Synthesis of glucopyranosyl amides using polymer-supported reagents

Article abstract of DOI:10.1081/SCC-120039504

2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl azide reacts efficiently with polymer-supported triphenylphosphine and various acid chlorides to yield glucopyranosyl amides with retention of the β-gluco stereochemistry.

Full text of DOI:10.1081/SCC-120039504

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Synthesis of Glucopyranosyl
Amides Using
Polymer‐Supported Reagents
Yuriko Y. Root a , Maximillian S. Bailor b & Peter
Norris a
a Department of Chemistry , Youngstown State
University , Youngstown, Ohio, 44555, USA
b Department of Chemistry , Grinnell College ,
Grinnell, Iowa, USA
Published online: 10 Jan 2011.
To cite this article: Yuriko Y. Root , Maximillian S. Bailor & Peter Norris (2004)
Synthesis of Glucopyranosyl Amides Using Polymer‐Supported Reagents, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:13, 2499-2506, DOI: 10.1081/SCC-120039504
To link to this article: http://dx.doi.org/10.1081/SCC-120039504
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2499–2506, 2004
Synthesis of Glucopyranosyl Amides Using
Polymer-Supported Reagents
Yuriko Y. Root,1 Maximillian S. Bailor,2 and Peter Norris1,
*
1Department of Chemistry, Youngstown State University,
Youngstown, Ohio, USA
2Department of Chemistry, Grinnell College, Grinnell, Iowa, USA
ABSTRACT
2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl azide reacts efficiently with
polymer-supported triphenylphosphine and various acid chlorides to
yield glucopyranosyl amides with retention of the b-gluco stereochemistry.
Key Words: Glycosyl amides; Triphenylphosphine; Polymer-bound
iminophosphorane; Polymer-supported Reagents.
Interest in the synthesis of glycosyl amides is inspired by the occurrence
of this motif in naturally occurring biomolecules such as glycoproteins (e.g., 1,
Fig. 1)[1] and nucleic acids (e.g., 2, Fig. 1). Glycosyl amides have been
suggested as potential glycomimetics for the inhibition of glycosyl
*
Correspondence: Peter Norris, Department of Chemistry, Youngstown State University,
Youngstown, OH 44555, USA; Fax: (330) 941-1579; E-mail: pnorris@ysu.edu.
2499
DOI: 10.1081/SCC-120039504
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2500
Root, Bailor, and Norris
Figure 1. The glycosyl amide motif in biomolecules.
hydrolases[2] and as a useful linkage in the synthesis of glycosylated materials
such as detergents.[3] Kunz and Pleuss have used N-glycosyl amides as precur-
sors to glycosyl donors.[4] Notably, Murphy and coworkers have reported that
synthetic glycosyl amide analogs have interesting biological properties, for
example, as inhibitors of the binding of fibroblast growth factor (FGF-2) to
heparin.[5]
Methods for the introduction of the glycosyl amide functionality (e.g., 5,
Sch. 1) have historically relied upon the formation of a glycosyl amine
(4, Sch. 1), followed by coupling with a carboxylic acid (or derivative
thereof).[6] However, this method is often complicated by anomeric intercon-
version resulting in lower anomeric stereoselectivity in the overall amide
synthesis. Several groups have addressed this problem and shown that use
of a Staudinger process,[3,5,7,8] in which a glycosyl azide (3, Sch. 1) reacts
with a phosphine followed by reaction of the resulting iminophosphorane
(6, Sch. 1) with a carboxylic acid derivative, is useful in that it avoids having
to form the glycosyl amine.
The choice of phosphine and carboxylic acid derivative are important, for
example, using the parent carboxylic acids requires the use of trialkylphos-
phines such as PBu3 since triarylphosphines do not result in conversion to
Scheme 1.

Synthesis of Glucopyranosyl Amides
2501
amides.[9] The latter may be used to generate the iminophosphorane if acti-
vated acid derivatives such as acid chlorides are employed,[3,8] and the resul-
tant glycosyl amides are generally formed without anomerization during the
reaction. Formation of triphenylphosphine oxide as a byproduct, however,
may result in increased difficulties with product purification, for example,
when using column chromatography. Potentially, the commercially available
polystyrene-supported triphenylphosphine (PS-PPh3) could be used in this
chemistry, thus avoiding problems with workup. Applications of PS-PPh3 in
related Staudinger-type chemistry have been reported,[10] and results compare
favorably with the use of PPh3 with the ease of workup making the former
reagent attractive. To investigate the application of polymer-supported
reagents in the rapid synthesis of glycosyl amides, we have studied the reac-
tion of 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide (7, Sch. 2)[11] with
PS-PPh3 and various acid chlorides using a parallel synthesizer to generate
a small library of glucosyl amides (9, Sch. 2). Several of the amides have
also been made using PPh3 to compare results and reaction times.
Using the FirstMate parallel synthesizer,[12] each reaction vessel was
charged with 1 equiv. of azide 7, 2 equiv. of acid chloride (Table 1), and
then PS-PPh3 was added, and the reaction mixture agitated at room tempera-
ture until the evolution of gas had ceased. The mixtures were then refluxed for
6 hr, the polymer filtered, and the filtrate treated with polymer-supported
tris(2-aminoethyl) amine to remove the excess acid chloride. Filtration and
evaporation of the solvent gave the amide products 9a–l in the yields
1
shown in Table 1. Analysis of the residues by H NMR showed that the
glycosyl amide was formed in most cases, and that the purity of the products
was generally .85%. Further purification is possible by eluting the amides
through a short silica gel column, which gave material of sufficient purity
for analysis.
Scheme 2.

2502
Root, Bailor, and Norris
The results in Table 1a give a general picture for the reactivity of acid
chlorides in this chemistry. In all cases, the starting azide 7 was consumed
after the PS-PPh3 was added, as seen from TLC analysis of the reaction
mixture, and after 6 hr at 408C only two reactions, that of 7 with PS-PPh3
and pyrrolidinoyl chloride (entry g, Table 1) and that of 7 with PS-PPh3 and
pivaloyl chloride (entry i, Table 1), failed to provide any amide product.
The azide was consumed in both cases, but little or no carbohydrate product
was isolated, which indicates that the intermediate (now polymer-bound)
iminophosphorane does not react efficiently with these acid chlorides under
these conditions. The highest yield, i.e., for the formation of the p-nitroben-
zoyl amide 9a, suggests that the polymer-bound iminophosphorane reacts
most efficiently with highly electrophilic acid chlorides. Furthermore, the
lack of an amide product from reaction with pivaloyl chloride indicates that
the large t-butyl substituent retards the rate of reaction between the poly-
mer-bound iminophosphorane and acid chloride. The remainder of the carbo-
hydrate material is presumably still attached to the polymer support.
aAll new compounds were homogeneous by TLC and at least 95% pure as indicated by
1H NMR spectra. All compounds gave satisfactory analytical data, including 1H NMR
(400 MHz), 13C NMR (100 MHz), and mass spectra. Typical procedure for the
formation of glucopyranosyl amides using polymer-supported triphenylphosphine:
D-glucosyl azide 7 (100 mg, 0.27 mmol) and p-nitrobenzoyl chloride (0.54 mmol)
were dissolved in CH2Cl2 (5.0 mL). Polymer-supported triphenylphosphine (ꢀ3 mmol/
g loading, 116 mg, ꢀ0.35 mmol) was added to the tube, and the mixture was agitated
until the release of nitrogen gas had ceased. The mixture was then agitated and
refluxed gently for 6 hr. The mixture was cooled, gravity filtered into another test
tube to remove polymer-supported triphenyphosphine oxide, which was washed with
CH2Cl2 (2 ꢀ 5 mL). Polystyrene-bound tris(2-aminoethyl) amine (4.0–5.0 mmol/g
loading, 200 mg, ꢀ0.88 mmol) was added to the solution, and the mixture was
agitated for 2 hr at room temperature. The polymer was removed via gravity filtration,
washed with CH2Cl2 (2 ꢀ 5 mL), and the filtrate was concentrated in vacuo to leave
the product residue. Physical characteristics for amide 9a: 400 MHz 1H NMR
(CDCl3) d 2.03, 2.04, 2.05 (3s, 12H total, 4 ꢀ COCH3), 3.91 (m, 1H, H-5), 4.09
(dd, 1H, H-6, J ¼ 1.83, 12.45 Hz), 4.31 (dd, 1H, H-60, J ¼ 4.39, 12.08 Hz), 5.05
(m, 2H, H-3, H-4), 5.39 (m, 2H, H-1, H-2), 7.32 (d, 1H, NH, J ¼ 9.15 Hz), 7.92
(d, 2H, Ar-H), 8.30 (d, 2H, Ar-H). 100 MHz 13C NMR (CDCl3): d 21.97, 62.63,
69.18, 72.09, 73.41, 74.87, 80.06, 124.96, 129.40, 129.60, 139.08, 151.05, 166.04,
170.77, 171.52, 172.84. Mass calculated: 497.15. Found: 497.18. [a]2D0 -19.3 (c 5.1,
CH2Cl2). TLC Rf-values for glycosyl amides (aluminum-backed silica gel plates
using 1 : 1 EtOAc/hexane as eluent and visualization with 5% H2SO4 in ethanol
followed by heating on a hot plate): 9a, 0.72; 9b, 0.66; 9c, 0.69; 9d, 0.70; 9e, 0.70;
9f, 0.70; 9h, 0.60; 9j, 0.69; 9k, 0.66; 9l, 0.36.

Synthesis of Glucopyranosyl Amides
Table 1. Glucopyranosyl amides synthesized via Sch. 2.
Acid chloride Amide product
2503
Entry
Yield (%)
93
a
b
c
40
72
d
e
f
55
66
56
g
—
—
61
h
(continued)

2504
Root, Bailor, and Norris
Table 1. Continued.
Amide product
Entry
Acid chloride
Yield (%)
—
i
—
j
61
k
l
60
40
Treatment of azide 7 with PPh3 in the presence of p-nitrobenzoyl chloride,
2-furoyl chloride, benzoyl chloride, and thiophene-2-carbonyl chloride
according to Boullanger’s method[3] afforded amides 9a (95% yield), 9b
(90% yield), 9d (81% yield), and 9f (92% yield) respectively, after only
30 min at room temperature. Purification required flash chromatography in
each case to separate the amide product from Ph3P55O; thus, there is a
trade-off between the ease of purification in the polymer-supported chemistry
and the longer reaction times required, a drawback that has been noted by
others previously.[13] The use of polymer-supported triphenylphosphine is,
however, amenable to parallel synthesis, where many related compounds
may be produced in the search for novel glycosyl amides with potentially use-
ful biological activity.
ACKNOWLEDGMENTS
The authors would like to acknowledge Research Corporation for funding
part of this work as well as the University Research Council at Youngstown
State University for a PACER award. M.S.B. was a summer student who

Synthesis of Glucopyranosyl Amides
2505
participated in YSU’s National Science Foundation-sponsored Research
Experience for Undergraduates program.
REFERENCES
1. Davis, B.G. Synthesis of glycoproteins. Chem. Rev. 2002, 102, 579–601.
2. Rottmann, A.; Synstad, B.; Eijsink, V.; Peter, M.G. Synthesis of N-
acetylglucos-aminyl and diacetylchitobiosyl amides of heterocyclic
carboxylic acids as potential chitinase inhibitors. Eur. J. Org. Chem.
1999, 2293–2297.
3. Boullanger, P.; Maunier, V.; Lafont, D. Syntheses of amphiphilic glyco-
sylamides from glycosyl azides without transient reduction to glycosyl-
amines. Carbohydr. Res. 2000, 324, 97–106.
4. Pleuss, N.; Kunz, H. N-Glycosyl amides: removal of the anomeric
protecting group and conversion into glycosyl donors. Angew. Chem.
Int. Ed. 2003, 42, 3174–3176.
5. Murphy, P.V.; Pitt, N.; O’Brien, A.; Enright, P.M.; Dunne, A.;
Wilson, S.J.; Duane, R.M.; O’Boyle, K.M. Identification of novel inhibi-
tors of fibroblast growth factor (FGF-2) binding to heparin and endothelial
cell survival from a structurally diverse carbohybrid library. Bioorg. Med.
Chem. Lett. 2002, 12, 3287–3290.
6. Paulsen, H.; Pflughaupt, K.W. Glycosylamines. In The Carbohydrates,
Chemistry and Biochemistry; Pigman, W., Horton, D., Eds.; Academic
Press: New York, 1980; 881–927.
¨
´
´
7. Kovacs, L.; Osz, E.; Domokos, V.; Holzer, W.; Gyorgydeak, Z. An easy
access to anomeric glycosyl amides and imines (Schiff bases) via trans-
formation of glycopyranosyl trimethylphosphinimides. Tetrahedron
2001, 57, 4609–4621.
8. Murphy, P.V.; Bradley, H.; Tosin, M.; Pitt, N.; Fitzpatrick, G.M.;
Glass, W.K. Development of carbohydrate-based scaffolds for restricted
presentation of recognition groups. Extension to divalent ligands and
implications for the structure of dimerized receptors. J. Org. Chem.
2003, 68, 5692–5704.
9. Garcia, J.; Urpi, F.; Vilarrasa, J. New synthetic tricks. Triphenylphos-
phine-mediated amide formation from carboxylic acids and azides.
Tetrahedron Lett. 1984, 25, 4841–4844.
´
10. Garcia-Moreno, M.I.; Diaz-Perez, P.; Benito, J.M.; Mellet, C.O.;
´
Defaye, J.; Fernandez, J.M.G. One-step synthesis of non-anomeric
sugar isothiocyanates from sugar azides. Carbohydr. Res. 2002, 337,
2329–2334.

2506
Root, Bailor, and Norris
11. Ibatullin, F.M.; Shabalin, K.A. A simple and convenient synthesis of
glycosyl azides. Synth. Commun. 2000, 30, 2819–2823 (and references
cited therein).
12. www.argotech.com.
13. Bhalay, G.; Dunstan, A.; Glen, A. Supported reagents: opportunities and
limitations. Synlett 2000, 1846–1859.
Received in the USA March 2, 2004