A study of polymer-supported bases for the solution phase synthesis of glycosyl trichloroacetimidates

Article abstract of DOI:10.1016/j.tetlet.2005.02.055

Polystyrene-supported strong organic bases are highly efficient reagents for the solution-phase synthesis of glycosyl trichloroacetimidates, affording quantitative yields of pure products in short reaction times after simple filtration and evaporation. Al

Full text of DOI:10.1016/j.tetlet.2005.02.055

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2445–2448
A study of polymer-supported bases for the solution phase
synthesis of glycosyl trichloroacetimidates
*
Jose Luis Chiara, Lourdes Encinas and Beatriz D ´ı az
Instituto de Qu ı´ mica Org a´ nica General, CSIC, Juan de la Cierva, 3, E-28006Madrid, Spain
Received 17 December 2004; revised 8 February 2005; accepted 9 February 2005
Abstract—Polystyrene-supported strong organic bases are highly efficient reagents for the solution-phase synthesis of glycosyl tri-
chloroacetimidates, affording quantitative yields of pure products in short reaction times after simple filtration and evaporation.
Although efficiency of the different bases varies with substrate structure, polymer-bound 1,8-diazabicyclo[5.4.0]undec-7-ene was
found to give the best results for all the substrates tested.
Ó 2005 Elsevier Ltd. All rights reserved.
1
To foster advances in the emerging field of glycomics,
the development of improved synthetic tools for the effi-
cient and facile assembly of complex oligosaccharides
and glycoconjugates is mandatory. In spite of recent
2
accomplishments in solid-phase and enzymatic meth-
3
ods, the synthesis of complex oligosaccharides is still
a very challenging undertaking. In recent years, new
solution-phase techniques have been developed to ease
reaction work-up and product isolation, avoiding the
pitfalls of solid-phase approaches. These techniques in-
4
clude the use of soluble polymer-supported methods,
5
6
lipophilic, or fluorophilic protecting groups, tagging
methods for post-synthesis purification using scavenging
Scheme 1.
7
8
resins, solid-phase capture–release strategies, sequen-
9
tial one-pot glycosylations, and polymer-bound
0
reagents and catalysts.
impaired by the acid lability of these glycosyl donors.
As part of a project aimed at the development of prac-
tical procedures for the solution synthesis of oligosac-
charides using polymer-supported reagents, we have
studied the preparation of a series of glycosyl trichloro-
acetimidates of common hexoses in the presence of dif-
1
11
Glycosyl trichloroacetimidates are very efficient and
widely used glycosylating reagents, which are readily
prepared by base-promoted addition of an anomeric hy-
droxyl group to trichloroacetonitrile using either inor-
ganic (e.g., NaH, K CO , or Cs CO ) or organic (e.g.,
1
3,14
ferent supported bases.
2
3
2
3
1
2
15
1
,8-diazabicyclo[5.4.0]undec-7-ene) bases (Scheme 1).
The set of bases and partially protected hexoses in-
cluded in this study are shown in Figure 1. Reactions
were performed at room temperature under mild mag-
netic stirring in an air atmosphere. After the specified
time, the reaction mixture was filtered, the resin was
rinsed with CH Cl and the solvent (and excess
Careful chromatographic purification of crude trichlo-
roacetimidates is usually necessary to remove all traces
of base that could interfere with the subsequent acid-cata-
lyzed glycosylation step. However, purification is often
2
2
Cl CCN) was removed at reduced pressure. The crude
3
Keywords: Carbohydrates; Solid-supported reagents; Glycosylation.
*
1
was analyzed by H NMR.
Corresponding author. Tel.: +34915622900; fax: +349156 48 53;
e-mail: jl.chiara@iqog.csic.es
Present address: GlaxoSmithKline S.A., P.T.M., Severo Ochoa, 2,
E-28760 Tres Cantos, Madrid, Spain.
Each supported base was assayed with all substrates in
three different solvents: CH Cl , THF, and toluene.
2
2
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.055

2446
J. L. Chiara et al. / Tetrahedron Letters 46(2005) 2445–2448
Figure 1.
The results obtained using this general procedure are
presented in Table 1.
(>24h). MP-CO3 is only efficient for acyl-substituted
hexoses (Table 1, entries 9, 10, 14, 17, and 21), what
can be attributed to the increased acidity of the anomeric
hydroxyl of these substrates due to the electron with-
drawing effect of the acyl groups. With the exception of
the D-mannopyranose derivative 3, anomeric mixtures
of glycosyl trichloroacetimidates are usually obtained.
As observed under homogeneous conditions, pro-
longed reaction times, stronger bases, or electron with-
drawing groups on the hexose favor formation of
increased amounts of the thermodynamically more sta-
ble a-imidate, in many cases being the exclusive product
(see Scheme 1). In the case of acyl-substituted hexoses,
best results are often obtained adding the base last
(method B). Use of larger amounts of base gives faster
Taking 2,3,4,6-tetra-O-benzyl-a-D-glucopyranose (1a) as
a reference substrate, the performance of the different
bases roughly follows the trend expected on the basis
1
6
of relative base strengths (Table 1, entries 1–3 and 6).
Of the solvents tested, CH Cl gives the best results
1
2
2
2
and THF performs poorly in general (Table 1, entries
–8). With regards to the bases tested, only PS-DBU
6
and PS-BEMP efficiently promote the reaction on all
substrates tested using a limited amount of base
(
61 equiv). PS-DIA is a poor base for this reaction
affording very low yields (<10%, Table 1, entries 2 and
1) of product even after extended reaction times
1
Table 1. Preparation of glycosyl trichloroacetimidates from hexoses 1–3 using the polymer-supported bases shown in Figure 1, under different
reaction conditions
a
b
Entry
Hexose
Base (equiv)
Cl
3
CCN (equiv)
Solvent
Method
Time (h)
Yield (%) (a/b ratio)
1
2
3
1a
MP-CO3 (1.5)
PS-DIA (1.5)
PS-DBU (1.5)
5.0
5.0
5.0
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
A
A
A
22
30
3.5
<10
N.R.
>99 (1:1)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
PS-DBU (1.0)
5.0
Toluene
5.0
5.0
5.0
5.0
5.0
5.0
5.5
5.0
3.5
5.0
5.0
5.0
5.0
5.0
5.0
3.5
3.5
5.0
3.5
A
15
>99 (2:3)
PS-TBD (1.5)
PS-BEMP (1.0)
PS-BEMP (1.5)
PS-BEMP (1.5)
MP-CO3 (1.0)
MP-CO3 (0.5)
PS-DIA (1.0)
PS-DBU (0.5)
PS-BEMP (0.5)
MP-CO3 (1.0)
PS-DBU (0.5)
PS-BEMP (1.0)
MP-CO3 (1.0)
PS-DBU (0.5)
PS-TBD (1.0)
PS-BEMP (0.5)
MP-CO3 (0.5)
PS-DBU (0.5)
PS-TBD (0.5)
CH
CH
2
Cl
Cl
2
2
A
A
A
A
B
A
B
B
B
B
B
B
B
B
B
B
A
B
B
25
20 (3:2)
>99 (3:2)
28 (1:1)
2
5.5
4.5
25
Toluene
THF
CH Cl
N.R.
1b
2
2
5
94( 4: 1)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
Toluene
3.5
36
>99 (1:0)
<10
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
1.5
1.7
4.5
1.1
1.5
3.5
1.5
1.5
1.5
1.7
1.1
2.2
>99 (1:0)
>99 (1:0)
>99 (9:1)
>99 (1:0)
>99 (1:0)
>99 (7:3)
>99 (9:1)
>99 (4:1)
>99 (9:1)
>99 (1:0)
>99 (1:0)
>99 (1:0)
1c
2
3
a
Method A: Cl
3
CCN was added dropwise to a suspension of hexose and base in the corresponding solvent. Method B: base was added in one portion
CCN in the corresponding solvent.
Determined by H NMR analysis.
to a solution of hexose and Cl
3
b
1

J. L. Chiara et al. / Tetrahedron Letters 46(2005) 2445–2448
2447
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1
1
Next we tested recycling of the supported base, since it
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dation reaction. PS-DBU and PS-TBD, but not the
strongest base PS-BEMP, could be completely regener-
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4
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2
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8
. (a) Ando, H.; Manabe, S.; Nakahara, Y.; Ito, Y. Angew.
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In summary, polystyrene-supported strong bases can be
used as efficient reagents for the facile and practical
preparation of glycosyl trichloroacetimidates, giving
quantitative yields of pure product in short reaction
times, under very mild conditions, and without any
chromatographic purification. An additional advantage
of the procedure is that the supported reagent can be
easily regenerated and reused. Of all supported bases
tested, PS-DBU is the most efficient under substoichio-
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for the general preparation of this important class of
glycosyl donors.
9
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Acknowledgments
We thank the Ministry of Education and Science of
Spain for financial support (projects BQU2000-1501-
C02-01 and BQU2003-03550-C03-02) and a predoctoral
fellowship to L.E.
1
947–1950; (h) Hashihayata, T.; Ikegai, K.; Takeuchi, K.;
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À
1
4. For a recent report on the use of Dowex 1-X8 OH resin
values reported for the conjugated acids of their corre-
sponding non-supported analogs are as follows: diisopro-
for imidation of a glucosamine derivative, see: Yoshizaki,
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1
7
pylethylamine: 18.1 (MeCN, 25 °C);
DBU: 24.13
1
8
(MeCN,
(TBD): 25.44 (MeCN, 25 °C), 24.70 (MeCN, 25 °C);
2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-
25 °C);
1,5,7-triazabicyclo[4.4.0]dec-5-ene
1
9
20
1
480; For a very recent example of imidation of an
unusual 2-deoxy amino sugar using PS-DBU, see:
Ohashi, I.; Lear, M. J.; Yoshimura, F.; Hirama, M.
Org. Lett. 2004, 6, 719–722; When this work was in
preparation, the use of PS-TBD in a one-pot glycosyla-
tion protocol was published: Oikawa, M.; Tanaka, T.;
Fukuda, N.; Kusumoto, S. Tetrahedron Lett. 2004, 45,
1
9
1,3,2-diazaphosphorine (BEMP): 27.63 (MeCN, 25 °C).
To our knowledge, there is no pK
À
a
value reported for
21
HCO3 ion in MeCN, and the value 10.25 (H
should be considered as a lower limit.
2
O, 25 °C),
17. Kelly-Rowley, A. M.; Lynch, V. M.; Anslyn, E. V. J. Am.
Chem. Soc. 1995, 117, 3438–3447.
4039–4042.
1
1
5. PS-CO3 (2.8–3.5 mmol/g) and PS-DIA (3.6 mmol/g) were
purchased from Argonaut, PS-TBD (2.6 mmol/g) was
from Aldrich, PS-BEMP (2.6 mmol/g) was from Fluka,
and PS-DBU (2.7 mmol/g) was prepared following a
literature procedure: Tomoi, M.; Kato, Y.; Kakiuchi, H.
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Ed., 82nd ed.; CRC: Boca Raton, 2002.
6. As an indication of the relative base strength of the
different supported bases used in this study, the pK
a