N-Dimethylphosphoryl-protection in the efficient synthesis of glucosamine-containing oligosaccharides with alternate N-acyl substitutions

Article abstract of DOI:10.1016/j.tetlet.2007.07.108

Ready transformation of N-dimethylphosphoryl-protection into the corresponding N-acyl derivatives (in the presence of acyl chlorides and DMAP in pyridine) provided an effective approach to the synthesis of glucosamine-containing oligosaccharides with alte

Full text of DOI:10.1016/j.tetlet.2007.07.108

Tetrahedron Letters 48 (2007) 7049–7052
N-Dimethylphosphoryl-protection in the efficient
synthesis of glucosamine-containing oligosaccharides
with alternate N-acyl substitutions
You Yanga,b and Biao Yua,*
aState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
bDepartment of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
Received 20 June 2007; revised 14 July 2007; accepted 16 July 2007
Available online 27 July 2007
Abstract—Ready transformation of N-dimethylphosphoryl-protection into the corresponding N-acyl derivatives (in the presence of
acyl chlorides and DMAP in pyridine) provided an effective approach to the synthesis of glucosamine-containing oligosaccharides
with alternate N-acyl substitutions.
Ó 2007 Elsevier Ltd. All rights reserved.
2-Amino-2-deoxy-D-glucopyranose
(D-glucosamine)
deprotection. Recently, we have shown that 2-N-dimeth-
ylphosphoryl(DMP)-glucosamine derivatives could be
effective glycosyl donors and acceptors in the synthesis
of glucosamine-containing oligosaccharides.8 However,
deprotection of the 2-N-DMP-group afterwards remains
problematic; the literature protocols, which require
strong hydrolytic conditions (NaOH, EtOH/H2O, reflux
or NH2NH2ÆH2O, EtOH, reflux), jeopardize the multi-
functional groups in the saccharide substrates and lead
to low yields of the hydrolyzed products.9 Herein, we
report the ready transformation of the 2-N-DMP-pro-
tection into N-acyl substitution under mild conditions
in excellent yields.
exists as an integral component of numerous biologi-
cally important prokaryotic and eukaryotic carbo-
hydrates, including chitin, peptidoglycans, mucopoly-
charides, lipopolysaccharides, and nodulation fac-
tors.1–3 The 2-amino-group of the D-glucosamine resi-
dues is mostly substituted with an acetyl group; while
replacement of the N-acetate with long chain acyl
groups occurs in the lipopolysaccharides2 and nodula-
tion factors,3 where the fatty acid moieties are crucial
to their biological functions. It is also noted that a vari-
ety of the synthetic N- and O-acylated glucosamine
derivatives show immuno-modulating and antitumor
effects of potentially clinical usefulness.4,5 Nevertheless,
introduction of the glucosamine residue into oligosac-
charides and glycoconjugates has been a long-standing
problem in preparative carbohydrate chemistry.6 The
2-N-protecting groups always play a key role in glyco-
sidic coupling with glucosamine derivatives as both
donors and acceptors.6,7 While the N-acyl-glucosamine
derivatives are usually not the choice for glycosylation
due to the involvement of the 2-amide function in side
reactions.6,7 Thus, the required N-acyl residues have to
be introduced at the final stage of synthesis after N-
We have found that N-transacylation could take place
on the 2-N-acetyl-a-D-glucosamine derivatives under
the action of an excess amount of acyl chlorides in
refluxing pyridine.10 Acyl replacement of the 2-N-phos-
phoryl group might also be feasible under similar condi-
tions, via N-acylphosphoramidates formation and the
subsequent P–N bond cleavage,11 thus applicable to
the sophisticated saccharide substrates. Expectedly,
treatment of p-methoxyphenyl 3,4,6-tri-O-acetyl-2-N-
DMP-2-deoxy-b-D-glucopyranoside (1)8 with acetyl
chloride (10 equiv) in the presence of DMAP in reflux-
ing pyridine overnight provided the desired 2-N-acetyl-
glucosamine derivative 2 in an excellent 91% yield
(Table 1, entry 1). To test the scope of this transforma-
tion, two disaccharides of glucosamine (7 and 8) with
Keywords: Dimethylphosphoryl; Protecting group; Glucosamine; Acyl-
ation; Oligosaccharide.
*
Corresponding author. E-mail: byu@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.108

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Y. Yang, B. Yu / Tetrahedron Letters 48 (2007) 7049–7052
Table 1. Ready transformation of the N-DMP-protected saccharides into the corresponding N-acyl derivativesa
Entry
1
Substrates
Acyl chloride
CH3COCl
Products
Yield (%)
91
OAc
O
OAc
O
AcO
AcO
AcO
AcO
OMP
OMP
NH
NH
DMP
O
1
2
OPiv
O
AcO
AcO
AcO
OPiv
O
AcO
AcO
O
O
O
PivO
O
PivO
OMP
OMP
OMP
OMP
AcO
2
3
4
5
6
7
8
CH3COCl
87
99
88
78
93
98
79
NH
NPhth
NH
NPhth
O
DMP
7
9a
OPiv
O
AcO
AcO
AcO
O
O
PivO
7
7
7
C5H11COCl
NH
NPhth
O
O
9b
OPiv
O
AcO
AcO
AcO
O
O
PivO
Undec-10-enoyl chloride
NH
NPhth
9c
OPiv
O
AcO
AcO
AcO
O
O
PivO
OMP
FmocCl
NPhth
NH2
9d
O
Ph
O
O
AcO
AcO
AcO
Ph
O
O
AcO
AcO
O
O
O
O
O
OMP
OMP
AcO
CH3COCl
NH
NH
NPhth
O
NPhth
DMP
8
10a
O
Ph
O
AcO
AcO
AcO
O
O
OMP
O
8
C5H11COCl
NH
NPhth
O
10b
O
Ph
O
AcO
AcO
AcO
O
O
OMP
O
NH
8
Undec-10-enoyl chloride
NPhth
O
10c
a For a typical procedure for this transformation: To a stirred mixture of 7 (39 mg, 0.04 mmol) and DMAP (3 mg, 0.025 mmol) in pyridine (2.5 mL)
at room temperature, was added dropwise undec-10-enoyl chloride (89 ll, 0.4 mmol) under the atmosphere of Ar. The temperature was allowed to
increase naturally to 120 °C to reflux and the stirring continued overnight. The mixture was then concentrated in vacuo. The residue was purified by
silica gel column chromatography (petroleum ether–EtOAc 3:1) to afford 9c (36 mg, 88%) as a white solid.
alternate N-phthalimido(Phth)- and DMP-protection
were readily prepared (Scheme 1)8 and applied to the
present selective N-acyl substitution reaction. The
results are listed in Table 1 (entries 2–8).
Under similar conditions (10 equiv of acyl chloride,
0.5 equiv of DMAP, pyridine, reflux, overnight), the
N-DMP-group (in saccharides 1, 7, and 8) was cleanly
replaced with N-acyl (acetyl, hexanoyl, and undec-10-

Y. Yang, B. Yu / Tetrahedron Letters 48 (2007) 7049–7052
7051
OPiv
AcO
OPiv
O
OH
O
6, b
O
O
a
AcO
AcO
HO
O
PivO
OMP
OMP
OMP
HO
HO
PivO
O
NH
NH
NPhth
NH
O
DMP
O
DMP
MeO
7
O
P
4
MeO
3
ref. 8
O
Ph
O
AcO
AcO
6, b
O
Ph
O
O
O
O
OMP
AcO
AcO
HO
AcO
NH
O
NH
CCl3
NH
NPhth
O
O
DMP
AcO
DMP
8
5
N
O
6
˚
Scheme 1. Reagents and conditions: (a) PivCl (6 equiv), pyridine, ꢀ4 °C, 65%; (b) TMSOTf (0.3 equiv), 4 A MS, CH2Cl2, ꢀ15 °C to rt, 49% (for 7;
49% 4 recovered); 64% (for 8).
enoyl) substitutions, affording the corresponding N-acyl
derivatives (2, 9a–c, and 10a–c) in 79–99% isolated
yields. The O-acyl (acetyl, pivaloyl) groups, the O-acetal
group, the 2-N-Phth group, and the glycosidic link-
ages stayed intact in this transformation. Interestingly,
when FmocCl (9-fluorenylmethoxycarbonyl chloride)
was used in the treatment of disaccharide 7, com-
pound 9d with a free 2-amino-group was obtained
exclusively in 78% yield (entry 5), where the correspond-
ing 2-N-Fmoc group could not survive in the presence of
DMAP in refluxing pyridine. This result provides an
easy entry to the selective deprotection of the 2-N-
DMP-group.
rides and glycoconjugates of biological and pharmaco-
logical significance.12
Acknowledgments
Financial support from the National Natural Science
Foundation of China (20572122, 20321202) and the
Committee of Science and Technology of Shanghai
(06XD14026) is gratefully acknowledged.
References and notes
Subsequent removal of the N-Phth, O-acyl, and O-acetal
protections in disaccharides 9a/b and 10a/b under con-
ventional acidic and basic conditions provided the corre-
sponding disaccharides 11a/b and 12a/b in satisfactory
yields (60–92%, Scheme 2), where the two 2-amino-
groups of the glucosamine residues could be distin-
guished with different substitutions.
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325779.
Given the efficiency of the present transformation of the
2-N-DMP-protection of glucosamines into the corre-
sponding N-acyl (and –NH2) derivatives (in the presence
of acyl chlorides and DMAP in pyridine), we can foresee
the further application of the 2-N-DMP-protection in
the synthesis of glucosamine-containing oligosaccha-
OH
O
OH
HO
HO
HO
HO
HO
O
O
a
b
O
O
HO
O
HO
9a, 9b
OMP
OMP
OMP
OMP
HO
NH
NH
NH2
NH2
O
O
11a (72%)
11b (92%)
OH
O
OH
O
HO
HO
HO
HO
HO
O
O HO
O
O
10a, 10b
HO
HO
NH
NH
NH2
NH2
O
O
12a (60%)
12b (71%)
Scheme 2. Reagents and conditions: (a) NH2NH2ÆH2O, MeOH, reflux, overnight; then 1 M MeONa in MeOH, rt, overnight; (b) TsOHÆH2O
(6 equiv), MeOH, rt, overnight; then NH2NH2ÆH2O, MeOH, reflux, overnight.

7052
Y. Yang, B. Yu / Tetrahedron Letters 48 (2007) 7049–7052
´
´
´
5. Garcıa-Alvarez, I.; Corrales, G.; Doncel-Perez, E.;
4.45 (m, 4H), 4.18 (t, 1H, J = 12.3 Hz), 3.88–3.99 (m, 3H),
3.71 (s, 3H), 3.62–3.64 (m, 1H), 2.19 (t, 2H, J = 7.5 Hz),
2.11 (s, 3H), 2.03 (s, 3H), 1.85 (s, 3H), 1.60–1.63 (m, 2H),
1.31–1.34 (m, 4H), 1.24 (s, 9H), 1.23 (s, 9H), 0.89 (t, 3H,
´
Munoz, A.; Nieto-Sampedro, M.; Fernandez-Mayoralas,
˜
A. J. Med. Chem. 2007, 50, 364–373.
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Bonnaffe, D. Eur. J. Org. Chem. 2004, 2107–2117; (c) Liao,
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(b) Heyns, K.; Harrison, R.; Propp, K.; Paulsen, H. J.
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65, 11–22; (f) Lafont, D.; Descotes, G. Carbohydr. Res.
1988, 175, 35–48.
J = 6.3 Hz).
MALDI-HRMS:
m/z
C49H64N2O18
[M+Na]+ calcd 991.4044, found 991.4046. Compound
28
9d: ½aꢁD ꢀ9.2 (c 0.85, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.83–7.86 (m, 2H), 7.72–7.75 (m, 2H), 6.85 (d,
2H, J = 8.7 Hz), 6.69 (d, 2H, J = 8.7 Hz), 5.85 (d, 1H,
J = 7.2 Hz), 5.79 (t, 1H, J = 9.3 Hz), 5.50 (d, 1H,
J = 8.4 Hz), 5.22 (d, 1H, J = 8.1 Hz), 5.11 (t, 1H,
J = 9.6 Hz), 4.34 (t, 1H, J = 9.6 Hz), 4.14–4.28 (m, 3H),
3.92–4.03 (m, 2H), 3.71 (s, 3H), 3.44–3.57 (m, 4H), 2.11 (s,
3H), 2.04 (s, 3H), 1.85 (s, 3H), 1.19 (s, 9H), 1.04 (s, 9H).
MALDI-HRMS: m/z C43H54N2O17 [M+Na]+ calcd
28
893.3307, found 893.3315. Compound 10b: ½aꢁD ꢀ5.7 (c
1
0.62, CHCl3); H NMR (300 MHz, CDCl3): d 7.12–7.68
(m, 9H), 6.87 (d, 2H, J = 9.3 Hz), 6.77 (d, 2H, J = 9.0 Hz),
6.11 (d, 1H, J = 6.6 Hz), 5.66–5.82 (m, 3H), 5.41 (s, 1H),
5.12 (t, 1H,J = 9.6 Hz), 4.87 (t, 1H, J = 10.2 Hz), 4.35 (dd,
1H, J = 8.4, 10.8 Hz), 4.23–4.28 (m, 2H), 4.11 (dd, 1H,
J = 5.7, 12.3 Hz), 3.69–3.82 (m, 6H), 3.51–3.57 (m, 1H),
3.19–3.27 (m, 1H), 2.13 (s, 3H), 1.99–2.06 (m, 5H), 1.81 (s,
3H), 1.43–1.54 (m, 2H), 1.19–1.34 (m, 4H), 0.87 (t, 3H,
10. Li, Y.; Li, C.; Wang, P.; Chu, S.; Guan, H.; Yu, B.
Tetrahedron Lett. 2004, 45, 611–613.
11. (a) Symes, J.; Modro, T. A. Can. J. Chem. 1986, 64, 1702–
1707; (b) Challis, B. C.; Iley, J. N. J. Chem. Soc., Perkin
Trans. 2 1987, 1489–1495.
J = 6.9 Hz).
MALDI-HRMS:
m/z
C46H52N2O16
12. All the new compounds in this work give satisfactory
analytical data; some selected data are shown below. 2:
[M+Na]+ calcd 911.3214, found 911.3209. Compound
28
11b: ½aꢁD ꢀ13.5 (c 0.83, MeOH); 1H NMR (300 MHz,
28
½aꢁD ꢀ10.1 (c 1.04, CHCl3); 1H NMR (300 MHz, CDCl3):
pyridine-d5): d 9.03 (d, 1H, J = 7.8 Hz), 7.32 (d, 2H,
J = 9.3 Hz), 6.92 (d, 2H, J = 9.0 Hz), 5.80 (d, 1H,
J = 7.5 Hz), 5.04 (d, 1H, J = 7.8 Hz), 4.64–4.66 (m, 2H),
4.48–4.52 (m, 1H), 4.28–4.41 (m, 4H), 4.18 (t, 1H,
J = 9.0 Hz), 3.94–4.01 (m, 3H), 3.62 (s, 3H), 3.31 (t, 1H,
J = 7.8 Hz), 2.41 (t, 2H, J = 7.5 Hz), 1.76–1.82 (m, 2H),
1.13–1.34 (m, 4H), 0.73 (t, 3H, J = 7.2 Hz). 13C NMR
(75 MHz, pyridine-d5): d 173.9, 155.6, 152.8, 118.6, 115.2,
105.3, 101.0, 81.3, 78.8, 78.1, 76.9, 73.5, 71.7, 62.4, 61.8,
58.6, 57.5, 55.7, 37.2, 31.8, 26.2, 22.8, 14.2. MALDI-
HRMS: m/z C25H40N2O11 [M+Na]+ calcd 567.2538,
found 567.2524.
d 6.92 (d, 2H, J = 9.0 Hz), 6.77 (d, 2H, J = 9.0 Hz), 5.97
(d, 1H, J = 9.0 Hz), 5.39 (t, 1H, J = 9.6 Hz), 5.08–5.15 (m,
2H), 4.27 (dd, 1H, J = 5.4, 12.6 Hz), 4.07–4.15 (m, 2H),
3.79–3.83 (m, 1H), 3.75 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H),
2.02 (s, 3H), 1.95 (s, 3H). MALDI-MS: m/z C21H27NO10
28
[M+Na]+ calcd 476.2, found 476.2. Compound 9b: ½aꢁD
ꢀ25.8 (c 0.52, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.83–7.86 (m, 2H), 7.74–7.78 (m, 2H), 6.77 (d, 2H,
J = 9.0 Hz), 6.69 (d, 2H, J = 9.0 Hz), 5.89 (d, 1H,
J = 9.6 Hz), 5.79 (t, 1H, J = 9.9 Hz), 5.46 (d, 1H, J =
7.8 Hz), 5.09–5.15 (m, 2H), 4.82 (d, 1H, J = 5.1 Hz), 4.25–