Traceless Staudinger ligation of glycosyl azides with triaryl phosphines: Stereoselective synthesis of glycosyl amides

Article abstract of DOI:10.1021/jo060409s

α-Glycosyl amides can be synthesized from the corresponding O-benzyl-α-glycosyl azides using a traceless Staudinger ligation with diphenylphosphanyl-phenyl esters 4. All the phosphines employed and their phenol precursors are stable to air at 4 °C for months. Fast intramolecular trapping of the reduction intermediates results in the direct formation of the amide link, which, in turn, prevents epimerisation and allows retention of configuration at the anomeric carbon. Yields and α-selectivity are high when the reaction is performed in polar aprotic solvents. Removal of the benzyl ether protecting groups is achieved by catalytic hydrogenation. α-Glycosyl amides represent a class of virtually unexplored nonhydrolyzable monosaccharide derivatives that may find a useful application as sugar mimics. Conformational studies by NMR spectroscopy confirm that deprotected α-glycosyl amides in the gluco, galacto, and fuco series retain the normal pyranose conformation of the monosaccharide. The reaction of phosphines 4 with tetra-O-acetyl-glycosyl azides is nonstereoconservative, and β-glycosyl amides are obtained in good yields and with complete stereoselectivity starting from both α and β azides.

Full text of DOI:10.1021/jo060409s

Traceless Staudinger Ligation of Glycosyl Azides with Triaryl
Phosphines: Stereoselective Synthesis of Glycosyl Amides†
Aldo Bianchi and Anna Bernardi*
UniVersita’ degli Studi di Milano, Dipartimento di Chimica Organica e Industriale and Centro di
Eccellenza CISI, Via Venezian 21, 20133 Milano, Italy
anna.bernardi@unimi.it
ReceiVed February 27, 2006
R-Glycosyl amides can be synthesized from the corresponding O-benzyl-R-glycosyl azides using a traceless
Staudinger ligation with diphenylphosphanyl-phenyl esters 4. All the phosphines employed and their
phenol precursors are stable to air at 4 °C for months. Fast intramolecular trapping of the reduction
intermediates results in the direct formation of the amide link, which, in turn, prevents epimerisation and
allows retention of configuration at the anomeric carbon. Yields and R-selectivity are high when the
reaction is performed in polar aprotic solvents. Removal of the benzyl ether protecting groups is achieved
by catalytic hydrogenation. R-Glycosyl amides represent a class of virtually unexplored nonhydrolyzable
monosaccharide derivatives that may find a useful application as sugar mimics. Conformational studies
by NMR spectroscopy confirm that deprotected R-glycosyl amides in the gluco, galacto, and fuco series
retain the normal pyranose conformation of the monosaccharide. The reaction of phosphines 4 with tetra-
O-acetyl-glycosyl azides is nonstereoconservative, and â-glycosyl amides are obtained in good yields
and with complete stereoselectivity starting from both R and â azides.
Introduction
for the isolation and characterization of animal and plant lectins,
for the separation of cells, as well as for the targeting of drugs,
artificial vaccines, and diagnostic reagents. Additionally, the
synthesis of neo-glycoconjugates is of great interest as a means
of obtaining unnatural compounds endowed with new properties.
Among these unnatural glycoconjugates, R-linked glycosyl
amides appear to be particularly interesting. Natural glycopep-
tides are almost invariably â-linked,2 hence, it is likely that the
unnatural, R-linked isomers may be stable to hydrolytic enzymes
and can be used for in vivo applications. Furthermore, it has
been recently shown that the peptide conformation of glyco-
peptides depends on the anomeric configuration of the appended
glycan,3 suggesting that R-linked glycopeptides may give new
molecules and materials which behave in an unprecedented
fashion.
Glycoproteins and glycolipids play central roles in human
health and disease, and their mimetics are interesting candidates
for drug development. The chemical synthesis of oligosaccha-
rides and glycoconjugates provides homogeneous material not
attainable from biosynthetic systems. Furthemore, chemical
synthesis can afford so-called neo-glycoconjugates, unnatural
molecules with largely unexplored physicochemical properties,
which are finding interesting applications in many fields of
glycochemistry and glycobiology.1 Neo-glycoconjugates are not
only useful for the basic understanding of protein-carbohydrate
interactions, but they have many practical applications. They
are powerful reagents in cell biology studies and excellent tools
† Dedicated to Professor Carlo Scolastico on the occasion of his 70th birthday.
(1) Neo-glycoconjugates, part B: biomedical applications. Methods in
Enzymology; Lee, Y., Lee, R., Abelson, J., Simon, M., Eds.; Academic
Press: New York, 1995; Vol. 247.
(2) One example of R-linked glycopeptide has been described: Shibata,
S.; Takeda, T.; Natori, Y. J. Biol. Chem. 1988, 263, 12843-12845.
10.1021/jo060409s CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/16/2006
J. Org. Chem. 2006, 71, 4565-4577
4565

Bianchi and Bernardi
SCHEME 1. Anomeric Isomerization of O-Acetyl-glycosyl Iminophosphoranes
SCHEME 2. Staudinger Reduction-Acylation of r-Glycosyl Azides Is Stereoconservative Only with Strong Acylating Agents15
The most widely employed method for the synthesis of
glycosyl amides is the condensation of protected or unprotected
glycosylamines4,5 with carboxylic acid derivatives. Several
examples of the reduction of glycosyl azides by catalytic
hydrogenation followed by acylation of the resulting glycosyl-
amines have been reported.6-8 Because glycosylamines rapidly
equilibrate to the most stable â-anomer, all the approaches that
make use of isolated amine intermediates afford â-glycosyl
amides. An alternative methodology attempts to avoid anomeric
equilibration by reducing glycosyl azides in the presence of
acylating agents.9-13 The group of Gyo¨rgydea´k investigated in
detail the stereochemical course of the reduction-acylation of
glycosyl azides by the Staudinger reaction14 to establish whether
R- and â-glycosyl amides can be derived in a stereoselective
fashion from the corresponding azides.15 Working with O-acetyl-
glycosyl azides, they showed that the Staudinger reduction of
glycosyl azides affords aza-ylide intermediates (also called
iminophosphoranes; Scheme 1), which can be trapped by
acylating agents to give configurationally stable acylamino
phosphonium salts that, in turn, yield the corresponding amides
upon quenching. However, like glycosylamines, the Staudinger’s
aza-ylides are also subject to anomeric isomerization, which is
biased toward the â-anomers. Thus, the synthesis of â-glycosyl
amides can be easily achieved in this process, but in most cases,
anomerization remains a significant problem during the synthesis
of R-glycosyl amides. In fact, the R/â ratio of the two anomeric
amides critically depends on the kac/keq ratio (Scheme 1), and
good levels of stereoselectivity can be reached only if the
acylation step is very fast.
For instance, the reaction of 2,3,4,6-tetra-O-acetyl-R-D-
glucopyranosyl azide 1R with trimethylphosphine followed by
acylation with acetic anhydride yields only the â product, while
acylation with trifluoroacetic anhydride gives a 78:22 mixture
of the R and â anomers, respectively (Scheme 2). Similar results
were obtained with 2,3,4,6-tetra-O-acetyl-R-D-galactopyranosyl
azide.15
(3) Bosques, C. J.; Tschampel, S. M.; Woods, R.; Imperiali, B. J. Am.
Chem. Soc. 2004, 126, 8421-8425.
(4) Hackenberger, C. P. R.; O’Reilly, M. K.; Imperiali, B. J. Org. Chem.
2005, 70, 3574-3578.
(5) Sridhar, P. R.; Prabhu, K. R.; Chandrasekaran, S. J. Org. Chem. 2003,
68, 5261-5264.
Only a handful of methods have been reported to afford
R-glycosyl amides, most of which require two steps and have
been described for a limited number of substrates.16-18
(6) Matsuo, I.; Nakahara, Y.; Ito, Y.; Nukada, T.; Nakahara, T.; Ogawa,
T. Bioorg. Med. Chem. 1995, 3, 1455-1463.
(7) Saha, U. K.; Roy, R. Tetrahedron Lett. 1995, 36, 3635-3638.
(8) Sabesan, S. Tetrahedron Lett. 1997, 38, 3127-3130.
(9) Inazu, T.; Kobayashi, K. Synlett 1993, 869-870.
(10) Bosch, I.; Romea, P.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1993,
34, 4671-4674.
We have recently reported19 a general procedure for the
reductive acylation of O-benzyl-R-glycosyl azides with the
functionalized triaryl phosphines 4 (Scheme 3) that are equipped
(11) Boullanger, P.; Maunier, V.; Lafont, D. Carbohydr. Res. 2000, 324,
97-106.
(16) Ratcliffe, A. J.; Fraser-Reid, B. J. Chem. Soc., Perkin Trans. 1 1989,
1805-1810. Ratcliffe, A. J.; Konradsson, P.; Fraser-Reid, B. J. Carbohydr.
Res. 1991, 216, 323-335.
(17) Damkaci, F.; DeShong, P. J. Am. Chem. Soc. 2003, 125, 4408-
4409.
(12) Malkinson, J. P.; Falconer, R. A.; Toth, I. J. Org. Chem. 2000, 65,
5249-5252.
(13) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J.
Am. Chem. Soc. 2003, 125, 7754-7755.
(14) (a) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635-646.
(b) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353-1407.
(15) Kova´cs, L.; O¨ sz, E.; Domokos, V.; Holzer, W.; Gyo¨rgydea´k, Z.
Tetrahedron 2001, 57, 4609-4621.
(18) Bianchi A. PhD Thesis, Universita’ di Milano, 2004-2005.
(19) (a) Bianchi, A.; Bernardi, A. Tetrahedron Lett. 2004, 45, 2231-
2234. (b) Bianchi, A.; Russo, A.; Bernardi, A. Tetrahedron: Asymmetry
2005, 16, 381-386.
4566 J. Org. Chem., Vol. 71, No. 12, 2006

StereoselectiVe Synthesis of Glycosyl Amides
SCHEME 3. Traceless Staudinger Ligation of r-Glycosyl Azides with Phosphines 419
CHART 1. Glycosyl Azides Used in This Study
to effect intramolecular acyl transfer after the azide reduction
step has generated the intermediate iminophosphorane.
This traceless Staudinger ligation20,21 proceeds with retention
of configuration at the anomeric carbon and was applied to
O-benzyl glycosyl azides in the fuco, gluco, and galacto series
to afford the corresponding R-glycosyl amides with good yields
and stereoselectivities for a range of acyl chains. This first group
of experiments provided the first general method for the
synthesis of R-glycosyl amides, however, various problems were
left unsolved. In particular, steric hindrance of the acyl chain
to be ligated appeared to slow the acyl transfer step, and often
phosphotriazadiene intermediates were isolated rather than the
expected amides.19b In some cases, low reactivity could be
overcome by sunlamp irradiation of the reaction mixture, but
the effect did not appear to be general, and the results varied
unpredictably with the type of substrate. When irradiation failed,
we found that purification of the intermediates from the reaction
mixtures allowed them to evolve spontaneously to the amide
products, which had to be separated from the phosphine oxide
byproduct. Hence, the final compounds could be obtained only
after two chromatographic isolations.19b
During the course of these studies, Kiessling and co-workers
published a paper on the traceless ligation of O-acetyl-glycosyl
azides with dialkylphosphino(borane)methanethioesters to give
â-glycosyl amides.22 Their work showed that the reaction is
sensitive to the polarity of the solvent and, in particular, it occurs
with higher yields in dipolar aprotic media. Similar observations
were reported in a mechanistic study from the Bertozzi
laboratory, showing that the Staudinger ligation proceeds faster
in solvents with higher dielectric constants.23 Our initial results
on glycosyl azides had been obtained in solvents of relatively
low polarity, typically toluene or chloroform.19 The new
literature reports prompted a re-examination of the solvent effect
in the ligation of O-benzyl-glycosyl azides with phosphines 4,
and the results are reported in this paper. We found that the
ligation is indeed accelerated using polar aprotic solvents, such
as N,N-dimethylformamide (DMF) or N,N-dimethylacetamide
(DMA). Under these improved conditions, the reaction of tetra-
O-benzyl-R-glucosyl and R-galactosyl azides was found to be
stereoconservative and to afford the corresponding R-glycosyl
amides in good yields and with good stereoselectivity for a broad
range of linear and branched acylating agents. We also studied
the reactivity of phosphines 4 as Staudinger ligation agents for
O-acetyl-glycosyl azides. With these substrates, the reaction was
found to be â-selective starting from both R- and â-tetra-O-
acetyl azides. This study establishes the diphenylphosphanyl-
phenyl esters 4 as powerful agents for the stereoselective
Staudinger ligation of glycosyl azides to give glycosyl amides
either in the R or â configuration, depending on the configu-
ration of the starting azide and on the oxygen protecting groups
in the starting monosaccharide. Phosphines 4 are air stable
reagents that can be easily synthesized and purified by flash
chromatography, which gives a significant advantage over other
ligation reagents,22 and their application in the stereoselective
synthesis of glycosyl amides should be particularly useful.
Results and Discussion
Synthesis of the Starting Materials and Reagents. The
azides 1 and 5-9 (Chart 1) used in this study are all known
compounds. Their synthesis and characterization are reported
in the Supporting Information. The 2,3,4,6-tetra-O-acetyl-â-D-
glucosyl azide 1â24 was synthesized with complete stereocontrol
by treating glucose pentaacetate with trimethylsilyl azide and
tin tetrachloride, as described by Paulsen.25 The 2,3,4,6-tetra-
O-acetyl-R-D-glucosyl azide 1r,24 the 3,4,6-tri-O-acetyl-2-N-
acetyl-2-deoxy-â-D-glucopyranosyl azide 8â,26 and the 3,4,6-
tri-O-acetyl-2-N-phthalimido-2-deoxy-R-D-glucopyranosyl azide
9r26 were stereoselectively prepared by SN2 displacement of
28
the corresponding anomeric halides27 with sodium azide or
(24) (a) Ogawa, T.; Nakabayashi, S.; Shibata, S. Agric. Biol. Chem. 1983,
47, 281-285. (b) Sabesan, S.; Neira, S. Carbohydr. Res. 1992, 223, 169-
185.
(25) (a) Paulsen H. AdV. Carbohydr. Chem. 1971, 26, 127. (b) Gyo¨rgy-
dea´k, Z.; Szila´gyi, L.; Paulsen H. J. Carbohydr. Chem. 1993, 12, 139-
163.
(20) (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007-2010. (b)
Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2, 2141-
2143. (c) Nillson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2,
1939-1941.
(21) Koehn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004, 43, 3106-
3116 and referencs therein.
(22) He, Y.; Hinklin, R. J.; Chang, J.; Kiessling, L. L. Org. Lett. 2004,
6, 4479-4482.
(23) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R. G.; Bertozzi,
C. J. Am. Chem. Soc. 2005, 127, 2686-2695.
(26) Szyla´gyi, L.; Gyo¨rgydea´k, Z. Carbohydr. Res. 1985, 143, 21-41.
(27) 2,3,4,6-tetra-O-acetyl-â-D-glucosyl chloride: Korytnyk, W.; Mills
J. A. J. Chem. Soc. 1959, 636-649. 3,4,6-tri-O-acetyl-2-N-acetyl-2-deoxy-
R-D-glucopyranosyl chloride: Martichonok, V.; Whitesides, G. M. J. Org.
Chem. 1996, 61, 1702-1706. 2-N-phthalimido-2-deoxy-3,4,6-tri-O-acetyl-
â-D-glucopyranosyl bromide: Baluja, G.; Chase, B. H.; Kenner, G. W.;
Todd, A. J. Chem. Soc. 1960, 4678-4681.
(28) Tropper, F. D.; Andersson, F. O.; Braun, S.; Roy, R. Synthesis 1992,
618-620.
J. Org. Chem, Vol. 71, No. 12, 2006 4567

Bianchi and Bernardi
CHART 2. Functionalized Phosphines 4a-i Used in This
Study
SCHEME 4. Staudinger Ligation of the
2,3,4,6-Tetra-O-benzyl-r-D-glucosyl Azide 5r with
Phosphines 4a-fa
TABLE 1. Staudinger Ligation of the Glycosyl Azide 5r with
Phosphines 4a-f
a Reagents and conditions: (i) (a) DMF, 70 °C, 20 h; (b) H2O, 70 °C,
2 h.
method Aa (CHCl3, hν)
method Bb (DMF)
yieldc
(%)
R/â
yieldc
(%)
R/â
ratiod
ratiod
Similar results were obtained starting from tetra-O-benzyl-
R-D-galactosyl azide 6R. For instance, product 12c was obtained
in good yield and with high stereoselectivity (70% and 98:2
R/â ratio) using phosphine 4c (Scheme 5).
phosphine product
4a
4b
4c
4d
4e
4f
11a
11b
11c
11d
11e
11f
77e
70
60
>99:1
84:16
83:17
84:16
85:15
83
81
76
56
65
93:7
95:5
>97:3
>97:3
93:7
40
N-linked glycopeptides are connected to the peptide aglycon
via the side chain of an Asn residue,32 therefore, N-glycosylation
of the aspartic acid side chain appears particularly useful to
obtain neo-glycopeptides. In our previous studies,19b however,
acyl transfer from the aspartic acid 4-(2-diphenylphosphanyl-
phenyl)ester 4g was found to be highly problematic; the reaction
with O-benzyl-R-D-glucosyl azide 5r in toluene or in CHCl3
afforded a pair of diastereomeric intermediates that were
tentatively assigned the phosphotriazadiene structures shown in
Figure 1. Conversion of the intermediates could not be obtained
in the reaction mixtures under a variety of conditions, including
sunlamp irradiation, but occurred spontaneously after chromato-
graphic isolation to yield an 86:14 R/â mixture of azides 11g,
which had to be further purified from the phosphinoxide
byproduct. This was particularly frustrating, and the solvent
effects on the yield and the selectivity of this Staudinger ligation
were extensively studied by testing different polar aprotic
solvents. The results are reported in Table 2 and Scheme 6.
In DMF, the conversion of the intermediates to product
improved significantly, but the R-stereoselectivity decreased
compared to toluene (Table 2, compare entries 1 and 6). In fact,
running the ligation in DMF at 70 °C, the amide 11g was
obtained in 51% yield as a 50:50 R/â mixture, and no
intermediates were isolated (Scheme 6, Table 2, entry 1). In
DMA (entry 2, Table 2), a better conversion was observed (65%
yield after 4 h at 70 °C), but the R/â ratio was not improved
(50:50 R/â ratio). Other polar solvents, like acetonitrile and
dimethyl sulfoxide (entry 3 and 4, Table 2), did not improved
the R-selectivity (35:65 and 50:50 R/â ratio, respectively). In
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU,
entry 5, Table 2), TLC analysis of the crude reaction mixture
apparently showed a good conversion, but the isolation of the
products was difficult because of the high boiling point of this
solvent. However, a 65:35 R/â mixture was obtained in 43%
yield.
65e
a Reaction performed in CCl4, from ref 19b. b Phosphine (1.2 equiv),
DMF, 70 °C, 18 h, then H2O, 70 °C, 2 h. c Isolated yield. d Determined by
1H NMR. e No irradiation required.
trimethylsilyl azide and tetrabutylammonium fluoride.29 The
2,3,4,6-tetra-O-benzyl-R-D-glucosyl azide 5r19a and the 2,3,4,6-
tetra-O-benzyl-R-D-galactosyl azide 6r19a were obtained as
70:30 mixtures of the easily separable R and â anomers from
the corresponding anomeric acetates with trimethylsilyl azide
and tin tetrachloride.25 The completely stereocontrolled synthesis
of 2,3,4-tri-O-benzyl-R-L-fucopyranosyl azide 7r from the
â-iodide30 was previously reported.19a
The functionalized phosphines employed are collected in
Chart 2. They were synthesized from the known o-diphen-
ylphosphinophenol 1031 using partially reported procedures.19b
Their synthesis and characterization are reported in the Sup-
porting Information. All the phosphines studied and their phenol
precursors were stable to air at 4 °C for months. They could be
purified by flash chromatography and generally handled with
no special precautions.
Traceless Staudinger Ligation of the Glycosyl Azides.
Ligation of the Perbenzylated Glycosyl Azides. In a first set
of experiments, ligation of 2,3,4,6-tetra-O-benzyl-R-D-glucosyl
azide 5r with phosphines 4a-i in DMF was examined and
compared with the results previously obtained in CHCl3 (Table
1, method A and Scheme 4).
In DMF (Table 1, method B) the acyl transfer step was indeed
faster than in CHCl3, and irradiation of the reaction mixture
was not required to achieve complete conversion of the
intermediates. Gratifyingly, higher yields and selectivities were
also achieved. Under these conditions (DMF at 70 °C for 18 h,
then water, at the same temperature for 2 h), the R-stereo-
selectivity was improved to synthetically useful levels, and in
all the cases, the R/â ratios were higher than 93:7.
The effect of the reaction temperature was also studied (Table
2, entries 7 and 8). In DMA at 110 °C, the yield of the reaction
was poor (42%) but, most importantly, the selectivity was shifted
in favor of the â epimer (24:76 R/â) (entry 7, Table 2).
Surprisingly, similar results were also obtained running the
(29) Soli, E. D.; Manoso, A. S.; Patterson, M. C.; DeShong, P. J. Org.
Chem. 1999, 64, 3171-3177.
(30) (a) Gervay, J.; Nguyen, T. N.; Hadd, M. J. Carbohydr. Res. 1997,
300, 119-125. (b) Hadd, M. J.; Gervay, J. Carbohydr. Res. 1999, 320,
61-69.
(32) Herzner, H.; Reipen, T.; Schultz, M.; Kunz, H. Chem. ReV. 2000,
100, 4495-4537.
(31) Rauchfuss, T. B. Inorg. Chem. 1977, 16, 2966-2968.
4568 J. Org. Chem., Vol. 71, No. 12, 2006

StereoselectiVe Synthesis of Glycosyl Amides
SCHEME 5. Staudinger Ligation of the Azide 2,3,4,6-Tetra-O-benzyl-r-D-galactosyl Azide 6r with Phosphine 4ca
a Reagents and conditions: (i) (a) DMF, 70 °C, 20 h; (b) H2O, 70 °C, 2 h.
TABLE 3. Staudinger Ligation of Azide 5r with Phosphine 4g:
Effect of Solvent Mixturesa
entry
reaction conditions
yieldb (%)
R/â ratioc
1
2
3
4
5
6
DMA/toluene 3:1, 4 h
DMA/toluene 1:1, 4 h
DMA/toluene 1:3, 4 h
DMA/toluene 1:9, 24 h
DMPU/toluene 1:1, 24 h
DMPU/toluene 1:9, 24 h
n.d.
84
68
59
56
63
55:45
61:39
75:25
75:25
54:46
79:21
FIGURE 1. Tentative structure of the stereoisomeric intermediates
isolated from the reaction of 5r and 4g in toluene (from ref 19b).
a In all cases, the reaction was performed with 1.2 equiv of 4g at 70 °C
for the time indicated, then water was added and the reaction mixture was
1
stirred at room temperature for18 h. b Isolated yields. c Determined by H
TABLE 2. Staudinger Ligation of Azide 5r with Phosphine 4ga
NMR.
entry
reaction conditions
yieldb (%)
11g R/â ratioc
1
2
3
4
5
6
7
8
DMF, 70 °C, 18 h
DMA, 70 °C, 4 h
CH3CN, 70 °C, 4 h
DMSO, 70 °C, 4 h
DMPU, 70 °C, 18 h
toluene, 70 °C, 18 hd
DMA, 110 °C, 4 h
DMA, rt, 18 h
51
65
50:50
50:50
35:65
50:50
65:35
86:14
22:78
24:76
Mixtures of DMPU and toluene were also used (Table 3,
entries 5 and 6). The best mixture was in this case 1:9 DMPU/
toluene, leading to a 79:21 R/â ratio (entry 6, Table 3). However,
even if the R-selectivity is slightly higher, the use of DMA/
toluene 1:3 is preferable from a practical standpoint, because
the high boiling point of DMPU complicates the isolation of
the products at the end of the reaction.
n.d.
n.d.
43
75e
40
42
a In all cases, the reaction was performed with 1.2 equiv of 4g at the
temperature and for the time indicated, then water was added and the
reaction mixture was stirred at the indicated temperature for 4-18 h.
b Isolated yields. c Determined by 1H NMR. d From ref 19b. e After two
chromatographic isolations.
The nature of the protecting groups on the amino acid does
not appear to affect either the stereoselectivity or the yield of
the reaction to a significant extent (Scheme 7). So ligation of
5r with phosphine 4h (NHBoc, benzyl ester) or 4i (NHFmoc,
allyl ester) gave a mixture of the two isomers in about a 3:1
R/â ratio (Scheme 7), and also, in these cases, the anomers can
be separated by flash chromatography.
Similar results were obtained starting from 2,3,4,6-tetra-O-
benzyl-R-D-galactosyl azide 6r, using the conditions optimized
for the synthesis of 11g-i (Scheme 8). However, the R-selectiv-
ity is lower and the chromatographic separation of the anomers
appears more difficult.
Ligation of the Peracetylated Glycosyl Azides. Phosphines
4 appeared to perform remarkably well in the Staudinger ligation
of O-benzyl-glycosyl azides. They also are very stable reagents
and easy to synthesize. We, therefore, decided to explore their
use in the ligation of O-acetyl-glycosyl azides. These substrates
have often been transformed in â-glycosyl amides using
Staudinger reduction-acetylation sequences11,12,15,33 or, more
recently, by Staudinger ligation with dialkylphosphino(borane)-
methanethioesters.22 The latter conditions were reported by
Kiessling and co-workers to yield â-glycosyl amides, irrespec-
tive of the configuration of the starting azide.
ligation at room temperature (entry 8, Table 2). Therefore, a
change in the reaction temperature did not improve the
R-selectivity.
In conclusion, the best R-selectivity for the ligation was
obtained using toluene as the solvent (Table 2, entry 6) but only
after isolation of the intermediates and their spontaneous
conversion to the amide products.19b On the other hand, the best
conversion was achieved in DMPU (Table 2, entry 5) or in
DMA (Table 2, entry 2), but in these solvents, no stereoselec-
tivity was observed.
Conversion and selectivity were finally optimized using
solvent mixtures (Table 3). As expected, increasing the amount
of toluene in the mixture improved the R-selectivity, while
increasing the amount of DMA accelerated the reaction and led
to a higher conversion of the intermediates. The optimal
conditions for the synthesis of 11g-r were shown to be DMA/
toluene 1:3 at 70 °C (Table 3, entry 3): under these conditions
a 75:25 R/â ratio and a 68% yield were obtained. The two
isomers 11g-r and 11g-â were separated by flash chromatog-
raphy.
The first attempts to obtain ligation from peracetylated azides
were conducted by reacting the 2,3,4,6-tetra-O-acetyl-â-D-
SCHEME 6. Staudinger Ligation of Azide 5r with Phosphine 4g
J. Org. Chem, Vol. 71, No. 12, 2006 4569

Bianchi and Bernardi
SCHEME 7. Staudinger Ligation of Azide 5r with Phosphines 4h and 4ia
a Reagents and conditions: (i) (a) 1:3 DMA/toluene, 70 °C, 4 h; (b) H2O, 70 °C, 18 h.
SCHEME 8. Staudinger Ligation of Azide 6r with Phosphines 4g and 4ha
a Reagents and conditions: (i) (a) 1:3 DMA/toluene, 70 °C, 4 h; (b) H2O, 70 °C, 18 h.
SCHEME 9. Staudinger Ligation O-Acetyl-â-azides 1â and 8âa
a Reagents and conditions: (i) CHCl3, 70 °C, 24 h; (ii) (a) DMA, 70 °C, 4 h; (b) H2O, 70 °C, 18 h.
glucopyranosyl azide 1â with diphenylphosphanyl-phenyl ac-
etate 4a in CHCl3 (Scheme 9). At 70 °C for 24 h clean ligation
was observed and the corresponding glucosyl acetamide 13a
was isolated in 81% yield (Scheme 9).
Acyl transfer from phosphine 4g proved to be more difficult,
and reduction intermediates were isolated running the reaction
in CHCl3 or toluene. However, clean ligation was obtained in
DMA (70 °C, 4 h) to give the glycosyl amino acid 13g with
complete â-stereoselectivity and in 69% yield (Scheme 9). The
same phosphine was used under the same conditions for the
synthesis of the glycosyl amino acid 14j (Scheme 9), starting
from the 3,4,6-tri-O-acetyl-2-N-acetyl-2-deoxy-â-D-glucopyra-
nosyl azide 8â. Again, the product was obtained with complete
â-stereoselectivity and in 51% yield.
To evaluate the behavior of O-acetyl R-azides in these
Staudinger ligations, the same reactions were performed using
the 2,3,4,6-tetra-O-acetyl-R-D-glucopyranosyl azide 1r. When
the ligation was run with phosphine 4a, either in CHCl3 or in
DMA, only the corresponding â-acetamide â-13a was isolated
in 70 and 45% yield, respectively (Scheme 10). Similarly,
â-selectivity was observed when the Staudinger ligation was
performed on the 3,4,6-tri-O-acetyl-2-N-phthalimido-2-deoxy-
R-D-glucopyranosyl azide 9r. For instance, the â-glycosyl amide
16f was isolated in 58% yield by treating 9r with phosphine 4f
in DMF at 70 °C for 20 h before adding water (Scheme 10).
(33) (a) Inazu, T.; Kobayashi, K. Synlett 1993, 869-870. (b) Bosch, I.;
Romea, P.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1993, 34, 4671-4674.
4570 J. Org. Chem., Vol. 71, No. 12, 2006

StereoselectiVe Synthesis of Glycosyl Amides
SCHEME 10. Staudinger Ligation of O-Acetyl r-azides 1r and 9ra
a Reagents and conditions: (i) (a) DMF, 70 °C, 22 h; (b) H2O, 70 °C, 20 h.
SCHEME 11. Staudinger Ligation of Azide 1r with Phosphine 4ga
a Reagents and conditions: (i) (a) DMA, rt, 2 h; (b) 40 °C, 4 h; (ii) (a) DMA, 70 °C, 2 h; (b) H2O, 70 °C, 18 h; (iii) H2O, 70 °C, 18 h.
The reaction with phosphine 4g was also extensively studied
(Scheme 11). In DMA at 70 °C, only the â-anomer (compound
13g) was obtained in 54% yield, thus, with complete inversion
of the anomeric configuration of the starting azide 1r. Lowering
the reaction temperature to 40 °C led to the isolation of the
r-Glycosyl Amides: Deprotection, Characterization, and
Conformational Analysis. Removal of the benzyl ether protect-
ing groups from compounds 17a, 11a, 12a,19a 11b, 11g and
11h was achieved by catalytic hydrogenation (Scheme 12). The
acetamides 17a, 11a, and 12a were deprotected with Pd-C in
MeOH under 1 atm of H2; the pentanamide 11b required a slight
H2 pressure (3 atm) and the N-aspartyl derivatives 11g and 11h
were deprotected using 3 bar of H2 and a 85:10:5 DMA/H2O/
AcOH mixture as solvent36 (Scheme 12).
The Nγ-(R-D-glucopyranosyl)-L-asparagine-O-methyl ester
19g was then acetylated (Ac2O, pyridine, DMAP catalyst), and
the 1H and 13C NMR spectra of 20g were found to be consistent
with those reported for the corresponding benzyl ester17 (Scheme
12).
1
R-iminophosphorane intermediate 15 (Scheme 11; H NMR,
CDCl3, 400 MHz: H1, 5.29 ppm, dd, J1-2 ) 3.7 Hz, J1-P
)
22.6 Hz) from which only the â-amide 13g was slowly formed
upon addition of water. Peracetylated glycosyl iminophospho-
ranes are more stable than their perbenzylated analogues and
have been previously isolated and observed by 1H NMR
spectroscopy.15,34,35 The same stereochemical outcome was
obtained by running the ligation in 1:3 DMA/toluene mixtures:
again, the only product isolated at the end of the reaction was
the â-amide â-13g (yield 51%).
The pyranose conformation of the R-glycosyl acetamides
18a-20a (Figure 2) was determined by NMR spectroscopy
(D2O, 298 K). The NOE contacts observed for each product
are schematically represented in Figure 1 (see Supporting
Information Table SI-1 for further details). Analysis of the
coupling constants and of the NOESY spectra allowed us to
establish that the R-glucosyl acetamide 19a and the R-galactosyl
Thus, the anomeric iminophosphoranes of O-acetyl sugars
appear to react more sluggishly than the corresponding O-benzyl
derivatives with acylating agents and to allow R to â anomer-
ization to occur prior to acyl transfer. Unlike the ligation of
tetra-O-benzyl-glycosyl azides, the reduction-acylation of tetra-
O-acetyl-glycosyl azides is a nonstereoconservative process, and
acyl transfer occurs more slowly than iminophosphorane ano-
merisation. These results are in agreement with recent literature
reports obtained by the Kiessling group using dialkylphosphino-
(borane)methanethioesters.22
4
acetamide 20a adopt the C1 conformation, whereas the R-fu-
cosyl amide 18a adopts a 1C4 conformation. Thus, all the
R-glycosyl amides examined so far appear to maintain the
normal pyranose conformation of the monosaccharide, which
represents an important feature for their use as sugar mimics.
(34) (a) Kova´cs, L.; Pinte´r, I.; Messmer, A. Carbohydr. Res. 1985, 141,
57-65. (b) Kova´cs, L.; Pinte´r, I.; Messmer, A. Carbohydr. Res. 1987, 166,
101-111.
(35) Johnson, A. W. Ylides and Imines of Phosphorus; Wiley: New York,
(36) Tachibana, Y.; Matsubara, N.; Nakajima, F.; Tsuda, T.; Tsuda, S.;
1993.
Monde, K.; Nishimura, S. I. Tetrahedron 2002, 58, 10213-10224.
J. Org. Chem, Vol. 71, No. 12, 2006 4571

Bianchi and Bernardi
SCHEME 12. Deprotection of O-Benzyl-r-glycosyl Amides 17a, 11a, 12a, 11b, 11g, and 11ha
a Reagents and conditions: (i) H2, Pd-C, MeOH; (ii) H2, 3 atm, Pd-C, MeOH; (iii) H2, 3 atm, Pd-C, 85:15:5 DMA, acetic acid, water; (iv) Ac2O,
DMAP, pyridine.
FIGURE 2. NOESY contacts in the R-acetamides 18a-20a (S, strong; M, medium, W, weak).
Discussion
starting from O-benzyl glycosyl azides, whereas anomerization
to the â-epimer is invariably observed starting from O-acetyl-
glycosyl azides.
Although the Staudinger reaction has been known from 1919,
and actually described before the Wittig counterpart, the
mechanism of this reaction is poorly understood. The Staudinger
reaction and its mechanism were reviewed by Gololobov et al.
in 198137 and 1992.14b More recently, mechanistic studies were
The traceless Staudinger ligation represents one interesting
approach to the synthesis of glycosyl amides starting from the
corresponding azides. In principle the reaction allows for
reduction of the starting material and fast intramolecular trapping
of the reduction intermediates and should therefore result in
the direct formation of the amide link. This in turn should
prevent epimerization and allow retention of configuration at
the anomeric carbon. Indeed, the studies described here show
that these expectations are indeed true if the ligation is performed
(37) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437-472.
4572 J. Org. Chem., Vol. 71, No. 12, 2006

StereoselectiVe Synthesis of Glycosyl Amides
SCHEME 13. Proposed Mechanism for the Staudinger Ligation
reported both using computational methods38 and using experi-
mental techniques.23 The number of the intermediates and
possible reaction pathways connecting them to each other and
to the starting and final products is high, and the potential energy
surface is extremely complex. A likely mechanistic scheme for
our reactions is shown in Scheme 13 and will be used to discuss
the many features that are left unexplained by the studies
described above.
The accepted mechanism for the Staudinger reduction of
azides with phosphines14b requires the formation of two
sequential intermediates. The initial nucleophilic attack of the
phosphine on the azide is expected to proceed through a
phosphotriazadiene 22 (often called phosphotriazene or phos-
phazene or phosphazide), which should be present as an
equilibrating Z-E mixture of zwitterions (23-Z and 23-E). This
intermediate is stabilized by electron-donating groups on the
phosphine, electron-withdrawing groups on the azide, or steri-
cally hindering groups on both the phosphine and the azide.37
Phosphotriazadienes have been isolated from Staudinger azide
reductions and characterized by X-ray crystallography and other
techniques14b,15,37,39,40 as zwitterionic species displaying a partial
double bond character at the central N-N linkage. The E
configuration of the N-N double bond (23-E, Scheme 13) is
generally observed,38 while the Z configuration has rarely been
isolated.38a In the reaction mixture, however, 23-E can isomerize
to the Z isomer 23-Z, which should decompose to afford N2
and the iminophosphorane 24. Glycosyl iminophosphoranes are
relatively stable species that have been isolated and characterized
in many instances.15,34,35 In the presence of acylating agents,
the iminophosphorane reacts at nitrogen to give, after hydrolysis,
the corresponding amide. In the traceless ligations under study,
intramolecular trapping of the iminophosphorane should occur
to afford 24. It appears that starting from tetra-O-benzyl-glycosyl
azides this process is faster than the anomeric equilibration of
23, thus allowing for retention of the anomeric configuration
of the starting azide. We speculate that tetra-O-acetyl-glycosyl
iminophosphoranes may be deactivated toward acyl transfer by
the electron-withdrawing effect of the acetates,41 which delo-
calizes the negative charge on the nitrogen atom and allows
anomeric equilibration to occur before the acyl transfer step.
In the course of our studies on the Staudinger ligation of the
tetra-O-benzyl-R-glucosyl azide 5R with phosphines 4 in
solvents of low polarity19 (toluene, CCl4, CHCl3), we could
indeed isolate intermediates that are consistent with the struc-
tures 23 with E/Z ratios that probably depend on the steric
(40) (a) Hillhouse, G. L.; Goeden, G. V.; Haymore, B. L. Inorg. Chem.
1982, 21, 2064. (b) Chernega, A. N.; Antipin, M. Y.; Struchkov, Y. T.;
Boldeskul, I. E.; Ponomarchuk, M. P.; Kasukhin, L. F.; Kukhar, V. P. Zh.
Obshch. Khim. 1984, 54, 1979. (c) Chidester, C. G.; Szmuszkovicz, J.;
Duchamp, D. J.; Laurian, L. G.; Freeman, J. P. Acta Crystallogr., Sect. C
1988, 44, 1080. (d) Chernega, A. N.; Antipin, M. Y.; Struchkov, Y. T.;
Ponomarchuk, M. P.; Kasukhin, L. F.; Kukhar, V. P. Zh. Obshch. Khim.
1989, 59, 1256. (e) Tolmachev, A. A.; Kostyuk, A. N.; Kozlov, E. S.;
Polishchuk, A. P.; Chernega, A. N. Zh. Obshch. Khim. 1992, 62, 2675. (f)
Goerlich, J. R.; Farkens, M.; Fischer, A.; Jones, P.; Schmutzler, R. Z. Anorg.
Allg. Chem. 1994, 620, 707. (g) Bieger, K.; Bouhadir, G.; Reau, R.; Dahan,
F.; Bertrand, G. J. Am. Chem. Soc. 1994, 118, 8087-8094.
(38) (a) Widauer, C.; Gru¨tzmacher, H.; Shevchenko, I.; Gramlich, V.
Eur. J. Inorg. Chem. 1999, 1659-1664 and references therein. (b) Alajar´ın,
M.; Conesa, C.; Rzepa, H. S. J. Chem. Soc., Perkin Trans. 2 1999, 1811-
1814. (c) Tian, W. Q.; Wang, Y. A. J. Org. Chem. 2004, 69, 4299-4308.
(c) Zhang, S.; Wang, Y. A. J. Chem. Theory Comput. 2005, 1, 353-362.
(39) (a) Molina, P.; Lo´pez-Leonardo, C.; Llamas-Bot´ıa, J.; Foces-Foces,
C.; Ferna´ndez-Castan˜o, C. Tetrahedron 1996, 52, 9629-9642. (b) Alajar´ın,
M.; Molina, P.; Lo´pez-Lazaro, A.; Foces-Foces, C. Angew. Chem., Int. Ed.
1997, 36, 67-70.
(41) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B.
J. Am. Chem. Soc. 1988, 110, 5583-5584. (b) Ottoson, H.; Udodong, U.;
Wu, Z.; Fraser-Reid, B. J. Org. Chem. 1990, 55, 6068-6070.
J. Org. Chem, Vol. 71, No. 12, 2006 4573

Bianchi and Bernardi
hindrance of the acyl group that is transferred (86:14 ratio from
4b and 50:50 from 4g). These compounds, once isolated from
the reaction mixture by chromatography, appear to evolve
rapidly and spontaneously to the amide product. We were unable
to fully characterize them or to observe the putative imino-
phosphorane intermediates. Sunlamp irradiation appeared to
accelerate the decomposition of some, but not all, of the
intermediates:19b the reactions of phosphines 4b-d with 5r
could be driven to completion but the reaction of 4e and 4g
could not, even using different wavelengths. It is not yet clear
if the transfer seen for 4b-d is due to acceleration of the E to
Z isomerization of the N-N double bond in the phosphotri-
azadiene or to the intervention of a different reaction pathway
that facilitates the nitrogen extrusion, nor is it clear why this
pathway is not available to phosphotriazadienes formed by 4e
or by the aspartyl phosphine 4g. Acceleration of the acyl transfer
was obtained more reliably using aprotic dipolar solvents. The
best results were obtained in DMF or DMA, where the ligation
products from O-benzyl-R-glycosyl azides were consistently
obtained in good yields. An accurate kinetic study of the ligation
of glycosyl azides was not performed. The reduction of the azide
may well be the rate-determining step of the process when polar
aprotic solvents such as DMF are employed. On the contrary,
in less polar solvents, the intramolecular acyl transfer is
obviously the rate-determining step. The acceleration obtained
by sunlamp irradiation may be useful from a preparative point
of view, but its scope and the mechanism by which it operates
are not yet fully understood. Hence, the use of polar solvents
represents a significant advantage for these transformations. In
DMA, the ligation appears to have a general scope: various
alkyl and alkenyl groups, both linear and branched, were
transferred with good results. Functional groups (carbamates,
esters, amides) were tolerated both on the azide and on the
phosphine. The R/â selectivity was also improved in these
solvents, but phosphine 4g represents one exception because
the reaction became nonstereoconservative. Starting from
O-benzyl-R-glycosyl azides, R-glycosyl amides were generally
synthesized with high stereoselectivity, although some excep-
tions were observed. In particular, the transfer of the aspartyl
side chain occurred without stereocontrol in DMA and was
modestly R-selective using DMA/toluene mixtures. Nonetheless,
the method described here represents one of the most general
syntheses of R-glycosyl amides. These molecules are almost
nonexistent in nature and can potentially be used as nonhydro-
lyzable mimics of carbohydrates and glycoconjugates. In this
respect, it was gratifying to observe that removal of the benzyl
protecting groups was straightforward and that the R-glycosyl
acetamides that we have synthesized so far appear to retain the
ring conformation adopted in the parent pyranose.
electronic effects. Peracetylated compounds are scarcely reactive
under the conditions employed, and this difference can be
explained considering the arming-disarming effect of the
protective groups.41 The traceless Staudinger ligation of O-acetyl
glycosyl azides with functionalized phosphines has been de-
scribed to give â-glycosyl amides also using dialkylphosphino-
(borane)methanethioesters.22,42 The ligation with phosphines 4
compares favorably with the reported method because it occurs
with similar yields and selectivity, but the phosphines are easier
to synthesize and handle.
Conclusions
A new method for the stereoselective synthesis of glycosyl
amides based on the traceless Staudinger ligation of glycosyl
azides with phosphines 4 has been developed and partly
optimized. The functionalized phosphine reagents employed in
this reaction can be easily prepared on multigram scale. As a
result of their stability, they can be handled in air and purified
by flash chromatography. The procedure described in this paper
has a general scope, and the ligation is tolerant of many alkyl
and alkenyl groups, both linear and branched, and of various
functional groups.
The reaction of 4 with tetra-O-benzyl-R-azides leads to the
corresponding R-glycosyl amides in good yields and stereo-
selectivity when the reaction is performed in polar aprotic
solvents such as DMF or DMA . These are the best conditions
identified so far for the stereoselective synthesis of R-glycosyl
amides via Staudinger ligation. R-Glycosyl amides constitute a
class of virtually unexplored nonhydrolyzable monosaccharide
derivatives that may find useful applications as sugar mimics.
As an initial step, we were able to establish by NMR studies
reported in this paper that R-glycosyl amides in the gluco,
galacto, and fuco series retain the normal pyranose conformation
of the monosaccharide.
On the contrary, the reaction of phosphines 4 with tetra-O-
acetyl azides is nonstereoconservative, and â-glycosyl amides
are obtained in good yield and complete stereoselectivity starting
from both R- and â-azides. The yields and selectivity observed
for this reaction in polar solvents compare favorably with the
ligation of glycosyl azides recently reported using similar
phosphines of lower air stability.22
Experimental Section
Azides 1r and 1â,24 5r, 6r, and 7r,19a 8â,24 and 9r26 are all
known compounds. Their synthesis is described in the Supporting
Information, and some spectroscopic data are shown. The synthesis
and the NMR characterization of phosphines 4a-4i are also
reported in the Supporting Information. The glycosyl amides 11a-
11e have been previously described.19b
General Procedure for the Ligation in DMF/DMA. Synthesis
of Glycosyl Amides 11b-11f and 12c. The phosphine (4b-4i,
1.2 mol equiv) was added, at room temperature and under argon,
to a solution of the azide 5r or 6r (1 mol equiv) in dry (molecular
sieves) DMF (0.1 M). The solution was heated to 70 °C and stirred
for 4 h. The disappearance of the starting material was monitored
by TLC (8:2 toluene/acetone). Then water was added, and the
mixture was stirred for 18 h at the same temperature. The solvent
was evaporated under reduced pressure, and the crude was purified
by flash chromatography.
The ligation of O-acetyl-glycosyl azides with phosphines 4
was found not to be stereoconservative, and â-amides were
obtained from both R- and â-azides. Glycosyl iminophospho-
ranes were isolated from the ligation of tetra-O-acetyl-glucosyl
azides 1â and 1r with phosphines 4, particularly at low
temperature. As discussed above, the reactivity of the Staudinger
intermediates is influenced by steric and electronic factors. In
our studies, both the acyl phosphine and the starting azide are
hindered, which is reported to favor the isolation of phospho-
triazadienes and explains the observations on the tetra-O-benzyl
azide 5r. The tetra-O-acetyl glucosyl azide 1r may give rise
to iminophosphoranes directly because of a diminished steric
hindrance relative to the O-benzyl azide 5r or because of
(42) Grandjean, C.; Boutonnier, A.; Guerreiro, C.; Fournier, J.-M.;
Mulard, L. A. J. Org. Chem. 2005, 70, 7123-7132.
4574 J. Org. Chem., Vol. 71, No. 12, 2006

StereoselectiVe Synthesis of Glycosyl Amides
N-Pentanedioic Acid 2,3,4,6-Tetra-O-benzyl-r-D-glucopyra-
nosylamide Methyl Ester (11f). Flash chromatography: 55:45
hexane/AcOEt; R/â ratio 97:3; yield ) 70%. 1H NMR (400 MHz,
CDCl3): 7.47-7.24 (m, 18H, aromatics), 7.17-7.12 (m, 2H,
aromatics), 6.29 (d, 1H, NH, J1-NH ) 6.7 Hz), 5.81 (dd, 1H, H1,
J1-2 ) 5.3 Hz, J1-NH ) 6.7 Hz), 4.94 (d, 1H, sCH2Ph, J ) 11.0
Hz), 4.82-4.78 (m, 2H, sCH2Ph), 4.64-4.46 (m, 5H, sCH2Ph),
4.74 (d, 1H, sCH2Ph, J ) 11.3 Hz), 4.63 (d, 1H, sCH2Ph, J )
12.1 Hz), 4.55 (d, 1H, sCH2Ph, J ) 10.8 Hz), 3.86-3.60 (m, 6H,
H2, H3, H4, H5, H6, and H6′), 3.76 (s, 3H, COOCH3), 2.38 (m, 2H,
sCOCH2), 2.31 (t, 2H, sCOCH2, J ) 7.8 Hz), 1.96 (m, 2H, s
COCH2, J ) 7.8 Hz). 13C NMR (100.6 MHz, CDCl3): 173.1, 138.4,
138.1, 137.3, 132.5, 132.0, 128.6, 128.4, 128.1, 128.0, 127.8, 127.8,
81.9, 77.7, 75.4, 75.0, 74.6, 73.6, 72.6, 71.3, 68.4, 51.6, 35.4, 32.9,
29.7, 20.7. ESI-MS: 690.3 (M + Na+). HRMS (ESI): calculated
for C40H45 NO8 [M + Na]+, 690.30374; found [M + Na]+,
690.30181.
N-(3-Methylbutanoyl)-2,3,4,6-tetra-O-benzyl-r-D-galactopy-
ranosylamine (12c). Flash chromatography: 7:3 hexane/AcOEt;
R/â ratio 98:2; yield ) 70%. 1H NMR (400 MHz, CDCl3): 7.40-
7.23 (m, 20H, aromatics), 6.11 (d, 1H, NH, J1-NH ) 6.4 Hz), 5.81
(dd, 1H, H1, J1-2 ) 4.6 Hz, J1-NH ) 6.4 Hz), 4.88-4.40 (m, 8H,
sCH2Ph), 4.10-4.02 (m, 2H, H2 and H4), 3.95-3.88 (m, 1H, H5),
3.73-3.68 (m, 2H, H6 and H6′), 3.65-3.60 (m, 1H, H3), 2.14-
2.02 (m, 3H, sCH2s and sCHs), 0.98-0.90 (m, 6H, 2 × CH3).
13C NMR (100.6 MHz, CDCl3): 173.2, 138.4, 138.3, 137.6, 128.8,
128.5, 128.4, 128.3, 128.0, 127.7, 127.5, 92.0, 77.9, 75.3, 73.8,
73.7, 73.5, 73.0, 72.9, 71.4, 67.8, 46.1, 26.1, 22.5. HRMS (ESI):
calculated for C39H45NO6 [M + Na]+, 646.31391; found [M +
Na]+, 646.31263.
1.41 (s, 9H, NHBoc). 13C NMR (100.6 MHz, CDCl3): 171.1, 171.0,
138.4, 138.1, 137.9, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9,
127.7, 81.9, 77.7, 77.6, 75.5, 75.0, 74.9, 73.6, 72.7, 71.2, 68.3, 67.4,
50.6, 38.2, 28.3. ESI-MS: 867.4 (M + Na+). HRMS (ESI):
calculated for C50H56N2O10 [M + Na]+, 867.38272; found [M +
Na]+, 867.38104. IR (Nujol): 3351, 1730, 1715, 1655. [R]25
+38.6 (c ) 0.5, CHCl3).
)
D
Nr-Fluoren-9-ylmethoxycarbonyl-Nγ-(2,3,4,6-tetra-O-benzyl-
r-D-glucopyranosyl)-L-asparagine-O-allyl Ester (11i). Flash chro-
matography: 9:1 toluene/AcOEt; R/â ratio 70:30; yield ) 65%.
1H NMR (400 MHz, CDCl3): 7.81-7.77 (m, 2H, aromatics Fmoc),
7.65-7.58 (m, 2H, aromatics Fmoc), 7.45-7.12 (m, 24H, aromat-
ics), 6.35 (m, 1H, NHsCH), 6.12 (d, 1H, NHsFmoc, J ) 8.0 Hz),
5.91 (m, 1H, dCH), 5.75 (dd, 1H, H1, J1-2 ) 4.85 Hz, J1-NH
)
8.1 Hz), 5.37-5.30 (m, 1H, dCH2), 5.27-5.21 (m, 1H, dCH2),
4.98-4.92 (m, 1H, CH2sPh), 4.87-4.80 (m, 2H, sCH2Ph), 4.76-
4.59 (m, 5H, sCH2Ph), 4.58-4.43 (m, 3H, sCHNH, sCH2All),
4.32-4.21 (m, 2H, Fmoc), 3.85 (dd, 1H, H2, J1-2 ) 4.85 Hz, J2-3
) 9.1 Hz), 3.83-3.61 (m, 5H, H3, H4, H5, H6, and H6′), 3.11 (dd,
1H, sCH2sCH, J ) 4.9, 17.3 Hz), 2.87 (dd, 1H, sCH2sCH, J
) 4.1, 17.3 Hz). 13C NMR (100.6 MHz, CDCl3): 170.9, 170.5,
156.3, 143.8, 141.3, 138.4, 137.1, 134.4, 129.1, 128.8, 128.6, 128.4,
128.2, 128.1, 128.0, 127.7, 127.1, 125.2, 125.1, 120.0, 118.7, 81.9,
77.5, 76.9, 75.5, 75.04, 74.97, 73.6, 72.7, 68.3, 67.4, 66.4, 50.8,
47.1, 38.0. ESI-MS: 939.4 (M + Na+). HRMS (ESI): calculated
for C56H56N2O10 [M + Na]+, 939.38272; found [M + Na]+,
939.38034. IR (Nujol): 3353, 1735, 1720, 1651. [R]25 ) +27.5
D
(c ) 0.5, CHCl3).
Nr-Benzyloxycarbonyl-Nγ-(2,3,4,6-tetra-O-benzyl-r/b-D-ga-
lactopyranosyl)-L-asparagine-O-methyl Ester (12g). Flash chro-
matography: 65:35 hexane/AcOEt; R/â ratio 65:35; yield ) 65%.
1H NMR (400 MHz, CDCl3; R): 6.31 (d, NH, J1-NH ) 6.6 Hz),
5.70 (dd, H1, J1-2 ) 4.6 Hz, J1-NH ) 6.6 Hz). 1H NMR (400 MHz,
General Procedure for the Synthesis of Glycosyl Amides
11g-11i and 12g-12h. The phosphine (4g-4i; 1.2 mol equiv)
was added, at room temperature and under argon, to a solution of
the azide 5r or 6r (1 mol equiv) in a mixture of toluene and DMA
3:1 (0.1 M). The solution was heated to 70 °C and stirred for 4 h.
The disappearance of the starting material was monitored by TLC
(8:2 toluene/acetone). Then water was added, and the mixture was
stirred for 18 h at the same temperature. The solvent was evaporated
under reduced pressure, and the crude was purified by flash
chromatography.
CDCl3; â): 5.51 (d, NH, J1-NH ) 9.4 Hz), 4.98 (dd, H1, J1-2
8.6 Hz, J1-NH ) 9.4 Hz).
)
Nr-t-butoxycarbonyl-Nγ-(2,3,4,6-tetra-O-benzyl-r/â-D-galac-
topyranosyl)-L-asparagine-O-benzyl Ester (12h). Flash chroma-
tography: 70:30 hexane/AcOEt; R/â ratio 68:32; yield ) 71%. 1H
NMR (400 MHz, CDCl3; R): 6.22 (d, NH, J1-NH ) 6.5 Hz), 5.71
1
(dd, H1, J1-2 ) 4.5 Hz, J1-NH ) 6.5 Hz). H NMR (400 MHz,
Nr-Benzyloxycarbonyl-Nγ-(2,3,4,6-tetra-O-benzyl-r-D-glu-
copyranosyl)-L-asparagine-O-methyl Ester (11g). Flash chroma-
CDCl3; â): 5.39 (d, NH, J1-NH ) 9.0 Hz), 4.99 (dd, H1, J1-2
8.4 Hz, J1-NH ) 9.0 Hz).
)
1
General Procedure for the Deprotection of Glycosyl Acet-
amides 17a, 11a, and 12a. Synthesis of 18a-20a. A 0.1 M
solution of the substrate (1 mol equiv) in MeOH was prepared.
The catalyst (10 wt % Pd-C) was added, and the mixture was
placed under an atmosphere of hydrogen (1 bar). The mixture was
stirred at room temperature for 20 h, and the reaction was monitored
by TLC (6:4 toluene/AcOEt and 9:1 CHCl3/MeOH). The catalyst
was then filtered on a Celite pad and washed with MeOH. The
solvent was removed under reduced pressure.
tography: 8:2 toluene/AcOEt; R/â ratio 75:25; yield ) 68%. H
NMR (400 MHz, CDCl3): 7.40-7.21 (m, 23H, aromatics), 7.13-
7.11 (m, 2H, aromatics), 6.33 (d, 1H, NH, J ) 6.3 Hz), 5.99 (d,
1H, NH, J ) 8.1 Hz), 5.68 (dd, 1H, H1, J1-2 ) 5.1, J1-NH ) 8.1
Hz), 5.15-5.03 (m, 2H, CH2sPh), 4.92-4.89 (m, 1H, CH2sPh),
4.80-4.76 (m, 2H, sCH2Ph), 4.68-4.38 (m, 6H, sCH2Ph, CH),
3.81-3.57 (m, 6H, H2, H3, H4, H5, H6, and H6′), 3.70 (s, 3H,
COOCH3), 2.97 (dd, 1H, sCH2sCH, J ) 5.1, 15.7 Hz), 2.75 (dd,
1H, sCH2sCH, J ) 4.7, 15.7 Hz). 13C NMR (100.6 MHz,
CDCl3): 171.6, 171.5, 171.0, 138.6, 138.2, 138.1, 137.3, 129.2,
129.1, 129.0, 128.8, 128.7, 128.63, 128.60, 128.4, 128.3, 128.2,
128.1, 128.0, 127.92, 127.89, 82.1, 79.6, 78.6, 77.7, 77.1, 76.6,
75.7, 75.2, 73.7, 72.9, 71.5, 68.5, 67.3, 53.0, 50.9, 38.3. MALDI-
TOF-MS: 825.93 (M + Na+), 841.84 (M + K+). IR (Nujol): 3361,
N-Acetyl-r-L-fucopyranosylamine (18a). Quantitative yield. 1H
NMR (400 MHz, D2O): 5.52 (d, 1H, H1, J1-2 ) 5.7 Hz), 3.98 (dd,
1H, H2, J1-2 ) 5.7 Hz, J2-3 ) 10.5 Hz), 3.87 (q, 1H, H5, J
)
)
4-5
0 Hz, J 5-Me ) 6.5 Hz), 3.80 (dd, 1H, H3, J2-3 ) 10.5 Hz, J3-4
3.4 Hz), 3.76 (d, 1H, H4, J3-4 ) 3.4 Hz, J4-5 ) 0 Hz), 2.04 (s, 3H,
sCOCH3), 1.14 (d, 3H, sCH3, J 5-Me ) 6.5 Hz). 13C NMR (100.6
MHz, D2O, HETCOR): 76.5, 71.6, 69.5, 67.6, 66.1, 21.9, 15.9.
N-Acetyl-r-D-glucopyranosylamine (19a). Quantitative yield.
1H NMR (500 MHz, D2O): 5.48 (d, 1H, H1, J1-2 ) 5.5 Hz), 3.71
(dd, 1H, H2, J1-2 ) 5.5 Hz, J2-3 ) 10.2 Hz), 3.69-3.66 (m, 2H,
H6 and H6′), 3.63 (apparent triplet, 1H, H3, J2-3 ) J3-4 ) 10.2
Hz), 3.43 (m, 1H, H5), 3.34 (apparent triplet, 1H, H4, J3-4 ) J4-5
) 10.2 Hz), 2.01 (s, 3H, sCH3). 13C NMR (125.75 MHz, D2O,
HETCOR): 76.4, 72.9, 72.5, 69.2, 69.2, 60.2, 21.9.
1733, 1716, 1653. [R]25 ) +37.9 (c ) 0.5, CHCl3).
D
Nr-t-Butoxycarbonyl-Nγ-(2,3,4,6-tetra-O-benzyl-r-D-glucopy-
ranosyl)-L-asparagine-O-benzyl Ester (11h). Flash chromatog-
raphy: 7:3 hexane/AcOEt; R/â ratio 75:25; yield ) 63%. 1H NMR
(400 MHz, CDCl3): 7.36-7.24 (m, 23H, aromatics), 7.13-7.11
(m, 2H, aromatics), 6.40 (d, 1H, NH, J ) 6.3 Hz), 5.78 (d, 1H,
NH, J ) 8.1 Hz), 5.71 (dd, 1H, H1, J1-2 ) 5.3 Hz, J1-NH ) 8.1
Hz), 5.18 (d, 1H, COOCH2Ph, J ) 12.2 Hz), 5.14 (d, 1H, COOCH2-
Ph, J ) 12.2 Hz), 4.91 (d, 1H, CH2sPh, J ) 11.0 Hz), 4.80 (d,
1H, CH2sPh, J ) 11.0 Hz), 4.79 (d, 1H, CH2sPh, J ) 11.0 Hz),
4.62-4.43 (m, 5H, CH2sPh), 3.81 (dd, 1H, H2, J1-2 ) 5.3 Hz,
J2-3 ) 9.3 Hz), 3.75-3.57 (m, 5H, H3, H4, H5, H6, and H6′), 2.96
(m, 1H, sCH2sCH), 2.78 (dd, 1H, sCH2sCH, J ) 4.4, 15.7 Hz),
N-Acetyl-r-D-galactopyranosylamine (20a). Quantitative yield.
1H NMR (500 MHz, D2O): 5.52 (d, 1H, H1, J1-2 ) 5.5 Hz), 3.97
(dd, 1H, H2, J1-2 ) 5.5 Hz, J2-3 ) 10.5 Hz), 3.90 (d, 1H, H4, J3-4
) 3.4 Hz, J4-5 ) 0 Hz), 3.76 (dd, 1H, H3, J2-3 ) 10.5 Hz, J3-4
)
J. Org. Chem, Vol. 71, No. 12, 2006 4575

Bianchi and Bernardi
3.4 Hz), 3.69 (m, 1H, H5), 3.64-3.61 (m, 2H, H6 and H6′), 2.01 (s,
3H, sCH3). 13C NMR (125.75 MHz, D2O, HETCOR): 76.6, 71.1,
69.3, 68.8, 66.2, 61.0, 21.9.
169.3, 169.1, 74.2, 70.1, 68.6, 68.29, 68.3, 61.8, 52.9, 49.1, 37.9,
23.1, 20.7, 20.6, 20.5. ESI-MS: 541.1 (M + Na+). HRMS (ESI):
calculated for C21H30N2O13 [M + Na]+, 541.16401; found [M +
Na]+, 541.16363. [R]25 ) +86.6 (c ) 0.3, CHCl3).
Synthesis of N-Pentanoyl-r-D-glucopyranosylamine (19b). A
solution of the substrate 11b (10 mg, 0.016 mmol) in MeOH (160
µL, 0.1 M) was prepared. The catalyst (10 wt % Pd-C) was added,
and the mixture was placed under an atmosphere of hydrogen (3
bar). The mixture was stirred at room temperature for 6 h, and the
reaction was monitored by TLC (6:4 AcOEt/toluene and 8:2 CHCl3/
MeOH). The catalyst was then filtered on a Celite pad and washed
with MeOH. The solvent was then removed under reduced pressure.
D
Synthesis of N-Acetyl-2,3,4,6-tetra-O-acetyl-r-D-glucopyra-
nosylamine (13a). A solution of the azide 1â (21.8 mg, 0.058
mmol, 1 mol equiv) and of the phosphine 4a (22.3 mg, 0.07 mmol,
1.2 mol equiv) in CHCl3 (580 µL, 0.1 M) was prepared at room
temperature and under argon. The solution was heated at 70 °C
and stirred for 24 h. Then AcOEt was added, and the solution was
washed with water. The organic layer was dried over Na2SO4,
filtered, and evaporated under reduced pressure. The product was
purified by flash chromatography using 8:2 toluene/acetone as the
1
Quantitative yield. H NMR (400 MHz, D2O): 5.60 (d, 1H, H1,
J1-2 ) 5.4 Hz), 3.83 (dd, 1H, H2, J1-2 ) 5.4 Hz, J2-3 ) 9.4 Hz),
3.86-3.71 (m, 3H, H3, H6, and H6′), 3.53-3.49 (m, 1H, H5), 3.46
(apparent triplet, 1H, H4, J3-4 ) J4-5 ) 9.4 Hz), 2.39 (m, 2H, s
COCH2s), 1.62 (m, 2H, sCH2s), 1.35 (m, 2H, sCH2s), 0.92 (t,
3H, sCH3, J ) 7.5 Hz). 13C NMR (100.6 MHz, D2O): 179.4,
76.5, 73.0, 72.7, 69.4, 69.3, 60.5, 35.3, 27.5, 21.5, 13.0.
1
eluent. Yield ) 81%. H NMR (400 MHz, CDCl3): 6.27 (d, 1H,
NH, J1-NH ) 9.5 Hz), 5.29 (apparent triplet, 1H, H3, J2-3 ) J3-4
) 9.5 Hz), 5.22 (apparent triplet, 1H, H1, J1-2 ) J1-NH ) 9.5 Hz),
5.04 (apparent triplet, 1H, H4, J3-4 ) J4-5 ) 9.5 Hz), 4.89 (apparent
Synthesis of Nγ-(r-D-Glucopyranosyl)-L-asparagine-O-methyl
Ester (19g). A solution of the substrate 11g (20 mg, 0.025 mmol)
in 85:10:5 DMA/AcOH/H2O (2.5 mL, 0.01 M) was prepared. The
catalyst (10 wt % Pd-C) was added, and the mixture was placed
under an atmosphere of hydrogen (3 bar). The mixture was stirred
at room temperature for 48 h, and the reaction was monitored by
TLC (9:1 CHCl3/MeOH and 60:35:5 CHCl3/MeOH/H2O). The
catalyst was then filtered on a Celite pad and washed with MeOH
and water. The solvent was then removed under reduced pressure.
triplet, 1H, H2, J1-2 ) J2-3 ) 9.5 Hz), 4.29 (dd, 1H, H6, J5-6
)
4.4 Hz, J6-6′ ) 12.5 Hz), 4.06 (dd, 1H, H6′, J5-6′ ) 2.2 Hz, J6-6′
) 12.5 Hz), 3.80 (ddd, 1H, H5, J5-6 ) 4.4 Hz, J5-6′ ) 2.2 Hz, J4-5
) 9.5 Hz), 2.09, 2.07, 2.05, 2.03, 1.99 (5s, 15H, 5 × sCOCH3).
General Procedure for the Synthesis of Glycosyl Amides 13g
and 14g. A solution of the phosphine 11g (1.2 mol equiv) in DMA
was added, at room temperature and under argon, to a solution of
the azide 1â or 8â (1 mol equiv) in DMA (0.1 M). The solution
was heated to 70 °C and stirred for 4 h. The disappearance of the
starting material was monitored by TLC. After 4 h water (44 µL)
was added, and the mixture was stirred for an additional 18 h at
the same temperature. The solvent was evaporated under reduced
pressure, and the crude was purified by flash chromatography.
1
Quantitative yield. H NMR (400 MHz, CD3OD): 5.47 (d, 1H,
H1, J1-2 ) 4.3 Hz), 3.96 (m, 1H, CH), 3.73 (s, 3H, COOCH3),
3.72-3.68 (m, 1H, H3 or H4), 3.63-3.56 (m, 3H H2, H6, and H3
or H4), 3.37 (m, 1H, H5), 3.27-3.22 (m, 1H, H6′), 2.89 (m, 1H,
sCH2sCH), 2.81 (m, 1H, sCH2sCH). 13C NMR (100.6 MHz,
CD3OD, HETCOR): 78.2, 75.1, 74.7, 71.7, 62.8, 62.7, 53.2, 51.6,
38.5.
Nr-Carbobenzyloxy-Nγ-(2,3,4,6-tetra-O-acetyl-â-D-glucopyra-
nosyl)-L-asparagine-O-methyl Ester (13g). Flash chromatography
using 6:4 toluene/AcOEt; yield ) 69%. 1H NMR (400 MHz,
Synthesis of Nr-t-Butoxycarbonyl-Nγ-(r-D-glucopyranosyl)-
L-asparagine (19h). A solution of the substrate 11h (28 mg, 0.035
mmol) in 85:10:5 DMA/AcOH/H2O (3.5 mL, 0.01 M) was
prepared. The catalyst (10 wt % Pd-C) was added, and the mixture
was placed under an atmosphere of hydrogen (3 bar). The mixture
was stirred at room temperature for 24 h, and the reaction was
monitored by TLC (6:4 toluene/AcOEt). The catalyst was then
filtered on a Celite pad and washed with MeOH and water. The
solvent was then removed under reduced pressure. Quantitative
CDCl3): 7.42-7.33 (m, 5H, aromatics), 6.35 (d, 1H, NH, J1-NH
)
9.0 Hz), 5.89 (d, 1H, NH, J1-NH ) 8.6 Hz), 5.22 (apparent triplet,
1H, H3, J2-3 ) J3-4 ) 9.5 Hz), 5.16 (apparent triplet, 1H, H1, J1-2
) J2-3 ) 9.4 Hz), 5.05 (m, 2H, sCH2Ph), 4.98 (apparent triplet,
1H, H4, J3-4 ) J4-5 ) 9.5 Hz), 4.83 (apparent triplet, 1H, H2, J1-2
) J2-3 ) 9.5 Hz), 4.54 (m, 1H, CH), 4.21 (dd, 1H, H6, J5-6 ) 4.3
Hz, J6-6′ ) 12.5 Hz), 3.99 (dd, 1H, H6′, J5-6′ ) 1.5 Hz, J6-6′
)
12.5 Hz), 3.68 (m, 1H, H5), 3.66 (s, 3H, COOMe), 2.81 (dd, 1H,
CH2, J ) 16.2 Hz, J ) 3.7 Hz), 2.63 (dd, 1H, CH2, J ) 16.2 Hz,
J ) 3.9 Hz), 2.11, 2.10, 2.07, 2.06 (4s, 12H, 4 × sCOCH3). 13C
NMR (100.6 MHz, CDCl3): 171.4, 171.2, 170.6, 169.8, 169.5,
129.0, 128.8, 128.7, 128.2, 128.0, 78.1, 73.8, 72.6, 70.6, 68.1, 67.1,
61.6, 52.7, 50.4, 37.8, 20.7, 20.6. ESI-MS: 611.0 (M + H+), 633.1
(M + Na+). HRMS (ESI): calculated for C27H34N2O14 [M + Na]+,
1
yield. H NMR (400 MHz, CD3OD): 5.53 (d, 1H, H1, J1-2 ) 4.4
Hz), 4.37 (m, 1H, CH), 3.81 (m, 1H, H6), 3.74-3.61 (m, 3H), 3.49
(m, 1H), 3.34 (m, 1H), 2.86-2.79 (m, 2H, sCH2sCH), 2.88-
2.77 (m, 2H, sCH2sCH), 1.45 (s, 9H, C(CH3)3). 13C NMR (100.6
MHz, CD3OD, HETCOR): 77.0, 73.3, 13.0, 70.2, 70.1, 61.3, 51.8,
3, 27.4.
Synthesis of Nr-Acetyl-Nγ-(2,3,4,6-tetra-O-acetyl-r-D-glucopy-
ranosyl)-L-asparagine-O-methyl Ester (21g). Acetic anhydride (35
µL, 0.36 mmol, 15 mol equiv) and a catalytic amount of N,N-
(dimethylamino)pyridine were added, at room temperature, to a
solution of 19g (7.5 mg, 0.024 mmol, 1 mol equiv) in dry pyridine
(5.7 mL, 0.15 M). The solution was stirred for 24 h and then was
concentrated in vacuo. The residue was dissolved in CH2Cl2 and
washed with 5% aqueous HCl, 5% aqueous NaHCO3, and water.
The organic layer was dried over Na2SO4 and concentrated to give
the product. Yield ) 70%. 1H NMR (400 MHz, CDCl3): 7.27 (d,
1H, NH, J ) 7.5 Hz), 6.79 (d, 1H, NH, J ) 7.5 Hz), 5.86 (dd, 1H,
H1, J1-2 ) 5.4 Hz, J1-NH ) 8.1 Hz), 5.39 (dd, 1H, H3, J2-3 ) 10.1
Hz, J3-4 ) 9.6 Hz), 5.16 (dd, 1H, H2, J1-2 ) 5.4 Hz, J2-3 ) 10.1
Hz), 5.08 (apparent triplet, 1H, H4, J3-4 ) J4-5 ) 9.6 Hz), 4.86-
4.80 (m, 1H, sCHCOOCH3), 4.29 (dd, 1H, H6, J5-6 ) 4.3 Hz,
J6-6′ ) 12.3 Hz), 4.07 (dd, 1H, H6′, J5-6′ ) 2.5 Hz, J6-6′ ) 12.3
Hz), 3.98-3.92 (m, 1H, H5), 3.78 (s, 3H, COOCH3), 2.99 (dd, 1H,
sCH2sCH, J ) 4.9, 15.9 Hz), 2.88 (dd, 1H, sCH2sCH, J )
633.19022; found [M + Na]+, 633.18914. [R]25 ) +19.4 (c )
D
1.0, CHCl3).
Nr-Carbonzyloxy-Nγ-(3,4,6-tri-O-acetyl-2-N-acetyl-2-deoxy-
â-D-glucopyranosyl)-L-asparagine-O-methyl Ester (14g). Flash
chromatography: 98:2 CHCl3/MeOH; yield ) 50%. 1H NMR (400
MHz, CDCl3): 7.40-7.30 (m, 5H, aromatics), 7.12 (d, 1H, NH,
J1-NH ) 8.3 Hz), 6.06 (d, 1H, NH, J2-NH ) 8.0 Hz), 6.00 (d, 1H,
NH, JCH-NH ) 8.6 Hz), 5.16-5.11 (m, 3H, H4 and sCH2Ph), 5.05
(apparent triplet, 2H, H1 and H3, J1-2 ) J1-NH ) J2-3 ) J3-4
)
9.6 Hz), 4.64 (m, 1H, CH), 4.30 (dd, 1H, H6, J5-6 ) 4.1 Hz, J6-6′
) 12.7 Hz), 4.16-4.07 (dd, 1H, H6′ and H2), 3.77-3.70 (m, 1H,
H5), 3.74 (s, 3H, COOMe), 2.89 (dd, 1H, CH2, J ) 16.2 Hz, J )
3.9 Hz), 2.73 (dd, 1H, CH2, J ) 16.2 Hz, J ) 4.0 Hz), 2.09, 2.08,
2.05, 1.98 (4s, 12H, 4 × sCOCH3). 13C NMR (100.6 MHz,
CDCl3): 172.4, 172.0, 171.5, 171.0, 170.6, 169.2, 128.5, 128.2,
128.1, 80.4, 73.6, 72.8, 68.1, 67.1, 61.7, 53.5, 52.7, 50.4, 37.7, 23.0,
20.7, 20.6. ESI-MS: 632.2 (M + Na+). HRMS (ESI): calculated
for C27H35N3O13 [M + Na]+, 632.20621; found [M + Na]+,
4.4, 15.9 Hz), 2.09, 2.05, 2.04, 2.01 (4s, 12H, 4 × sCOCH3). 13
C
NMR (100.6 MHz, CDCl3): 171.2, 170.9, 170.8, 170.4, 170.3,
623.20531. [R]25 ) +7.25 (c ) 0.5, CHCl3).
D
4576 J. Org. Chem., Vol. 71, No. 12, 2006

StereoselectiVe Synthesis of Glycosyl Amides
1
Iminophosphorane 15. H NMR (400 MHz, CDCl3): 7.78-
Hz), 4.39 (dd, 1H, H6, J5-6 ) 4.3 Hz, J6-6′ ) 12.4 Hz), 4.29 (dd,
1H, H2, J1-2 ) 9.9 Hz, J2-3 ) 10.0 Hz), 4.17-4.11 (m, 1H, H6′),
4.04-3.99 (m, 1H, H5), 3.62 (s, 3H, COOCOOCH3), 2.23-2.08
(m, 4H, sCOCH2), 1.78 (m, 2H, sCOCH2, J ) 7.5 Hz), 2.13,
2.05, 1.91 (3s, 9H, 3 × sCOCH3). 13C NMR (100.6 MHz,
CDCl3): 172.2, 170.7, 169.9, 169.7, 134.7, 134.3, 124.1, 123.5,
75.9, 73.7, 70.6, 68.6, 61.9, 54.2, 51.5, 35.1, 32.6, 29.7, 20.7, 20.6,
20.4, 20.1. HRMS (ESI): calculated for C26H30N2O12 [M + H]+,
563.18715; found [M + H]+, 563.18765.
7.25 (m, 19H, aromatics), 5.94 (dd, 1H, H3, J2-3 ) J3-4 ) 9.6
Hz), 5.75 (d, 1H, NH, J ) 8.9 Hz), 5.29 (dd, 1H, H1, J1-2 ) 3.7
Hz, J1-P ) 22.6 Hz), 5.16 (s, 2H, sCH2Ph), 5.09 (apparent triplet,
1H, H4, J3-4 ) J4-5 ) 9.6 Hz), 4.85 (dt, 1H, H2, J1-2 ) J2-P ) 3.7
Hz, J2-3 ) 9.6 Hz), 4.61 (m, 1H, H5), 4.47 (m, 1H, sCHNH),
4.19 (dd, 1H, H6, J5-6 ) 3.9 Hz, J6-6′ ) 12.0 Hz), 3.84 (m, 1H,
H6′), 3.73 (s, 3H, sCOOCH3), 2.52 (dd, 1H, CH2, J ) 17.4 Hz, J
) 5.9 Hz), 2.03 (m, 1H, CH2), 2.09, 2.04, 2.02, 1.76 (4s, 12H, 4
× sCOCH3). 13C NMR (100.6 MHz, CDCl3, HETCOR): 73.8,
71.7, 69.1, 67.2, 65.7, 62.8, 52.7, 50.4, 35.7, 21.6, 20.9, 20.8.
Synthesis of 1-N-Pentanedioic Acid 2-N-Phthalimido-2-deoxy-
3,4,6-tri-O-acetyl-â-D-glucopyranosyl Amide Methyl Ester (16f).
A solution of the phosphine 4f (11.3 mg, 0.029 mmol, 1.2 mol
equiv) in DMF was added, at room temperature and under argon,
to a solution of the azide 9r (11.1 mg, 0.024 mmol, 1 mol equiv)
in DMF (240 µL, 0.1 M). The solution was heated to 70 °C and
stirred for 20 h. The disappearance of the starting material was
monitored by TLC (1:1 hexane/AcOEt). After 20 h water (24 µL)
was added, and the mixture was stirred for an additional 20 h at
the same temperature. The solvent was evaporated under reduced
pressure, and the crude was purified by flash chromatography using
Acknowledgment. The project was supported by the Eu-
ropean program “Improving Human Potential” under contract
HPRNCT-2002-00173 (Glycidic Scaffolds Network). We thank
Silvia Mari and Jesus Jime´nez Barbero for the NOESY spectra
of 19a and 20a.
Supporting Information Available: Procedures for the syn-
thesis of glycosyl azides 1r, 1â, 5r, 5â, 6r, 6â, 7r, 8â, and 9r,
synthesis and characterization of the functionalized phosphines 4,
NOE contacts and coupling constants of the R-acetamides 18a-
1
20a, H, 13C, and 31P NMR spectra for compounds 4a-4i, 11f-
1
65:35 hexane/AcOEt as the eluent. Yield ) 58%. H NMR (400
11i, 12c, 18a, 19a, 20a, 19b, 19g, 19h, 21g, 13g, 14g, and 16f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
MHz, CDCl3): 7.90-7.80 (m, 2H, aromatics), 7.77-7.72 (m, 2H,
aromatics), 6.08 (d, 1H, NH, J1-NH ) 8.3 Hz), 6.05 (dd, 1H, H1,
J1-2 ) 9.9 Hz, J1-NH ) 8.3 Hz), 6.03 (dd, 1H, H3, J2-3 ) 10.0 Hz,
J3-4 ) 9.5 Hz), 5.18 (apparent triplet, 1H, H4, J3-4 ) J4-5 ) 9.5
JO060409S
J. Org. Chem, Vol. 71, No. 12, 2006 4577