, 30, 35, 38 and 41, respectively, under Staudinger reaction
conditions (Table 1, entries 5, 6, 7, 8, and 9).
Keeping the above-mentioned acceptor-reactivity-based
regio- and stereoselective glycosylation of 1,2-cyclopropane-
carboxylated sugar donors in mind, we further planned to
synthesise an OGAA derivative. Towards this goal, the ben-
zylidine protecting group in a-iodocarboxylate 24 was de-
protected by using p-TsOH·H2O/MeOH to give disaccharide
triol 42. A second acceptor-reactivity-based glycosylation
was performed by treating 1 with triol 42 in presence of
NIS/TMSOTf to give trisaccharide 43 in good yield as the
only isolated product. Treatment of 43 with NaN3/DMF
gave diazide 44. The free hydroxyls were acetylated to give
compound 45, which gave OGAA derivative 46 under Stau-
dinger reaction conditions (Scheme 3).
Experimental Section
General procedure for the glycosylation of 1,2-cyclopropanecarboxylated
sugar donors: N-iodosuccinimide (0.55 mmol) and trimethylsilyl trifluoro-
methane sulfonate (0.01 mmol) were added to a stirred suspension of 1,2-
cyclopropanecarboxylated sugar derivative (0.50 mmol), glycosyl acceptor
(0.55 mmol), and a 4-ꢁ molecular sieve in dichloromethane (5 mL) at
08C under a nitrogen atmosphere. The temperature was slowly raised to
258C and the mixture was stirred for 6 h (until reaction completion, as
determined by using TLC). The reaction mixture was diluted with di-
chloromethane, filtered and washed with aqueous sodium thiosulfate
(5%), then the organic layer was dried over anhydrous sodium sulphate
and concentrated under vacuum. Column chromatography of the crude
product with ethyl acetate/hexane afforded the pure glycosidation prod-
uct.
Acknowledgements
In summary, a new glycosylation method that uses carbo-
hydrate-derived donor–acceptor cyclopropanes as glycosyl
acceptors has been developed. To the best of our knowl-
This work was supported by the Department of Science and Technology
(DST) FAST track project grant.
7528
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7526 – 7529

2-C-Branched Oligo(Glyco–Amino Acid)s
COMMUNICATION
275, 11002; b) X. Li, T. Uchiyama, C. R. H. Raetz, O. Hindsgaul,
Org. Lett. 2003, 5, 539.
Keywords: carbohydrates · donor–acceptor systems · glyco–
amino acids · glycosylation · oligosaccharides
[10] For a recent review on sugar-derived substrates, see: a) M. Yu, B. L.
Pagenkopf, Tetrahedron 2005, 61, 321; for leading reviews, see:
b) H. U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151; c) H. U.
Reissig, Top. Curr. Chem. 1988, 144, 73; d) E. Wenkert, Acc. Chem.
Res. 1980, 13, 27.
[11] a) J. Beyer, R. Madsen, J. Am. Chem. Soc. 1998, 120, 12137; b) J.
Beyer, P. R. Skaanderup, R. Madsen, J. Am. Chem. Soc. 2000, 122,
9575.
[12] a) T. Linker, K. Hartmann, T. Sommermann, D. Scheutzow, E.
Ruckdeschel, Angew. Chem. 1996, 108, 1819; Angew. Chem. Int. Ed.
Engl. 1996, 35, 1730; b) T. Linker, T. Sommermann, F. Kahlenberg,
J. Am. Chem. Soc. 1997, 119, 9377.
[1] For recent reviews, see: a) F. Schweizer, Angew. Chem. 2002, 114,
240; Angew. Chem. Int. Ed. 2002, 41, 230; b) S. A. W. Gruner, E. Lo-
cardi, E. Lohof, H. Kessler, Chem. Rev. 2002, 102, 491; c) A. Dondo-
ni, A. Marra, Chem. Rev. 2000, 100, 4395. For a compendium of
sugar–amino acids, see: M. D. P. Risseeuw, M. Overhand, G. W. J.
Fleet, M. I. Simone, Tetrahedron: Asymmetry 2007, 18, 2001.
[2] A glyco–amino acid (GAA) is a saccharide attached to a single
amino acid by any kind of covalent bond, see: J. P. McDevitt, P. T.
Lansbury, Jr., J. Am. Chem. Soc. 1996, 118, 3818.
[3] a) A. Rosenthal, K. Shudo, J. Org. Chem. 1972, 37, 4391; b) T. Goto,
Y. Toya, T. Ohgi, T. Kondo, Tetrahedron Lett. 1982, 23, 1271; c) S.
Haranda, T. Kishi, J. Antibiot. 1977, 30, 11; d) P. Garner, J. M. Park,
J. Org. Chem. 1990, 55, 3772.
[4] H. Seto, M. Koyama, H. Ogino, T. Tsuruoka, Tetrahedron Lett. 1983,
24, 1805.
[13] J. Yin, T. Linker, Chem. Eur. J. 2009, 15, 49.
[14] a) M. Yu, B. L. Pagenkopf, J. Am. Chem. Soc. 2003, 125, 8122; b) M.
Yu, B. L. Pagenkopf, Org. Lett. 2003, 5, 5099.
[15] a) C. V. Ramana, R. Murali, M. Nagarajan, J. Org. Chem. 1997, 62,
7694, and references therein; b) C. Kim, T. Brady, S. H. Kim, E. A.
Theodarakis, Synth. Commun. 2004, 34, 1951.
[5] C. S. Stauffer, P. Bhaket, A. W. Fothergill, M. G. Rinaldi, A. Datta,
J. Org. Chem. 2007, 72, 9991.
[6] G. Casiraghi, L. Colombo, G. Rassu, P. Spanu, J. Org. Chem. 1991,
56, 6523.
[7] a) O. Jimꢂnez, G. de La Rosa, R. Lavilla, Angew. Chem. 2005, 117,
6679; Angew. Chem. Int. Ed. 2005, 44, 6521; b) P. R. Sridhar, K. C.
Ashalu, S. Chandrasekaran, Org. Lett. 2004, 6, 1777.
[16] TMSOTf has been used as an activator in various reactions of
donor–acceptor cyclopropanes.
1
[17] Based on the H and 13C NMR spectra.
[18] The site of reactivity was found by acetylating the free hydroxyl
group in disaccharide 24 and observing a downfield shift in the
signal of the C2 proton in compound 25. Please see the Supporting
Information.
[8] H. C. Hang, C. R. Bertozzi, J. Am. Chem. Soc. 2001, 123, 1242.
[9] a) J. E. Jackman, C. A. Fierke, L. N. Tumey, M. Pirrung, T. Uchiya-
ma, S. H. Tahir, O. Hindsgaul, C. R. H. Raetz, J. Biol. Chem. 2000,
Received: April 17, 2009
Published online: July 8, 2009
Chem. Eur. J. 2009, 15, 7526 – 7529
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7529