N-Dimethylphosphoryl-protected glucosamine trichloroacetimidate as an effective glycosylation donor

Article abstract of DOI:10.1016/j.tetlet.2007.04.150

Glycosylation of a variety of alcohols with 3,4,6-tri-O-acetyl-2-N-dimethylphosphoryl-2-deoxy-α-d-glucopyranosyl trichloroacetimidate as a glycosyl donor provided the corresponding coupled products in high yields and good β-selectivity. N-Dimethylphosphor

Full text of DOI:10.1016/j.tetlet.2007.04.150

Tetrahedron Letters 48 (2007) 4557–4560
N-Dimethylphosphoryl-protected glucosamine
trichloroacetimidate as an effective glycosylation donor
You Yanga and Biao Yub,*
aDepartment of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
bState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 2 April 2007; revised 26 April 2007; accepted 26 April 2007
Available online 5 May 2007
Abstract—Glycosylation of a variety of alcohols with 3,4,6-tri-O-acetyl-2-N-dimethylphosphoryl-2-deoxy-a-D-glucopyranosyl tri-
chloroacetimidate as a glycosyl donor provided the corresponding coupled products in high yields and good b-selectivity. N-Di-
methylphosphoryl-protection stayed stable under acidic and basic conditions for further elaboration of the glucosamine-
containing oligosaccharides.
Ó 2007 Elsevier Ltd. All rights reserved.
2-Amino-2-deoxy-D-glucopyranose (D-glucosamine) is
an integral component of numerous biologically impor-
tant prokaryotic and eukaryotic glycoconjugates.1 Nev-
ertheless, introduction of the glucosamine residue into
oligosaccharides has been a long-standing problem in
preparative carbohydrate chemistry.2–19 It has been
found that the 2-N-protecting groups always play a
key role in glycosidic coupling with glucosamine deriva-
tives as both donors2–18 and acceptors.19 A wide variety
of the protecting groups for the 2-amino group of gluco-
samine have been developed, those include N-phthal-
oyl,3 N-dichlorophthaloyl,4 N-tetrachlorophthaloyl,5
N-dithiasuccinoyl,6 N-2,2,2-trichloroethoxycarbonyl,7
N-trichloroacetyl,8 N-trifluoroacetyl,9 N,N-diacetyl,10
N-acetyl-N-2,2,2-trichloroethoxycarbonyl,11 N-p-nitro-
benzyloxycarbonyl,12 N-dimethylmaleoyl,13 and N-di-
benzyl group.14 In addition, masking of the 2-amino
group as 1,2-oxazoline,15 azide,16 dimethylpyrrole,17 or
the recent 2N,3O-oxazolidinone18 also renders a choice
for the synthesis of glucosamine-containing oligosaccha-
rides. These protecting protocols have been proven suc-
cessful to a certain extent; however, the non-generality
of glycosylation and protection–deprotection conditions
restricts their ubiquitous application.
Zervas and Konstas reported in 1960 the use of a
2-N-diphenylphosphoryl(DPP)-protected glucosamine
1-bromide (i.e., 3,4,6-tri-O-acetyl-2-N-DPP-2-deoxy-
glucopyranosyl bromide) as a glycosyl donor.20 Glyco-
sylation with such a donor under Koenigs–Knorr condi-
tions that employed poisonous heavy metal salts (e.g.,
Hg(CN)2) as promoters gave the corresponding b-glyco-
sides selectively albeit in very low yields. This has dis-
couraged further application of these type of 2-N-
phosphoryl-protected glucosamine derivatives in oligo-
saccharide synthesis.21 However, one might envision
the enhancement of the coupling efficiency by changing
the leaving group to trichloroacetimidate, because gly-
cosyl trichloroacetimidates have been proved to be, in
general, superior to glycosyl bromides as glycosylation
donors.22 Thus, N-phosphoryl-protection shall find
new applications in modern carbohydrate synthesis.
Herein, we report the preliminary experimental results
on this matter.23
Starting from D-glucosamine, 1,3,4,6-tetra-O-acetyl-b-
D-glucosamine hydrochloride (1) was readily prepared
in an overall 52% yield through three steps without the
need of column chromatography, that is, condensation
of the 2-amino group with p-anisaldehyde, acetylation
of the remaining hydroxyl groups, and releasing of the
2-amino group with HCl in acetone (Scheme 1).24 Treat-
ment of amine 1 with diphenyl chlorophosphate in the
presence of DMAP and Et3N gave N-DPP-glucosamine
derivative 2 in 96% yield. However, selective removal of
Keywords: Dimethylphosphoryl; Protecting group; Glucosamine;
Trichloroacetimidate; Glycosylation.
*
Corresponding author. Tel.: +86 54925131; fax: +86 64166128;
e-mail: byu@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.150

4558
Y. Yang, B. Yu / Tetrahedron Letters 48 (2007) 4557–4560
the anomeric O-acetyl group on 2 met with difficulties;
OAc
O
treatment with hydrazine acetate,25 benzylamine,26 or
ethylene diamine27 did not lead to clean reactions.
Fortunately, upon subjection of compound 2 to ammo-
nia in THF/MeOH, lactol product 3 was isolated in an
excellent 94% yield, where the trans-esterification reac-
tion also took place to convert the 2-N-DPP group into
the 2-N-dimethylphosphoryl(DMP) group. Treatment
of lactol 3 with CCl3CN in the presence of DBU affor-
ded a-trichloroacetimidate 4 in 82% yield, which was
found stable under storage. The corresponding b-ano-
mer was not detected.
ref. 24
AcO
AcO
D-Glucosamine
OAc
3 steps, 52%
NH2HCl
1
OAc
OAc
O
O
a
c
b
AcO
AcO
AcO
AcO
OAc
OH
NH
2
NH
DPP
DMP
3
O
P
OAc
O
OPh
OPh
DPP =
DMP =
AcO
AcO
CCl3
NH
O
P
OMe
OMe
NH
O
To examine the donor properties of 2-N-DMP-protected
glucosame imidate 4 in glycosylation, a series of alcohols
(5a–h) were selected as acceptors, and a typical set of
conditions for glycosylation with trichloroacetimidates
DMP
4
Scheme 1. Reagents and conditions: (a) (PhO)2POCl (2 equiv), DMAP
(0.2 equiv), Et3N (3 equiv), CH2Cl2, 0 °C to rt, 3 h, 96%; (b) NH3,
THF/MeOH (7:3), 0 °C, 40 min, 94%; (c) CCl3CN (5 equiv), DBU
(0.1 equiv), CH2Cl2, rt, 3 h, 82%.
˚
(0.1 equiv of TMSOTf, 4 A MS, CH2Cl2, rt, over-
night)22 was applied. The results are listed in Table 1.
The corresponding coupling products (6a–h) were
Table 1. Glycosylation of alcohols (5a–h) with 3,4,6-tri-O-acetyl-2-N-DMP-2-deoxy-glucopyranosyl trichloroacetimidate (4)a
OAc
O
OAc
O
TMSOTf (0.1 equiv),
AcO
AcO
AcO
AcO
O
+
ROH
5a-h
(1 equiv)
CCl3
NH
R
4A MS, CH2Cl2,
-15 oC to rt
NH
O
NH
DMP
DMP
6a-h
4 (1.4 equiv)
Entry ROH
Product
b:a H-1 (ppm, J)
Yield (%)
88
OAc
O
AcO
AcO
6a
O
1
2
3
AllOH (5a)
b only 4.38, 8.1 Hz
b only 4.32, 7.8 Hz
b only 4.40, 7.9 Hz
NHDMP
OAc
O
AcO
AcO
n-C7H15OH (5b)
81
92
OC7H15
6b
NHDMP
O
OAc
O
O
O
AcO
AcO
6c
H
H
H
H
H
NHDMP
5c
HO
OAc
O
4b
4.3:1 4.82, 8.4 Hz (b) 5.40, br s (a)
95
AcO
AcO
HO
OMe
5d
OMP
6d
NHDMP
OAc
O
O
5b
3.2:1, 4.94, 7.8 Hz (b) 5.50, 3.0 Hz (a) 89
AcO
AcO
HO
6e
5e
NHDMP
OAc
OH
O
O
O
O
AcO
AcO
O
O
O
6f
5f
O
6
b only 4.49, 7.8 Hz
85
NHDMP
O
O
O
O

Y. Yang, B. Yu / Tetrahedron Letters 48 (2007) 4557–4560
4559
Table 1 (continued)
Entry ROH
Product
b:a H-1 (ppm, J)
Yield (%)
O
O
OAc
O
O
O
AcO
AcO
7
b only 4.79, 8.4 Hz
86
HO
O
6g
5g
O
O
O
O
NHDMP
O
O
O
OAc
O
O
O
OH
AcO
AcO
O
8c
1.8:1 4.50, 8.1 Hz (b) 5.03, br s (a)
90
6h
5h
O
NHDMP
O
O
O
O
a
˚
For a typical procedure for glycosylation: To a stirred mixture of 4 (56 mg, 0.1 mmol), acceptor 5c (29 mg, 0.07 mmol), and pulverized 4 A
molecular sieves (80 mg) in CH2Cl2 (2 mL) at ꢀ15 °C, was added dropwise a solution of TMSOTf in CH2Cl2 (0.1 M, 0.1 mL) under the protection
of Ar. After 0.5 h, the temperature was allowed to warm up naturally to room temperature and the stirring continued overnight. The mixture was
then filtered through a pad of Celite and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether–
EtOAc 1:1) to afford 6c (52 mg, 92%) as a white solid.
b 1:1 equiv of 4 and 5d/e were used.
c 0.3 equiv of TMSOTf was used to drive the reaction to completion.
obtained in high yields (81–95%), whether simple alco-
hols (allyl alcohol, n-heptanol, p-methoxylphenol, and
3,5-dimethylphenol), steroidal alcohol (5c), or sugar
alcohols (5f–h) were used as acceptors. Most of the cou-
pling reactions provided b-glycosides exclusively (entries
1–3, 6, and 7). However, coupling with phenols (5d/e)
and furanose derivative 5h provided a considerable
amount of the a-anomers (entries 4, 5, and 8). The
neighboring participation of the 2-dialkylphosphate
group in glycosylation has been proven unfavorable,
therefore, the present 1,2-trans-b-selectivity might be ex-
plained by a SN2 attack of the alcohol on the glycosyl a-
triflate (or imidate) intermediate.23 While coupling via
SN1 attack on a transient glycosyl oxacarbenium inter-
mediate leads to minor a-glycosides.
(K2CO3, MeOH/CH2Cl2) to remove the 3,4,6-O-acetyl
groups, providing triols 7a/b (90%), followed by acidic
conditions (TsOHÆH2O, DMF, 43 °C) to form the 4,6-
benzylidene, affording 8a/b (82%). The 2-N-DMP-pro-
tected glucosamine derivatives 8a/b were then employed
as acceptors to couple with 2-N-DMP-protected gluco-
samine donor 4. Under similar conditions described
above, glycosylation of 8a/b with 4 furnished the
(1!3)-linked-b-disaccharides in satisfactory yields
(77% and 79%); the corresponding a products were
again not isolated.
In summary, we have shown that 3,4,6-tri-O-acetyl-2-
N-dimethylphosphoryl-2-deoxy-a-D-glucopyranosyl tri-
chloroacetimidate is a readily accessible and effective
glycosylation donor. The glycosidic bond formation is
high yielding and b-selective. The 2-N-DMP-protection
can tolerate certain basic and acidic conditions for the
manipulation of other protecting groups, and could be
removed finally in the presence of NaOH21 or hydra-
zine.28 Thus, the present 2-N-DMP-protection shall find
applications in the synthesis of glucosamine-containing
glycoconjugates.29
The compatibility of the 2-N-DMP group in the subse-
quent oligosaccharide synthesis was then briefly exam-
ined (Scheme 2). Thus, the allyl and p-methoxylphenol
b-glycosides (6a/6db) were subjected to basic conditions
OH
O
Ph
6a
O
O
a
O
HO
HO
b
OR
OR
HO
or
NH
NH
6dβ
Acknowledgements
DMP
AcO
DMP
7a R = All
7b R = MP
8a R = All
8b R = MP
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.
O
Ph
O
O
4, c
O
OR
9a R = All
AcO
AcO
O
NH
NH
DMP
9b R = MP
DMP
References and notes
Scheme 2. Reagents and conditions: (a) K2CO3 (0.1 equiv), MeOH/
CH2Cl2, rt, 2 h, 90%; (b) PhCH(OMe)2 (2 equiv), TsOHÆH2O
(0.2 equiv), DMF, 43 °C (reduced pressure), overnight, 82%; (c) 4
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(1.4 equiv), TMSOTf (0.3 equiv), 4 A MS, CH2Cl2, ꢀ15 °C to rt,
overnight, 79% (for 9a), 77% (for 9b).

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Y. Yang, B. Yu / Tetrahedron Letters 48 (2007) 4557–4560
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2005, 70, 6265–6273.
20. Zervas, L.; Konstas, S. Chem. Ber. 1960, 93, 435–446.
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28. Lafont, D.; Descotes, G. Carbohydr. Res. 1988, 175, 35–
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29. All the new compounds appearing in this work give
satisfactory analytical data; some selected data are shown
below. Compound 4: 1H NMR (300 MHz, CDCl3): d 8.81
(s, 1H), 6.36 (d, 1H, J = 3.3 Hz), 5.28 (t, 1H, J = 10.2 Hz),
5.16 (t, 1H, J = 9.9 Hz), 4.25 (dd, 1H, J = 3.6, 12.3 Hz),
4.13–4.06 (m, 2H), 3.71–3.63 (m, 7H), 2.79 (t, 1H,
J = 10.8 Hz), 2.08 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H).
MALDI-MS: m/z C16H24Cl3N2O11P [MꢀCCl3CN+Na+]
calcd 436.1; found, 436.4. Compound 6a: 1H NMR
(300 MHz, CDCl3): d 5.96–5.85 (m, 1H), 5.31 (d, 1H,
J = 17.7 Hz), 5.21 (d, 1H, J = 10.5 Hz), 5.05–4.97 (m,
2H), 4.40–4.35 (m, 2H), 4.25 (dd, 1H, J = 4.8, 12.0 Hz),
4.14–4.09 (m, 2H), 3.76–3.63 (m, 7H), 3.25–3.19 (m, 1H),
2.89 (t, 1H, J = 9.9 Hz), 2.07 (s, 3H), 2.05 (s, 3H), 2.01 (s,
3H). 13C NMR (75 MHz, CDCl3): d 170.9, 170.6, 169.4,
133.5, 118.3, 101.3 (d, JC,P = 3.1 Hz), 74.0 (d,
JC,P = 1.6 Hz), 71.7, 70.4, 68.7, 62.2, 56.6, 53.5 (t,
JC,P = 3.4 Hz), 20.7, 20.7, 20.6. MALDI-HRMS: m/z
C17H28NO11P [M+Na+] calcd 476.1309; found,
1
476.1292. Compound 7a: H NMR (300 MHz, CD3OD):
d 6.02–5.90 (m, 1H), 5.37–5.30 (m, 1H), 5.18–5.14 (m, 1H),
4.45–4.38 (m, 1H), 4.32 (d, 1H, J = 8.4 Hz), 4.15–4.08 (m,
1H), 3.87 (dd, 1H, J = 1.5, 11.7 Hz), 3.75–3.63 (m, 7H),
3.32–3.23 (m, 3H), 2.89–2.85 (m, 1H). 13C NMR (75 MHz,
CD3OD): d 136.0, 117.7, 103.3 (d, JC,P = 3.1 Hz), 78.1 (d,
JC,P = 2.5 Hz), 78.0, 72.6, 71.4, 63.1, 60.1, 54.3 (d,
JC,P = 4.1 Hz). MALDI-HRMS: m/z C11H22NO8P
[M+Na+] calcd 350.0986; found, 350.0975. Compound
8a: 1H NMR (300 MHz, CDCl3): d 7.51–7.48 (m, 2H),
7.36–7.35 (m, 3H), 5.98–5.87 (m, 1H), 5.55 (s, 1H), 5.32 (d,
1H, J = 17.4 Hz), 5.23 (d, 1H, J = 10.2 Hz), 4.45 (d, 1H,
J = 8.4 Hz), 4.42–4.31 (m, 2H), 4.11 (dd, 1H, J = 6.6,
12.0 Hz), 4.02 (br d, 1H), 3.90–3.64 (m, 8H), 3.57 (t, 1H,
J = 9.3 Hz), 3.49–3.41 (m, 1H), 3.21 (t, 1H, J = 7.8 Hz),
3.11–3.01 (m, 1H). MALDI-HRMS: m/z C18H26NO8P
[M+Na+] calcd 438.1279; found, 438.1288. Compound 9a:
1H NMR (300 MHz, CDCl3): d 7.47–7.45 (m, 2H), 7.30–
7.25 (m, 3H), 5.96–5.87 (m, 1H), 5.52 (s, 1H), 5.29 (d, 1H,
J = 17.4 Hz), 5.16 (d, 1H, J = 10.8 Hz), 5.00–4.95 (m,
2H), 4.85 (d, 1H, J = 8.4 Hz ), 4.67 (d, 1H, J = 6.6 Hz),
4.55 (t, 1H, J = 8.1 Hz), 4.41–4.29 (m, 2H), 4.22–4.06 (m,
3H), 3.80–3.42 (m, 18H), 3.29–3.01 (m, 2H), 2.01 (s, 3H),
1.96 (s, 3H), 1.95 (s, 3H). MALDI-HRMS: m/z
C32H48N2O18P2 [M+Na+] calcd 833.2247; found,
833.2270.
23. During this work, 2-O-dialkylphosphates were reported to
be effective protecting groups for the 1,2-trans-glycosyl-
ation, see: Yamada, T.; Takemura, K.; Yoshida, J.;
Yamago, S. Angew. Chem., Int. Ed. 2006, 45, 7575–7578.