A one-step synthesis of azide-tagged carbohydrates: Versatile intermediates for glycotechnology

Article abstract of DOI:10.1055/s-2006-926264

Herein we describe a simple and practical methodology for accessing both the α-anomers (D-mannose, N-acetyl-D-glucosamine, N-acetyl-D- galactosamine, D-lactose) and α- and β-anomers (D-glucose, D-galactose, L-fucose) of 2′-azidoethyl and azidotriethylene glycol glycosides using free sugars and Dowex 50 (resin) as an efficient catalyst. These azidoalkyl glycosides are increasingly useful synthetic intermediates for glycotechnology. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926264

LETTER
455
A One-Step Synthesis of Azide-Tagged Carbohydrates: Versatile
Intermediates for Glycotechnology
O
ne-Ste
p
Synthesi
d
s
of
A
zide-T
i
agged C
t
arboh
y
ydrate
s
a K. Sanki, Lara K. Mahal*
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station, A5300, Austin, TX 78712-0165, USA
Fax +1(512)4718696; E-mail: lmahal@cm.utexas.edu
Received 22 November 2005
corresponding 2¢-azidoethyl glycoside, using BF3·OEt2 as
Abstract: Herein we describe a simple and practical methodology
the catalyst.7b However, purification of the product in this
report was laborious. There is no general, and simple
methodology in the literature for the synthesis of an array
for accessing both the a-anomers (D-mannose, N-acetyl-D-glu-
cosamine, N-acetyl-D-galactosamine, D-lactose) and a- and b-ano-
mers (D-glucose, D-galactose, L-fucose) of 2¢-azidoethyl and
azidotriethylene glycol glycosides using free sugars and Dowex 50 of azidoalkyl glycosides in a single reaction.
(resin) as an efficient catalyst. These azidoalkyl glycosides are in-
Herein we report a simple, one-step reaction for the
creasingly useful synthetic intermediates for glycotechnology.
synthesis of azidoalkyl glycosides using resin-catalyzed
Key words: azidoethyl glycosides, azidotriethylene glycol glyco-
glycosylation. Resin-catalyzed glycosylation has been
sides, glycotechnology, resin-catalyzed glycosylation
known in the literature for decades, though its use has
mostly been limited to the preparation of methyl glyco-
sides.11 We found no examples where resin-catalyzed gly-
Azidoalkyl glycosides have become synthetic intermedi-
cosylation was used as a methodology for the synthesis of
ates of increased importance due in part to the recent dis-
covery of chemoselective ligation reactions utilizing alkyl
2¢-azidoethyl or azidotriethylene glycol glycosides. It is a
convenient method for glycoside synthesis, as the catalyst
azides as a reaction partner, including the ‘Staudinger li-
is stable to hydrolysis, unlike most glycosylation cata-
gation’1 and ‘Click’ chemistry (also known as the copper-
lysts, and is easily removed by filtration. Our results on
catalyzed Huisgen reaction).2 This chemistry has been ex-
the resin-catalyzed glycosylation of 2-azidoethanol and
ploited for the generation of carbohydrate arrays,3
azidotriethylene glycol with a selected set of biologically
glycodendrimers4 and defined glycoproteins.5 In addition,
important free sugars are detailed below.
the aminoalkyl glycosides, which are typically derived
We began our initial study with a panel of commercially
from the corresponding azidoalkyl glycosides, have seen
available and biologically relevant sugars including D-
widespread use in the areas of a) synthesis of neoglyco-
glucose (I), D-mannose (II), D-galactose (III), N-acetyl-
D-galactosamine (V), L-fucose (VI) and the a-isomers of
N-acetyl-D-glucosamine (IV), and D-lactose (VII) as the
starting materials (Figure 1).
conjugates, glycopolymers, and glycodendrimers,6 b)
modification and synthesis of glycolipids, glyco-
sphingolipids, oligosaccharides and polysaccharides,7 c)
spacer-arm photoaffinity glycosides, cluster glycosides,
multivalent carbohydrate ligands, calixarene scaffolds
(protein binding carbohydrates), and supramolecular
gelators8 and most recently d) in the generation of carbo-
hydrate microarrays.9
OH
OH
OH
OH
HO
HO
O
O
O
HO
HO
OH
OH
OH
HO
HO
OH
OH
A review of the literature shows that the most common
methods for the synthesis of azidoalkyl glycosides in-
volve reaction of an activated sugar donor (peracetates,
glycosyl halides or trichloroacetimidates) with an alcohol/
glycol bearing a leaving group (halogen or tosyl) followed
by displacement of the latter by the azide anion to yield
the azidoalkyl glycoside.10 The typical synthesis of each
azidoalkyl sugar derivative is thus lengthy, requiring four
to five steps including protection of the hydroxyls, activa-
tion of the sugar, glycosylation with the alcohol, displace-
ment of the leaving group by the azide and deprotection.
Typical overall yields for these reaction sequences range
from 27–55%. We have found only a single report in the
literature of a one-step conversion of a free sugar to the
I
II
III
OH
O
OH
OH
O
HO
HO
HO
OH
AcHN
IV
NHAc
OH
V
OH
OH
OH
OH
OH
O
O
O
O
HO
HO
OH
OH
OH
OH
OH
VI
VII
Figure 1 Panel of sugars for resin-catalyzed glycosylation
SYNLETT 2006, No. 3, pp 0455–0459
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926264; Art ID: S11605ST
© Georg Thieme Verlag Stuttgart · New York

456
A. K. Sanki, L. K. Mahal
LETTER
In general, the reaction was carried out by mixing the free Polyethylene glycol linkers are widely known to prevent
sugar with anhydrous Dowex 50 (120 mg/mmol of sub- protein absorption and are often used to link biologically
strate) in neat 2-azidoethanol or azidotriethylene glycol (4 relevant molecules.13 We therefore examined the reaction
mL/mmol) at temperatures ranging from 80–90 °C of 2-[2-(2-azidoethoxy)ethoxy]ethanol (azidotriethylene
(Scheme 1). The results are summarized in Table 1.
glycol) with the sugar panel shown in Figure 1. The ano-
meric mixtures observed for the sugars under consider-
ation were similar to those previously described for the 2¢-
azidoethyl glycosides with a single exception, N-acetyl-D-
galactosamine (V), which yielded a mixture of isomers 12
[30%, a:b (2.4:1), Table 2], of which only the a-isomer
12a16 (21%) could be separated in pure form via column
chromatography. D-Mannose (II), N-acetyl-a-D-glu-
cosamine (IV) and a-D-lactose (VII) produced only the a-
isomers 9 (54%),14 11 (30%) and 14 (60%), respectively
(Table 2). D-Glucose (I), D-galactose (III) and L-fucose
(VI) yielded mixtures of a- and b-isomers 8 (53%,
a:b = 2:1), 10 (44%, a:b = 3:1) and 13 (51%, a:b = 2:1),
respectively, based on 1H NMR (Table 2).17
Yields ranged from 33–56%, which were comparable to
or better than yields obtained using the previously de-
scribed multi-step methodology.10 D-Mannose (II), N-
acetyl-a-D-glucosamine (IV), N-acetyl-D-galactosamine
(V), and a-D-lactose (VII) afforded single isomers (a) 2,
4, 5 and 7 in 49%, 45%, 40% and 56% yields, respective-
ly, as the sole products, whereas D-glucose (I), D-galac-
tose (III) and L-fucose (VI) generated a mixture of
anomers 1 (46%, a:b = 2.6:1), 3 (33%, a:b = 2:1) and 6
(51%, a:b = 2:1) based on 1H NMR (Table 1).
2-azidoethanol or
azidotriethylene glycol
O
O
/Dowex 50
R
N3
R
Compounds 8, 10, 11, 12, 13 and 14 were colorless gums
and unknown in the literature. Single compounds 11, 12
and 14 were characterized as the unprotected
carbohydrates16,17 whereas the anomeric mixtures of 8, 10
and 13 were characterized as their corresponding per-
acetylated derivatives 18 (98%), 19 (97%) and 20
(96%).15,16 Initial yields obtained with N-acetyl-a-D-glu-
cosamine (IV) and a-D-lactose (VII) were low (14% and
OH
O
80–90 °C
n
sugars (I–VII)
2′-azidoethyl glycosides (1–7), n = 1 or,
2-[2-(2-azidoethoxy)ethoxy]ethyl
glycosides (8–14), n = 3
Scheme 1 Resin-catalyzed glycosylation of 2-azidoethanol and
azidotriethylene glycol
Compounds 1,6d,7e 2,7c,e 3b,6d,7e 4,6e 5,7b,e and 6a,7e have 35%, respectively). We believe that this was due to their
previously been characterized. Compounds 7, 3a [1H poor solubility in azidotriethylene glycol as discussed
NMR (DMSO-d6 + D2O): d = 4.67 (1 H, d, J = 3.3 Hz, H- below.
1)] and 6b [1H NMR (DMSO-d6 + D2O): d = 4.09 (1 H, d,
In most cases, the reactions did not go to completion at the
glycosylation stage and a portion of starting material re-
mained unreacted. No significant by-products were ob-
served as analyzed by thin-layer chromatography. It was
J = 7.5 Hz, H-1)] were unknown in the literature. Com-
pound 7 was characterized as its amino derivative (7a)12
after reduction via hydrogenation (Scheme 2). As might
be expected, the a/b-mixtures of 1, 3 and 6 were not sep-
initially thought that the starting material contained mois-
arable by flash chromatography. Therefore they were sep-
ture, causing the reaction not to proceed to completion,
arated after conversion to their corresponding
however, drying the starting material, using increasing
peracetylated derivatives in good yields 15 (97%), 16
amounts of catalyst (resin), an increased excess of 2-azi-
doethanol, and prolonged reaction times did not signifi-
(95%) and 17 (95%, Scheme 2).15,16
cantly increase glycoside formation. Furthermore,
increasing the temperature did not aid product formation.
Most glycotechnology applications are biological in ori-
gin, thus the prevention of non-specific binding by pro-
teins to the synthesized epitope is often desired. Instead, we observed destruction of the resin with
Table 1 2¢-Azidoethyl Glycosides
Table 2 2-[2-(2-Azidoethoxy)ethoxy]ethyl Glycosides
Starting sugars
D-Glucose (I)
Products Time (h) Ratio (a:b) Yield (%)
Starting sugars
D-Glucose (I)
Product
Time (h) Ratio (a:b) Yield (%)
1
2
3
4
2–3
2–3
2–3
2–3
2.6:1
a
46
49
33
45
8
9
1.5
3
2:1
a
53
54
44
30
D-Mannose (II)
D-Galactose (III)
D-Mannose (II)
D-Galactose (III)
2:1
a
10
11
2
3:1
a
N-Acetyl-a-D-
glucosamine (IV)
N-Acetyl-a-D-
glucosamine (IV)
1.5
N-Acetyl-D-
galactosamine (V)
5
2–3
a
40
N-Acetyl-D-
galactosamine (V)
12
4
2.4:1
30
L-Fucose (VI)
6
7
2–3
2–3
2:1
51
56
L-Fucose (VI)
13
14
2
2
2:1
51
60
a-D-Lactose (VII)
a
a-D-Lactose (VII)
a
Synlett 2006, No. 3, 455–459 © Thieme Stuttgart · New York

LETTER
One-Step Synthesis of Azide-Tagged Carbohydrates
457
A.
O
O
N3
R
NH2
R
a
O
O
n
n
azidoalkyl glycoside
R = OH, n = 1, 3
aminoalkyl glycoside
R = OH, n = 1, 3
B.
O
O
b
N3
N3
R
R
O
O
n
n
azidoalkyl glycoside, R = OH, n = 1, 3
peracetylated azidoalkyl glycoside,
R = OAc, n = 1, 3
Scheme 2 Hydrogenation and acetylation of azidoalkyl glycosides. Reagents and conditions: a) Pd/C, H2, MeOH, 12 h, quant.; b) Ac2O,
pyridine, DMAP, r.t., 2–12 h, for n = 1, 15 = 97%, 16 = 95%, 17 = 95%; for n = 3, 18 = 98%, 19 = 97%, and 20 = 96%.
(3) (a) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong,
C. H. J. Am. Chem. Soc. 2002, 124, 14397. (b) Huang, G.-
L.; Liu, T.-C.; Liu, M.-X.; Mei, X.-Y. Anal. Biochem. 2005,
340, 52. (c) Feizi, T.; Fazio, F.; Chai, W. C.; Wong, C. H.
Curr. Opin. Struct. Biol. 2003, 13, 637.
(4) Joosten, J. A. F.; Tholen, N. T. H.; Maate, F. A. E.; Brouwer,
A. J.; Wilma van Esse, G.; Rijkers, D. T. S.; Liskamp, R. M.
J.; Pieters, R. J. Eur. J. Org. Chem. 2005, 3182.
prolonged stirring at high temperatures (above 100 °C).
Attempts to pull water out of the reaction mixture using
vacuum distillation resulted in the loss of 2-azidoethanol.
A significant improvement in yield was obtained for the
glycosylation of N-acetyl-a-D-glucosamine (IV) and a-D-
lactose (VII) with azidotriethylene glycol by the addition
of anhydrous DMSO as a co-solvent (30% and 60%,
compared to 14% and 35%, respectively). With both
nucleophiles (2-azidoethanol and azidotriethylene glycol)
the anomeric ratio (a/b) varies from 100% a to 2:1 a:b.
Results from these glycosylation reactions are consistent
with both the existing data on methyl glycosides11 and
with theoretical predictions that the most thermodynami-
cally stable compounds (a-isomers) will be formed
preferentially.
(5) Grandjean, C.; Boutonnier, A.; Guerreiro, C.; Fournier, J.-
M.; Mulard, L. A. J. Org. Chem. 2005, 70, 7123.
(6) (a) Chernyak, A.; Sharma, G. V. M.; Kononov, L. O.;
Krishna, P. R.; Levinsky, A. B.; Kochetkov, N. K.
Carbohydr. Res. 1992, 223, 303. (b) Chernyak, A.;
Oscarson, S.; Turek, D. Carbohydr. Res. 2000, 329, 309.
(c) Sallas, F.; Nishimura, S. I. J. Chem. Soc., Perkin Trans.
1 2000, 2091. (d) Susaki, H.; Suzuki, K.; Ikeda, M.;
Yamada, H.; Watanabe, H. K. Chem. Pharm. Bull. 1994, 42,
2090. (e) Roy, R.; Kim, J. M. Tetrahedron 2003, 59, 3881.
(f) Roy, R.; Kim, J. M. Angew. Chem. Int. Ed. 1999, 38, 369.
(g) Sun, X. L.; Faucher, K. M.; Houston, M.; Grande, D.;
Chaikof, E. L. J. Am. Chem. Soc. 2002, 124, 7258.
(7) (a) Lee, K. J.; Mao, S. L.; Sun, C. Z.; Gao, C. S.; Blixt, O.;
Arrues, S.; Hom, L. G.; Kaufmann, G. F.; Hoffman, T. Z.;
Coyle, A. R.; Paulson, J.; Felding-Habermann, B.; Janda, K.
D. J. Am. Chem. Soc. 2002, 124, 12439. (b) Blixt, O.; Allin,
K.; Pereira, L.; Datta, A.; Paulson, J. C. J. Am. Chem. Soc.
2002, 124, 5739. (c) Alpe, M.; Oscarson, S.; Svahnberg, P.
J. Carbohydr. Chem. 2003, 22, 565. (d)Amvamzollo, P. H.;
Sinay, P. Carbohydr. Res. 1986, 150, 199. (e) Ni, J. H.;
Singh, S.; Wang, L.-X. Bioconjugate Chem. 2003, 14, 232.
(f) Hasegawa, A.; Terada, T.; Ogawa, H.; Kiso, M. J.
Carbohydr. Chem. 1992, 11, 319.
Herein we present a simple synthesis of 2¢-azidoethyl and
azidotriethylene glycol glycosides of both mono and di-
saccharides using resin-catalyzed glycosylation. Al-
though the panel presented here is a simplified one, it can
be extended to the synthesis of more complicated glycans.
For example, the glycosides formed can serve as scaffolds
for chemoenzymatic synthesis of diverse epitopes. Recent
developments in the use of azidoalkyl glycosides to create
tools for glycotechnology highlight the importance of
facile and practical methodologies for the synthesis of this
compound class.
(8) (a) Lindhorst, T. K.; Kotter, S.; Krallmann-Wenzel, U.;
Ehlers, S. J. Chem. Soc., Perkin Trans. 1 2001, 823.
(b) Pathak, A. K.; Pathak, V.; Riordan, J. M.; Gurcha, S. S.;
Besra, G. S.; Reynolds, R. C. Carbohydr. Res. 2004, 339,
683. (c) Kleinert, M.; Rockendorf, N.; Lindhorst, T. K. Eur.
J. Org. Chem. 2004, 3931. (d) Patel, A.; Lindhorst, T. K.
Eur. J. Org. Chem. 2002, 79. (e) Kiyonaka, S.; Shinkai, S.;
Hamachi, H. Chem. Eur. J. 2003, 9, 976.
Acknowledgment
The authors would like to thank Professor Philip D. Magnus for
reviewing the manuscript and the Arnold and Mabel Beckman
Foundation for financial support.
References and Notes
(9) (a) Disney, M. D.; Seeberger, P. H. Chem. Biol. 2004, 11,
1701. (b) Khan, I.; Desai, D. V.; Kumar, A. J. Biosci.
Bioeng. 2004, 98, 331.
(10) (a) See ref. 6e,f, 7e, 8a,d, and 9a. (b) Ballell, L.; Alink, K.
J.; Slijper, M.; Versluis, C.; Liskamp, R. M.; Pieters, R. J.
ChemBioChem 2005, 6, 291; and references cited therein.
(c) Tagmose, T. M.; Bols, M. Chem. Eur. J. 1997, 3, 453;
and references cited therein.
(1) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000,
2, 2141.
(2) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Bräse, S.; Gil, C.; Knepper, K.;
Zimmermann, V. Angew. Chem. Int. Ed. 2005, 44, 5188.
Synlett 2006, No. 3, 455–459 © Thieme Stuttgart · New York

458
A. K. Sanki, L. K. Mahal
LETTER
(11) Cadotte, J. E.; Smith, F.; Spriestersbach, D. J. Am. Chem.
Soc. 1952, 74, 1501.
2-[2-(2-Azidoethoxy)ethoxy]ethyl-2,3,4,6-tetra-O-acetyl-
a-D-glucoside (18a) and 2-[2-(2-Azidoethoxy)ethoxy]eth-
yl-2,3,4,6-tetra-O-acetyl-b-D-glucoside (18b).
(12) Procedure for the Reduction of Azidoalkyl Glycosides.
To a well-stirred solution of the azidoalkyl glycoside in
MeOH (4 mL/mmol) was added Pd/C (40 mg/mmol) and a
balloon of H2 (g). The reaction mixture was monitored for 12
h. After completion of the reaction (TLC), the mixture was
filtered through Celite® and the filtrate was concentrated to
dryness to give the title compound quantitatively.
2¢-Aminoethyl-a-D-lactoside(7a): yield: 100%; a yellow
fluffy material (hygroscopic). IR (KBr plate): 3370 (br, OH
+ NH2) cm–1. 1H NMR (300 MHz, DMSO-d6 + D2O): d =
4.65 (1 H, d, J = 3.9 Hz, H-1), 4.12 (1 H, d, J = 8.1 Hz, H-
1¢), 4.09 (1 H, d, J = 7.5 Hz), 3.71–3.30 (10 H, m), 3.23–2.96
(3 H, m), 2.67 (2 H, m). HRMS (EI): m/z calcd for
C14H28NO11 [M + H]+: 386.1662; found: 386.1662.
(13) Hermanson, G. T. Bioconjugate Techniques; Academic
Press: San Diego, 1996.
Compound 18a: a colorless gum. IR (CHCl3): 2109 (N3),
1750 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 5.43 (1
H, t, J = 10.2 Hz), 5.08 (1 H, d, J = 3.6 Hz, H-1), 5.01 (1 H,
t, J = 10.2 Hz), 4.81 (1 H, dd, J = 3.6, 10.2 Hz), 4.21 (1 H,
dd, J = 3.9, 12.0 Hz), 4.06 (2 H, m), 3.74 (1 H, m), 3.62 (9
H, m), 3.35 (2 H, t, J = 5.4 Hz), 2.03 (3 H, s, CH3), 2.01 (3
H, s, CH3), 1.97 (3 H, s, CH3), 1.95 (3 H, s, CH3). 13C NMR
(75.47 MHz, CDCl3): d = 170.4 (C=O), 169.9 (C=O), 169.4
(C=O), 95.6 (C-1), 70.6 (CH2), 70.5 (CH2), 69.9, 68.3, 67.5
(CH2), 67.0, 61.7 (CH2), 50.5 (CH2), 20.5 (CH3), 20.49
(CH3), 20.42 (CH3). HRMS (EI): m/z calcd for C20H32N3O12
[M + H]+: 506.1986; found: 506.1982.
Compound 18b: a colorless gum. IR (CHCl3): 2108 (N3),
1755 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 5.17 (1
H, t, J = 9.3 Hz), 5.04 (1 H, t, J = 9.6 Hz), 4.95 (1 H, dd,
J = 8.1, 9.6 Hz), 4.58 (1 H, d, J = 8.1 Hz, H-1), 4.22 (1 H, dd,
J = 4.5, 12.3 Hz, C6-H¢), 4.09 (1 H, dd, J = 2.4, 12.3 Hz, C6-
H), 3.90 (1 H, m, C5-H), 3.75–3.56 (10 H, m), 3.36 (2 H, t,
J = 5.1 Hz), 2.05 (3 H, s, CH3), 2.01 (3 H, s, CH3), 1.98 (3 H,
s, CH3), 1.96 (3 H, s, CH3). 13C NMR (75.47 MHz, CDCl3):
d = 170.7 (C=O), 170.3 (C=O), 169.5 (C=O), 169.4 (C=O),
100.9 (C-1), 72.9, 71.8, 71.3, 70.8 (CH2), 70.5 (CH2), 70.1
(CH2), 69.1 (CH2), 68.5, 62.0 (CH2), 50.7 (CH2), 20.8 (CH3),
20.7 (CH3), 20.7 (CH3), 20.6 (CH3). HRMS (EI): m/z calcd
for C20H32N3O12 [M + H]+: 506.1986; found: 506.1999.
2-[2-(2-Azidoethoxy)ethoxy]ethyl-2,3,4,6-tetra-O-acetyl-
a-D-galactoside (19a) and 2-[2-(2-azidoethoxy)eth-
oxy]ethyl-2,3,4,6-tetra-O-acetyl-b-D-galactoside (19b).
Compound 19a: a brown-colored gum. IR (CHCl3): 2108
(N3), 1747 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d =
5.12 (1 H, d, J = 1.8 Hz, H-1). 13C NMR (75.47 MHz,
CDCl3): d = 170.5 (C=O), 170.3 (C=O), 170.1 (C=O), 96.3
(C-1), 70.82 (CH2), 70.8 (CH2), 67.7 (CH2), 61.7 (CH2), 50.7
(CH2). HRMS (EI): m/z calcd for C20H32N3O12 [M + H]+:
506.1986; found: 506.1987.
(14) (a) Li, J.; Zacharek, S.; Chen, X.; Wang, J.; Zhang, W.;
Janczuk, A.; Wang, P. G. Bioorg. Med. Chem. 1999, 7,
1549. (b) See ref. 8a.
(15) General Procedure for the Acetylation of Azidoalkyl
Glycosides.
To a well-stirred solution of the azidoalkyl glycoside in dry
pyridine (4 mL/mmol) under N2 was added DMAP (catalytic
amount). Then, Ac2O (10–12 equiv) was added to the
mixture dropwise by syringe and the reaction was stirred for
2–12 h at ambient temperature. After completion (TLC,
charred in 2% methanolic H2SO4), a small amount of ice was
added and the reaction was stirred for ca. 30 min. The
reaction mixture was then poured into H2O (30 mL/mmol)
and extracted with CHCl3 (3 × 40 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered
and the filtrate was concentrated to dryness in vacuo.
Column chromatography (230–400 mesh) was carried out
using acetone–CHCl3–hexanes (1:1:8) to separate both
a- and b-isomers.
(16) Characterization of Compounds.
The full characterization for one representative compound
for each glycoside (16a for the 2¢-azidoethyl glycosides and
18a,b for the azidotriethylene glycosides) is given. Key data
are shown for all other unknown compounds. For 13C NMR
all methylenes (CH2) were identified by DEPT. NMR
exchange data for the anomeric protons of the unprotected
mixtures are shown in ref. 17.
Compound 19b: a colorless gum. IR (CHCl3): 2106 (N3),
1747 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 4.55 (1
H, d, J = 8.1 Hz, H-1). 13C NMR (75.47 MHz, CDCl3): d =
170.6 (C=O), 170.4 (C=O), 170.32 (C=O), 169.6 (C=O),
101.5 (C-1), 70.9 (CH2), 70.85 (CH2), 70.8 (CH2), 69.2
(CH2), 61.5 (CH2), 50.8 (CH2). HRMS (EI): m/z calcd for
C20H32N3O12 [M + H]+: 506.1986; found: 506.1997.
2-[2-(2-Azidoethoxy)ethoxy]ethyl-2,3,4-tri-O-acetyl-a-L-
fucoside (20a) and 2-[2-(2-Azidoethoxy)ethoxy]ethyl-
2,3,4-tri-O-acetyl-b-l-fucoside (20b).
Compound 20a: a colorless gum. IR (CHCl3): 2107 (N3),
1743 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 5.03 (1
H, d, J = 1.5 Hz, H-1). 13C NMR (75.47 MHz, CDCl3): d =
170.4 (C=O), 170.2 (C=O), 169.8 (C=O), 96.0 (C-1), 70.5
(CH2), 70.4 (CH2), 70.0 (CH2), 67.8 (CH2), 50.4 (CH2).
HRMS (EI): m/z calcd for C18H30N3O10 [M + H]+: 448.1931;
found: 448.1944.
Compound 20b: a colorless gum. IR (CHCl3): 2106 (N3),
1751 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 4.49 (1
H, d, J = 8.1 Hz, H-1). 13C NMR (75.47 MHz, CDCl3): d =
170.7 (C=O), 170.2 (C=O), 169.6 (C=O), 101.1 (C-1), 70.7
(CH2), 70.6 (CH2), 70.4 (CH2), 70.0 (CH2), 69.1 (CH2), 50.6
(CH2). HRMS (EI): m/z calcd for C18H30N3O10 [M + H]+:
448.1931; found: 448.1933.
2¢-Azidoethyl-2,3,4,6-tetra-O-acetyl-a-D-galactoside
(16a).
An amorphous hygroscopic solid. IR (CHCl3): 2931, 2108
(N3), 1747 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d =
5.47 (1 H, m), 5.36 (1 H, dd, J = 3.3, 10.5 Hz), 5.16 (1 H, s,
H-1), 5.13 (1 H, dd, J = 8.4, 15.0 Hz), 4.25 (1 H, t, J = 6.6
Hz), 4.10 (2 H, d, J = 6.9 Hz), 3.86 (1 H, m), 3.63 (1 H, m),
3.52–3.34 (2 H, m), 2.14 (3 H, s, CH3), 2.08 (3 H, s, CH3),
2.04 (3 H, s, CH3), 1.98 (3 H, s, CH3). 13C NMR (75.47 MHz,
CDCl3): d = 170.5 (C=O), 170.4 (C=O), 170.2 (C=O), 169.9
(C=O), 96.4 (C-1), 68.0, 67.8, 67.4, 67.3 (CH2), 66.5, 61.7
(CH2), 50.4 (CH2), 20.7 (CH3), 20.7 (CH3), 20.62 (CH3),
20.6 (CH3). HRMS (EI): m/z calcd for C16H24N3O10 [M +
H]+: 418.1462; found: 418.1451.
2¢-Azidoethyl-2,3,4-tri-O-acetyl-b-L-fucoside (17b).
A colorless gum. IR (CHCl3): 2106 (N3), 1752 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.52 (1 H, d, J = 8.1 Hz, H-
1). 13C NMR (75.47 MHz, CDCl3): d = 170.6 (C=O), 170.1
(C=O), 169.5 (C=O), 100.8 (C-1), 68.2 (CH2), 50.5 (CH2).
HRMS (EI): m/z calcd for C14H22N3O8 [M + H]+: 360.1407;
found: 360.1411.
2-[2-(2-Azidoethoxy)ethoxy]ethyl-2-N-acetamido-2-
deoxy-a-D-glucoside (11).
A colorless gum. IR (KBr plate): 3290 (br, OH), 2111 (N3),
1652 (C=O) cm–1. 1H NMR (300 MHz, DMSO-d6): d = 4.68
(2 H, t, J = 4.8 Hz, H-1 and 1 H). 13C NMR (75.47 MHz,
Synlett 2006, No. 3, 455–459 © Thieme Stuttgart · New York

LETTER
DMSO-d6): d = 169.4 (C=O), 97.0 (C-1), 69.9 (CH2), 69.7
One-Step Synthesis of Azide-Tagged Carbohydrates
459
(17) 1H NMR Exchange Data for the Anomeric Position of
a/b-Mixtures 8, 10, 13 and a-Glycosides 11 and 14.
Compound 8a: 1H NMR (DMSO-d6 + D2O): d = 4.63 (1 H,
d, J = 3.9 Hz, H-1).
(CH2), 69.5 (CH2), 69.3 (CH2), 66.5 (CH2), 60.8 (CH2), 50.0
(CH2). HRMS (EI): m/z calcd for C14H27N4O8, [M + H]+:
379.1829; found: 379.1833.
2-[2-(2-Azidoethoxy)ethoxy]ethyl-2-N-acetamido-2-
deoxy-a-D-galactoside (12a).
A brown-colored gum. IR (KBr-plate): 3305 (OH), 2110
(N3), 1646 (C=O) cm–1. 1H NMR (300 MHz, DMSO-d6): d =
4.67 (1 H, d, J = 3.6 Hz, H-1). 13C NMR (75.47 MHz,
DMSO-d6): d = 169.6 (C=O), 97.4 (C-1), 69.8 (CH2), 69.7
(CH2), 69.5 (CH2), 69.3 (CH2), 66.5 (CH2), 60.6 (CH2), 50.0
(CH2). HRMS (EI): m/z calcd for C14H27N4O8 [M + H]+:
379.1829; found: 379.1830.
Compound 8b: 1H NMR (DMSO-d6 + D2O): d = 4.12 (1 H,
d, J = 7.5 Hz, H-1).
Compound 10a: 1H NMR (DMSO-d6 + D2O): d = 4.66 (1 H,
d, J = 3.0 Hz, H-1).
Compound 10b: 1H NMR (DMSO-d6 + D2O): d = 4.08 (1 H,
d, J = 7.5 Hz, H-1).
Compound 13a: 1H NMR (DMSO-d6 + D2O): d = 4.59 (1 H,
d, J = 2.7 Hz, H-1).
Compound 13b: 1H NMR (DMSO-d6 + D2O): d = 4.07 (1 H,
d, J = 7.2 Hz, H-1).
2-[2-(2-Azidoethoxy)ethoxy]ethyl-a-D-lactoside (14).
A yellow gum. IR (KBr plate): 3387 (br, OH), 2109 (N3),
1652 (C=O) cm–1. 1H NMR (300 MHz, DMSO-d6): d = 4.65
Compound 11: 1H NMR (DMSO-d6 + D2O): d = 4.68 (1 H,
d, J = 3.3 Hz, H-1).
(1 H, t, J = 3.0 Hz, H-1), 4.10 (1 H, d, J = 7.8 Hz, H-1¢). 13
C
Compound 14: 1H NMR (DMSO-d6 + D2O): d = 4.64 (1 H,
d, J = 3.9 Hz, H-1 and 4.13 (1 H, d, J = 7.8 Hz, H-1¢).
NMR (75.47 MHz, DMSO-d6): d = 102.5 (C-1), 98.4 (C-1¢).
HRMS: m/z calcd for C18H34N3O13 [M + H]+: 500.2092;
found: 500.2086.
Synlett 2006, No. 3, 455–459 © Thieme Stuttgart · New York