6- O -Amino-2- O -carboxymethyl glucopyranoside as novel glycoaminoxy acid building block for the construction of oligosaccharide mimetics

Article abstract of DOI:10.1055/s-0030-1260139

The synthesis of diversely functionalized carbohydrate building blocks is of great interest towards the generation of new carbohydrate mimetics. Glycoaminoxy acids are recently developed glycoamino acid analogues with both an aminoxy and a carboxyl group

Full text of DOI:10.1055/s-0030-1260139

PAPER
2761
6-O-Amino-2-O-carboxymethyl Glucopyranoside as Novel Glycoaminoxy
Acid Building Block for the Construction of Oligosaccharide Mimetics
N
ovel Glycoa
m
h
inoxy Acid
B
u
uilding Blo
o
S
ide Mimeticsong,a Xiao-Peng He,a,b Guo-Rong Chen,*a Juan Xie*b
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology,
Shanghai 200237, P. R. of China
Fax +86(21)64252758; E-mail: mrs_guorongchen@ecust.edu.cn
PPSM, ENS Cachan, CNRS, 61 Ave President Wilson, 94230 Cachan, France
Fax +33(1)47402454; E-mail: joanne.xie@ens-cachan.fr
b
Received 22 April 2011; revised 13 June 2011
teins’,7 or as chemoselective reagents for the covalent
capture of glycans in microarray.8 Preparation of various
glycoaminoxy acid derivatives would therefore furnish
versatile building units for the subsequent chemical liga-
Abstract: The synthesis of diversely functionalized carbohydrate
building blocks is of great interest towards the generation of new
carbohydrate mimetics. Glycoaminoxy acids are recently devel-
oped glycoamino acid analogues with both an aminoxy and a car-
boxyl group connected to the sugar scaffold. These molecules could tions with peptides or numerous other biomolecules
through either amide, oxime, or oxyamine bonds.9
be readily used for the synthesis of various glycoconjugates through
N-oxy amide or oxime bond, thus providing a potent tool for the de-
sign of novel functional carbohydrate mimetics. Here, the efficient
synthesis of 2,6-functionalized pyranoid glycoaminoxy acid from
commercially available methyl glucopyranoside is reported. The
subsequent assembly of this glycoaminoxy acid building unit via N-
acylation led successfully to the novel 2,6-linked oligosaccharide
mimetics.
O
O
glycoaminoxy acids
(PG1 = PG2
protecting groups):
H2N
OH
=
β-aminoxy acid
Key words: aminoxy acids, glycoaminoxy acids, oligosaccharide
mimetics, carbohydrates, oligomers
O
O
O
O
O
O
PG2O2C
PG1HNO
PG2O2C
PG1HNO
Development of diversely functionalized carbohydrate
building blocks represents a useful tactic for the synthesis
of novel carbohydrate mimetics. Multifunctionalized car-
bohydrate derivatives such as sugar amino acids have
been successfully utilized as building blocks toward the
construction of various glycoconjugates as well as the de-
sign of bioactive molecules for drug discovery.1
A
B
BnO
OBn
BnO
BnO
OBn
PG2O2C
O
ONHPG1
ONHPG1
O
O
MeO
CO2PG2
Recently, aminoxy acids, a unique class of unnatural ami-
no acids wherein an aminoxy function was introduced in
place of the amine group (Figure 1), have emerged as very
attractive chemical scaffolds since specific turns and helix
conformations could be discovered in peptidomemitics
comprising these moieties.2 We first synthesized the pyr-
anoid glycoaminoxy acid C (Figure 1) with aminoxy and
carboxylic functions on the 1,6-position of the sugar ring
as a new range of sugar building block from the respective
a-C-allyl glycoside.3 This compound has been successful-
ly applied for the synthesis of N-oxy amide-linked disac-
charide and glycosyl amino acid mimetics. Moreover, the
synthesis of the oligomers of furanoid glycoaminoxy
acids A4 and B5 have also been reported.
C
D
Figure 1 Structures of aminoxy acid and glycoaminoxy acid buil-
ding blocks
To the best of our knowledge, only three glycoaminoxy
acids (compounds A, B, and C, Figure 1) have been de-
veloped up to date. As a continuing program on the syn-
thesis of functional carbohydrate mimetics,10,11 we report
herein the synthesis of a novel pyranoid glycoaminoxy
acid D (Figure 1) with aminoxy and carboxylic function
on 2,6-position of the sugar template as well as the con-
struction of their oligomers.
To prepare pyranoid glycoaminoxy acid derivatives D, the
commercially available methyl 3,4-di-O-benzyl-a-D-glu-
copyranoside (1)12 was chosen as the starting material to
introduce aminoxy and carboxylic functions onto its 2,6-
positions (Scheme 1).
On the other hand, aminoxy-functionalized sugars have
been reported for the glycoconjugate synthesis,6 as
monosaccharide templates for the synthesis of ‘carbopro-
SYNTHESIS 2011, No. 17, pp 2761–2766
Advanced online publication: 28.07.2011
DOI: 10.1055/s-0030-1260139; Art ID: H42811SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1
The 6-hydroxy group was first regioselectively protected
via TBSCl to the TBS ether 2. The carboxyl function was
then easily introduced onto the 2-position through O-

2762
Z. Song et al.
PAPER
TBSO
BnO
HO
TBSO
BnO
O
O
O
OMe
OH
OMe
OH
OMe
O
a
b
BnO
CO2t-Bu
OBn
OBn
OBn
3
2
1
NH2
O
O
OMe
O
HO
PhthNO
BnO
BnO
BnO
O
O
OMe
OMe
O
OBn
e
f
c
d
CO2t-Bu
6
BnO
O
ONPhth
OBn
OBn
O
CO2t-Bu
OMe
O
CO2t-Bu
4
5
OBn
CO2H
7
Scheme 1 Synthesis of glycoaminoxy acid building blocks 6 and 7. Reagents and conditions: (a) TBSCl, DMAP, pyridine, 92%; (b)
BrCH2CO2t-Bu, NaH, DMF, 75%; (c) AcCl (cat.), MeOH, 94%; (d) Ph3P, DIAD, PhthNOH, CH2Cl2, 83%; (e) H2NNH2, MeOH, 75%; (f) TFA,
CH2Cl2, 85%.
alkylation with BrCH2CO2t-Bu in 75% yield. Notably, glucopyranoside template. Such a method should be
with catalytic amount of AcCl, the TBS group could be applicable to the synthesis of other glycoside-derived
selectively eliminated without deprotecting the tert-butyl glycoaminoxy acids. Furthermore, the obtained glyco-
ester on the 2-position of the sugar ring.
aminoxy acid was successfully used as a building block to
construct novel 2,6-linked oligosaccharide mimetics via
N-acylation.
Mitsunobu reaction of 4 with N-hydroxyphthalimide se-
quentially led to the glycoaminoxy ester 5 in its fully pro-
tected form in 83% yield. Nevertheless, it was noticed that It is projected that the glycoaminoxy acid building units
the introduction of the phthalimido group at the 6-position may serve as useful tools for the subsequent chemical li-
of compound 1 using Mitsunobu reaction followed by 2- gations with various amines, carboxylic acids or alde-
O-alkylation reaction failed to give the desired compound hydes through, respectively, the amide, oxime or
5, due most likely to the instability of phthalimidoxy oxyamine bond, leading to a novel flourish class of oli-
group under basic or nucleophilic conditions.5 A follow- gosaccharide mimetics with potentially diverse practical-
ing hydrazinolysis of 5 gave the oxyamine 6, while treat- ities. Programs related to this subject are currently
ment of the same compound with TFA offered the underway in our laboratories.
carboxylic acid 7 as the sole product.
After obtaining these functionalized glycoaminoxy acid
building blocks, the coupling of the oxyamine 6 with the
carboxylic acid 7 was sequentially realized. Under the ac-
tion of EDC/HOBt in a mixture of CH2Cl2 and DMF, the
corresponding dimer 8 was obtained in 74% yield
(Scheme 2). Subsequent treatment of 8 with hydrazine or
TFA similarly gave the corresponding oxyamine 9 and the
Solvents were purified by standard procedures. Petroleum ether
(PE) used refers to the fraction boiling in the range 60–90 °C. The
organic extracts were dried over MgSO4. 1H and 13C NMR spectra
were recorded on a Bruker AM 400 spectrometer in CDCl3 solu-
tions using TMS as the internal standard (chemical shifts in parts
per million). Standard abbreviations are used to describe the signal
multiplicity. All reactions were monitored by TLC (Yantai Marine
Chemical Co. Ltd., P. R. of China). Optical rotations were measured
carboxylic acid 10 in modest yields, respectively. Liga- using a Perkin-Elmer 241 polarimeter at r.t. in a 10 cm, 1 mL cell.
High-resolution mass spectra (HRMS) were recorded on a Waters
LCT Premier XE spectrometer using standard conditions (ESI, 70
eV).
tion of the dimer 10 with the monomeric oxyamine 6 led
to the trimer 11 in 51% yield. Eventually, the tetramer 12
could be obtained by the N-acylation of dimers 9 and 10
in a moderate yield of 48%.
Methyl 3,4-Di-O-benzyl-6-O-tert-butyldimethylsilyl-a-D-glu-
copyranoside (2)
The structures of these oligomers have been confirmed by
NMR and HRMS. The protons of all N-oxy amide bonds
appeared at around 10 ppm in their 1H NMR spectra (com-
pounds 8–12, see Supporting Information) in CDCl3 solu-
tion.
To a solution of compound 1 (560 mg, 1.50 mmol) in pyridine (10
mL) were added TBSCl (271 mg, 1.80 mmol) and DMAP (36 mg,
0.30 mmol) at 0 °C. The resulting mixture was stirred at r.t. for 5 h
under argon and then extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layers were washed with brine (20 mL), dried, fil-
tered, and evaporated. The residue was purified by column
chromatography over silica gel (EtOAc–PE, 1:8) to afford 2 as a
In summary, this paper depicts the efficient synthesis of
new glycoaminoxy acid derivatives in which aminoxy and
carboxylic acid functions have been easily introduced
onto the 2,6-position of a methyl 3,4-di-O-benzyl-a-D-
25
white powder (672 mg, 92%); Rf = 0.52 (EtOAc–PE, 1:3); [a]D
+64.2 (c 0.39, CH2Cl2).
Synthesis 2011, No. 17, 2761–2766 © Thieme Stuttgart · New York

PAPER
Novel Glycoaminoxy Acid Building Block for Oligosaccharide Mimetics
2763
6 + 7
a
74%
BnO
OBn
BnO
OBn
t-Bu
O
O
O
O
O
ONPhth
O
O
NH
O
MeO
MeO
8
64%
b
BnO
O
OBn
BnO
O
OBn
t-Bu
O
O
O
ONH2
O
O
NH
O
MeO
MeO
9
8
c
71%
BnO
OBn
BnO
OBn
HO
O
O
O
O
ONPhth
O
O
NH
O
MeO
MeO
10
6, a
51%
BnO
OBn
BnO
OBn
BnO
OBn
O
O
t-BuO2C
O
O
ONPhth
O
O
O
NH
O
MeO
O
NH
O
MeO
11
MeO
9 + 10
a
48%
BnO
OBn
BnO
OBn
BnO
OBn
O
O
t-BuO2C
O
O
ONPhth
O
O
O
NH
O
MeO
O
NH
O
MeO
12
MeO
2
Scheme 2 Synthesis of oligo glycoaminoxy acids. Reagents and conditions: (a) EDC, HOBt, CH2Cl2–DMF; (b) H2NNH2, MeOH; (c) TFA,
CH2Cl2.
1H NMR (400 MHz, CDCl3): d = 7.32–7.23 (m, 10 H), 4.84 (d,
J = 11.2 Hz, 1 H), 4.63 (m, 3 H), 4.58 (d, J = 3.6 Hz, 1 H), 4.03 (t,
J = 9.2 Hz, 1 H), 3.75–3.74 (m, 2 H), 3.54 (ddd, J = 2.4, 4.0, 9.6 Hz,
1 H), 3.40 (t, J = 9.2 Hz, 1 H), 3.30 (dd, J = 3.6, 9.6 Hz, 1 H), 3.27
(s, 3 H), 0.84 (s, 9 H), –0.001 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 138.7, 138.2, 128.5, 128.4, 128.1,
128.0, 127.9, 127.7, 97.3, 79.9, 77.6, 74.5, 73.6, 73.0, 71.2, 62.5,
54.9, 28.1, 28.0, 26.0, 18.4, –5.1, –5.3.
Methyl 3,4-Di-O-benzyl-6-O-tert-butyldimethylsilyl-2-O-tert-
butoxycarbonylmethyl-a-D-glucopyranoside (3)
To a solution of compound 2 (590 mg, 1.21 mmol) in DMF (5 mL)
were added NaH (43.7 mg, 1.82 mmol) and tert-butyl bromoacetate
(292 mL, 1.82 mmol) at 0 °C. After stirring at r.t. for 2 h under ar-
gon, the reaction was quenched with H2O (2–3 mL), and the mixture
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine (20 mL), dried, filtered, and evaporated.
The residue was purified by column chromatography over silica gel
(EtOAc–PE, 1:20) to afford 3 as a yellow paste (547 mg, 75%);
Rf = 0.59 (EtOAc–PE, 1:5); [a]D25 +35.2 (c 0.33, CH2Cl2).
HRMS (ESI): m/z calcd for C27H40O6Si + Na: 511.2492; found:
511.2497.
Synthesis 2011, No. 17, 2761–2766 © Thieme Stuttgart · New York

2764
Z. Song et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 7.35–7.22 (m, 10 H), 4.94 (d,
J = 10.8 Hz, 1 H), 4.75 (d, J = 12.4 Hz, 1 H), 4.60 (d, J = 10.8 Hz,
1 H), 4.59 (d, J = 12.4 Hz, 1 H), 4.48 (d, J = 3.6 Hz, 1 H), 4.37 (d,
J = 15.6 Hz, 1 H), 4.23 (d, J = 15.6 Hz, 1 H), 3.79–3.73 (m, 3 H),
3.53–3.51 (m, 2 H), 3.47 (dd, J = 3.6, 9.6 Hz, 1 H) 3.27 (s, 3 H),
1.42 (s, 9 H), 0.85 (s, 9 H), –0.003 (d, J = 1.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 168.9, 138.6, 138.3, 128.4, 128.3,
128.0, 127.8, 127.6, 97.7, 83.4, 81.6, 81.1, 77.1, 75.0, 73.3, 71.3,
68.4, 62.2, 54.8, 28.0, 25.9, 18.3, –5.2, –5.4.
with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with brine (20 mL), dried, filtered, and evaporated. The res-
idue was purified by column chromatography over silica gel
(EtOAc–PE, 1:2) to afford 6 as a yellow paste (180 mg, 75%);
Rf = 0.29 (EtOAc–PE, 1:1); [a]D25 +28.3 (c 0.25, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.38–7.28 (m, 10 H), 4.98 (d,
J = 10.8 Hz, 1 H), 4.78 (d, J = 12.4 Hz, 1 H), 4.65 (d, J = 10.8 Hz,
1 H), 4.62 (d, J = 12.4 Hz, 1 H), 4.49 (d, J = 3.2 Hz, 1 H), 4.42 (d,
J = 15.6 Hz, 1 H), 4.28 (d, J = 15.6 Hz, 1 H), 3.86–3.85 (m, 2 H),
3.80 (t, J = 8.8 Hz, 1 H), 3.73–3.67 (m, 1 H), 3.54–3.51 (m, 2 H),
3.31 (s, 3 H), 1.46 (s, 9 H).
HRMS (ESI): m/z calcd for C33H52O8Si: 603.3353; found:
603.3356.
13C NMR (100 MHz, CDCl3): d = 169.3, 150.6, 138.3, 138.1, 135.5,
127.7, 123.5, 115.5, 114.2, 98.0, 83.2, 81.3, 79.8, 73.4, 71.3, 70.9,
69.4, 55.1, 28.1.
Methyl 3,4-Di-O-benzyl-2-O-tert-butoxycarbonylmethyl-a-D-
glucopyranoside (4)
To a solution of compound 3 (883 mg, 1.47 mmol) in MeOH (10
mL MeOH) was added AcCl (16 mL, 0.22 mmol) at 0 °C. The re-
sulting mixture was stirred at 0 °C for 15 min under argon and then
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine (20 mL), dried, filtered, and evaporated.
The residue was purified by column chromatography over silica gel
(EtOAc–PE, 1:4) to afford 4 as a white powder (674 mg, 94%);
Rf = 0.32 (EtOAc–PE, 1:2); [a]D25 +72.5 (c 0.17, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.39–7.28 (m, 10 H), 4.99 (d,
J = 10.8 Hz, 1 H), 4.79 (d, J = 12.0 Hz, 1 H), 4.67 (d, J = 10.8 Hz,
1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.47 (d, J = 3.6 Hz, 1 H), 4.43 (d,
J = 15.6 Hz, 1 H), 4.29 (d, J = 16.0 Hz, 1 H), 3.83 (t, J = 9.2 Hz, 1
H), 3.75 (dd, J = 2.4, 11.6 Hz, 1 H), 3.67 (dd, J = 4.0, 12.0 Hz, 1 H),
3.61–3.57 (m, 1 H), 3.55–3.54 (m, 1 H), 3.50 (dd, J = 4.0, 9.6 Hz, 1
H), 3.30 (s, 3 H), 1.46 (s, 9 H).
HRMS (ESI): m/z calcd for C27H39NO8: 504.2597; found:
504.2596.
Methyl 3,4-Di-O-benzyl-2-O-carboxymethyl-6-O-phthalimido-
a-D-glucopyranoside (7)
To a solution of compound 5 (300 mg, 0.47 mmol) CH2Cl2 (10 mL)
was added CF3CO2H (35 mL, 0.47 mmol) at 0 °C. The resulting
mixture was stirred at r.t. for 45 min under argon and then extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with brine (20 mL), dried, filtered, and evaporated. The res-
idue was purified by column chromatography over silica gel
(EtOAc–PE, 3:1) to afford 7 as a white powder (233 mg, 85%);
Rf = 0.21 (EtOAc–PE, 5:1); [a]D25 +99.2 (c 0.18, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.85 (dd, J = 2.8, 5.6 Hz, 2 H),
7.77 (dd, J = 3.2, 5.6 Hz, 2 H), 7.41–7.30 (m, 10 H), 5.01 (d,
J = 10.8 Hz, 1 H), 4.88 (d, J = 10.8 Hz, 1 H), 4.76 (d, J = 12.0 Hz,
1 H), 4.67 (d, J = 12.0 Hz, 1 H), 4.61 (d, J = 3.6 Hz, 1 H), 4.47 (dd,
J = 3.2, 11.6 Hz, 1 H), 4.42–4.35 (m, 3 H), 4.03 (t, J = 10.0 Hz, 1
H), 3.81–3.77 (m, 2 H), 3.68–3.60 (m, 1 H), 3.30 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.4, 138.2, 129.8, 129.0, 128.5,
128.4, 128.3, 128.1, 128.0, 127.8, 123.3, 98.0, 83.1, 81.4, 80.0,
70.5, 61.9, 55.1, 28.1.
HRMS (ESI): m/z calcd for C27H36O8 + Na: 511.2308; found:
511.2309.
13C NMR (100 MHz, CDCl3): d = 172.3, 163.2, 137.4, 136.6, 134.6,
128.5, 128.2, 123.6, 97.2, 82.2, 78.4, 77.0, 75.6, 75.2, 73.0, 70.4,
69.5, 55.5.
Methyl 3,4-Di-O-benzyl-2-O-tert-butoxycarbonylmethyl-6-O-
phthalimido-a-D-glucopyranoside (5)
HRMS (ESI): m/z calcd for C31H31NO10 + Na: 600.1846; found:
To a solution of compound 4 (150 mg, 0.31 mmol) in CH2Cl2 (8
mL) were added Ph3P (113 mg, 0.43 mmol), PhthNOH (60 mg, 0.37
mmol), and DIAD (85 mL, 0.43 mmol) at 0 °C. The resulting mix-
ture was stirred at 0 °C for 1 h under argon and then extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with brine (20 mL), dried, filtered, and evaporated. The residue was
purified by column chromatography over silica gel (EtOAc–PE,
1:5) to afford 5 as a white powder (163 mg, 83%); Rf = 0.63
(EtOAc–PE, 1:2); [a]D25 +7.1 (c 0.16, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.83 (dd, J = 3.2, 5.6 Hz, 2 H),
7.74 (dd, J = 2.8, 5.2 Hz, 2 H), 7.40–7.23 (m, 10 H), 5.08 (d,
J = 10.4 Hz, 1 H), 5.01–4.95 (m, 1 H), 4.87 (d, J = 10.8 Hz, 1 H),
4.80 (d, J = 12.0 Hz, 1 H), 4.63 (d, J = 12.4 Hz, 1 H), 4.51 (d,
J = 3.2 Hz, 1 H), 4.46–4.39 (m, 3 H), 4.29 (d, J = 15.6 Hz, 1 H),
3.88–3.81 (m, 3 H), 3.59 (dd, J = 3.6, 9.2 Hz, 1 H), 3.35 (s, 3 H),
1.46 (s, 9 H).
600.1845.
Methyl 3,4-Di-O-benzyl-2-O-tert-butoxycarbonylmethyl-6-O-
[(methyl 3,4-di-O-benzyl-6-O-phthalimido-a-D-glucopyra-
nosid-2-yloxy)methylcarbonylamino]-a-D-glucopyranoside (8)
To a solution of compounds 6 (147 mg, 0.25 mmol) and 7 (125.8
mg, 0.25 mmol) in CH2Cl2–DMF (15 mL, 2:1 v/v) were added
EDC⋅HCl (86 mg, 0.45 mmol) and HOBt (61 mg, 0.45 mmol) at r.t.
The resulting mixture was stirred at r.t. for 3 h under argon and then
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine (20 mL), dried, filtered, and evaporated.
The residue was purified by column chromatography over silica gel
(EtOAc–PE, 1:2) to afford 8 as a white paste (199 mg, 74%);
Rf = 0.57 (EtOAc–PE, 1:1), [a]D25 +39.1 (c 0.18, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 10.04 (s, 1 H), 7.82–7.79 (m, 2 H),
7.76–7.73 (m, 2 H), 7.38–7.25 (m, 20 H), 4.96 (d, J = 10.8 Hz, 1 H),
4.91 (d, J = 10.4 Hz, 1 H), 4.85 (d, J = 10.8 Hz, 1 H), 4.75 (d,
J = 12.4 Hz, 1 H), 4.66 (d, J = 12.0 Hz, 2 H), 4.61 (d, J = 12.0 Hz,
2 H), 4.58 (t, J = 3.6 Hz, 2 H), 4.42–4.40 (m, 2 H), 4.39 (d, J = 15.6
Hz, 2 H), 4.25 (d, J = 15.6 Hz, 1 H), 3.99–3.91 (m, 3 H), 3.82 (d,
J = 9.6 Hz, 1 H), 3.77 (d, J = 9.2 Hz, 2 H), 3.74–3.69 (m, 1 H), 3.53
(dd, J = 3.2, 9.6 Hz, 1 H), 3.49 (dd, J = 3.6, 9.6 Hz, 1 H), 3.44 (t,
J = 9.2 Hz, 1 H), 3.32 (s, 3 H), 3.30 (s, 3 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 169.2, 163.2, 156.6, 138.3, 138.2,
134.5, 127.7, 123.5, 98.1, 83.1, 81.3, 79.5, 75.1, 73.4, 71.3, 70.0,
69.2, 55.5, 28.1, 21.9.
HRMS (ESI): m/z calcd for C35H39NO10 + Na: 656.2472; found:
656.2474.
Methyl 6-O-Amino-3,4-di-O-benzyl-2-O-tert-butoxycarbonyl-
methyl-a-D-glucopyranoside (6)
To a solution of compound 5 (300 mg, 0.47 mmol) in MeOH (6
mL), was added N2H4⋅H2O (46 mL, 0.94 mmol) at r.t. The resulting
mixture was stirred at r.t. for 2 h under argon and then extracted
13C NMR (100 MHz, CDCl3): d = 169.2, 166.9, 163.2, 138.4, 138.2,
137.3, 137.2, 134.6, 128.7, 128.2 (2), 128.0, 127.9, 127.7, 97.9,
97.5, 81.2, 75.0, 74.9, 73.3, 73.0, 71.5, 71.3, 69.5, 69.3, 60.4, 55.5,
55.3, 28.1.
Synthesis 2011, No. 17, 2761–2766 © Thieme Stuttgart · New York

PAPER
Novel Glycoaminoxy Acid Building Block for Oligosaccharide Mimetics
2765
HRMS (ESI): m/z calcd for C58H66N2O17 + Na: 1085.4259; found:
1085.4261.
13C NMR (100 MHz, CDCl3): d = 169.2, 167.2, 163.2, 138.4, 138.2,
137.3, 137.2, 137.1, 134.6, 127.6, 123.6, 97.9, 97.5, 97.2, 80.8,
79.3, 77.6, 77.0, 75.1, 73.3, 72.8, 69.5, 69.0, 58.4, 55.5, 55.3 55.2,
28.1.
Methyl 3,4-Di-O-benzyl-2-O-tert-butoxycarbonylmethyl-6-O-
[(methyl 6-O-amino-3,4-di-O-benzyl-a-D-glucopyranosid-2-
yloxy)methylcarbonylamino]-a-D-glucopyranoside (9)
Compound 8 (77 mg, 0.07 mmol) in MeOH (5 mL) was hydrazino-
lyzed with N2H4⋅H2O (7 mL, 0.14 mmol) as for compound 5. Puri-
fication by column chromatography over silica gel (EtOAc–PE,
1:3) afforded 9 as a white paste (43 mg, 64%); Rf = 0.27 (EtOAc–
PE, 1:1); [a]D25 +100.4 (c 0.11, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 10.10 (s, 1 H), 7.35–7.24 (m, 20
H), 4.90 (d, J = 10.8 Hz, 1 H), 4.77 (d, J = 12.0 Hz, 1 H), 4.72 (d,
J = 11.2 Hz, 1 H), 4.66–4.56 (m, 6 H), 4.48 (d, J = 3.2 Hz, 1 H),
4.41–4.37 (m, 3 H), 4.24 (d, J = 15.6 Hz, 1 H), 3.96 (dd, J = 4.4,
10.4 Hz, 1 H), 3.87–3.82 (m, 3 H), 3.77–3.73 (m, 2 H), 3.67–3.65
(m, 2 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 1.45 (s, 9 H).
HRMS (ESI): m/z calcd for C81H93N3O24 + Na: 1514.6047; found:
1514.6082.
Tetramer 12
To a solution of compounds 9 (35 mg, 0.04 mmol) and 10 (40 mg,
0.04 mmol) in CH2Cl2–DMF (9 mL, 2:1 v/v) were added EDC⋅HCl
(15 mg, 0.08 mmol) and HOBt (11 mg, 0.08 mmol) at r.t. The re-
sulting mixture was stirred at r.t. for 3 h under argon and then ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine (20 mL), dried, filtered, and evaporated.
The residue was purified by column chromatography over silica gel
(EtOAc–PE, 1:1) to afford 12 as a white powder (34 mg, 48%);
Rf = 0.31 (EtOAc–PE, 2:1); [a]D25 +43.8 (c 0.09, CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 169.2, 167.2, 138.4, 138.2, 137.0,
128.7, 128.2 (2 C), 128.1, 127.9, 127.6, 97.9, 97.3, 81.2, 75.3, 74.9
(2 C), 73.3, 72.8, 71.3, 69.5, 69.0, 55.2, 28.1.
1H NMR (400 MHz, CDCl3): d = 10.23 (s, 2 H), 10.09 (s, 1 H),
7.83–7.81 (m, 2 H), 7.77–7.75 (m, 2 H), 7.40–7.26 (m, 40 H), 4.99
(d, J = 10.8 Hz, 1 H), 4.87 (d, J = 10.4 Hz, 1 H), 4.85 (d, J = 10.4
Hz, 1 H), 4.75 (d, J = 11.6 Hz, 1 H), 4.70–4.45 (m, 14 H), 4.46 (d,
J = 3.6 Hz, 2 H), 4.39–4.35 (m, 5 H), 4.23 (d, J = 15.6 Hz, 1 H),
3.99–3.90 (m, 4 H), 3.74–3.63 (m, 10 H), 3.56 (dd, J = 2.8, 9.6 Hz,
2 H), 3.51–3.38 (m, 10 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 3.27 (s, 3 H),
3.26 (s, 3 H), 1.45 (s, 9 H).
HRMS (ESI): m/z calcd for C50H65N2O15: 933.4385; found:
933.4383.
Methyl 3,4-Di-O-benzyl-2-O-carboxymethyl-6-O-[(methyl 3,4-
di-O-benzyl-6-O-phthalimido-a-D-glucopyranosid-2-yl-
oxy)methylcarbonylamino]-a-D-glucopyranoside (10)
Compound 8 (130 mg, 0.13 mmol) in CH2Cl2 (5 mL) was treated
with CF3CO2H (10 mL, 0.13 mmol) as for compound 5. Purifica-
tion by column chromatography over silica gel (EtOAc–PE, 3:1) af-
forded 10 as a white paste (87 mg, 71%); Rf = 0.30 (EtOAc–PE,
4:1); [a]D25 +78.8 (c 0.1, CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 169.2, 167.2, 163.2, 138.4, 138.2,
137.2, 134.6, 128.3, 127.6, 123.6, 97.9, 97.5, 97.2, 83.0, 80.7, 80.5,
79.5, 79.3, 75.4, 73.0, 72.8, 71.3, 69.5, 58.5, 55.4, 55.3, 28.1.
HRMS (ESI): m/z calcd for C104H120N4O31 + Na: 1943.7834; found:
1943.7827.
1H NMR (400 MHz, CDCl3): d = 10.22 (s, 1 H), 7.83–7.81 (m, 2 H),
7.77–7.75 (m, 2 H), 7.40–7.26 (m, 20 H), 4.99 (d, J = 10.8 Hz, 1 H),
4.87 (td, J = 10.8 Hz, 1 H), 4.74–4.58 (m, 8 H), 4.47 (d, J = 3.6 Hz,
2 H), 4.40 (d, J = 11.2 Hz, 2 H), 4.35–4.27 (m, 2 H), 4.00–3.97 (m,
2 H), 3.85 (d, J = 8.8 Hz, 1 H), 3.80 (d, J = 9.6 Hz, 1 H), 3.71–3.66
(m, 2 H), 3.56–3.49 (m, 3 H), 3.47 (dd, J = 3.2, 9.6 Hz, 1 H), 3.30
(s, 3 H), 3.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 171.7, 163.2, 137.2, 136.4, 134.6,
128.6, 128.2, 123.6, 97.5, 96.9, 81.8, 78.2, 77.3, 75.5, 75.1, 73.0,
72.8, 70.3, 69.5, 69.4, 55.6, 55.4.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
X.-P. He gratefully acknowledges the French Embassy in Beijing,
China for a co-tutored doctorate fellowship. This project was sup-
ported by National Natural Science Foundation of China (Grant No.
20876045), Shanghai Science and Technology Community (No.
10410702700) and the Fundamental Research Funds for the Central
Universities (No. WK1013002).
HRMS (ESI): m/z calcd for C54H59N2O17: 1007.3814; found:
1007.3832.
Trimer 11
References
To a solution of compounds 6 (20 mg, 0.04 mmol) and 10 (40 mg,
0.04 mmol) in CH2Cl2–DMF (9 mL, 2:1 v/v) were added EDC⋅HCl
(15 mg, 0.08 mmol) and HOBt (11 mg, 0.08 mmol) at r.t. The re-
sulting mixture was stirred at r.t. for 3 h under argon and then ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine (20 mL), dried, filtered, and evaporated.
The residue was purified by column chromatography over silica gel
(EtOAc–PE, 1:2) to afford 11 as a white paste (30 mg, 51%);
Rf = 0.52 (EtOAc–PE, 2:1); [a]D25 +52.4 (c 0.1, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 10.20 (s, 1 H), 10.06 (s, 1 H),
7.83–7.80 (m, 2 H), 7.76–7.74 (m, 2 H), 7.40–7.24 (m, 30 H), 4.98
(d, J = 10.8 Hz, 1 H), 4.88 (d, J = 11.2 Hz, 1 H), 4.85 (d, J = 11.2
Hz, 1 H), 4.75 (d, J = 12.0 Hz, 1 H), 4.68 (d, J = 12.0 Hz, 2 H),
4.62–4.59 (m, 8 H), 4.47 (dd, J = 3.6, 15.6 Hz, 3 H), 4.40–4.36 (m,
4 H), 4.24 (d, J = 15.6 Hz, 1 H), 4.01–3.96 (m, 2 H), 3.92 (dd,
J = 5.2, 10.8 Hz, 1 H), 3.84–3.81 (m, 3 H), 3.78–3.76 (m, 1 H),
3.73–3.63 (m, 4 H), 3.58–3.54 (m, 2 H), 3.48–3.39 (m, 4 H), 3.30
(s, 3 H), 3.29 (s, 3 H), 3.28 (s, 3 H), 1.45 (s, 9 H).
(1) For reviews, see: (a) Sears, O.; Wong, C. H. Angew. Chem.
Int. Ed. 1999, 38, 2300. (b) Schweizer, F. Angew. Chem. Int.
Ed. 2002, 41, 230. (c) Gruner, S. A. W.; Locardi, E.; Lohof,
E.; Kessler, H. Chem. Rev. 2002, 102, 491.
(d) Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S. Curr.
Med. Chem. 2002, 9, 421. (e) Gervay-Hague, J.; Weathers,
T. M. Jr. J. Carbohydr. Chem. 2002, 7-9, 867.
(f) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B.
K. J. Chem. Sci. 2004, 116, 187. (g) Chakraborty, T. K.;
Srinivasu, P.; Tapadar, S.; Mohan, B. K. Bioconjugate J.
2005, 22, 83. (h) Risseeuw, M. D. P.; Overhand, M.; Fleet,
G. W. J.; Simone, M. I. Tetrahedron: Asymmetry 2007, 18,
2001. (i) Koester, D. C.; Holkenbrink, A.; Werz, D. B.
Synthesis 2010, 3217.
(2) (a) Yang, D.; Ng, F.-F.; Li, Z.-J.; Wu, Y.-D.; Chan, K. W.
K.; Wang, D.-P. J. Am. Chem. Soc. 1996, 118, 9794.
(b) Yang, D.; Qu, J.; Li, B.; Ng, F.-F.; Wang, X.-C.; Cheung,
K.-K.; Wang, D.-P.; Wu, Y.-D. J. Am. Chem. Soc. 1999,
121, 589. (c) Shin, I.; Lee, M.; Lee, J.; Jung, M.; Lee, W.;
Synthesis 2011, No. 17, 2761–2766 © Thieme Stuttgart · New York

2766
Z. Song et al.
PAPER
Yoon, J. J. Org. Chem. 2000, 65, 7667. (d) Yang, D.; Li, B.;
Ng, F.-F.; Yan, Y.-L.; Qu, J.; Wu, Y.-D. J. Org. Chem. 2001,
66, 7303. (e) Chen, F.; Song, K.-S.; Wu, Y.-D.; Yang, D.
J. Am. Chem. Soc. 2008, 130, 743. (f) Li, X.; Wu, Y.-D.;
Yang, D. Acc. Chem. Res. 2008, 41, 1428. (g) Li, X.; Yang,
D. Chem. Commun. 2006, 3367. (h) Yang, D.; Zhang,
D.-W.; Hao, Y.; Wu, Y.-D.; Luo, S.-W.; Zhu, N.-Y. Angew.
Chem. Int. Ed. 2004, 43, 6719. (i) Yang, D.; Zhang, X.-W.;
Zhang, D.-W.; Jiang, Z.-F.; Song, K.-S.; Zhang, Y.-H.; Zhu,
N.-Y.; Weng, L.-H.; Chen, M.-Q. J. Org. Chem. 2010, 75,
4796. (j) Zhang, Y.-H.; Song, K.; Zhu, N.-Y.; Yang, D.
Chem. Eur. J. 2010, 16, 577.
Gutiérrez Gallego, R.; Andreu, D. Bioorg. Med. Chem. Lett.
2007, 17, 5155.
(8) Clo, E.; Blixt, O.; Jensen, K. J. Eur. J. Org. Chem. 2010,
540.
(9) Tejler, J.; Salameth, B.; Leffler, H.; Nilsson, U. J. Org.
Biomol. Chem. 2009, 7, 3982.
(10) (a) Xie, J. Eur. J. Org. Chem. 2002, 3411. (b) Xie, J.
Carbohydr. Res. 2003, 338, 399. (c) Xie, J.; Durrat, F.;
Valéry, J. M. J. Org. Chem. 2003, 68, 7896. (d) Durrat, F.;
Xie, J.; Valéry, J. M. Tetrahedron Lett. 2004, 45, 1477.
(e) Ménand, M.; Blais, J.-C.; Hamon, L.; Valéry, J.-M.; Xie,
J. J. Org. Chem. 2005, 70, 4423. (f) Ménand, M.; Blais,
J.-C.; Valéry, J.-M.; Xie, J. J. Org. Chem. 2006, 71, 3295.
(g) Ayadi, E.; Czernecki, S.; Xie, J. J. Chem. Soc., Chem.
Commun. 1996, 347.
(11) (a) Song, S.-X.; Zhang, H.-L.; Kim, C.-K.; Sheng, L.; He,
X.-P.; Long, Y.-T.; Li, J.; Chen, G.-R. Tetrahedron 2010,
66, 9974. (b) Yang, J. W.; He, X.-P.; Li, C.; Gao, L.-X.;
Sheng, L.; Xie, J.; Shi, X.-X.; Tang, Y.; Li, J.; Chen, G.-R.
Bioorg. Med. Chem. Lett. 2011, 21, 1092. (c) He, X.-P.;
Wang, X.-W.; Jin, X.-P.; Zhou, H.; Shi, X.-X.; Chen, G.-R.;
Long, Y.-T. J. Am. Chem. Soc. 2011, 133, 3649.
(12) (a) Mereyala, H. B.; Gurrala, S. R.; Mohan, S. K.
Tetrahedron 1999, 55, 11331. (b) He, X.-P.; Li, C.; Jin, X.-
P.; Song, Z.; Zhang, H.-L.; Zhu, C.-J.; Shen, Q.; Zhang, W.;
Shi, X.-X.; Tang, Y.; Li, J.; Chen, G.-R.; Xie, J. New J.
Chem. 2011, 35, 622.
(3) Malapelle, A.; Ramozzi, R.; Xie, J. Synthesis 2009, 888.
(4) Chandrasekhar, S.; Rao, C. L.; Reddy, M. S.; Sharma, G. D.;
Kiran, M. U.; Naresh, P.; Chaitanya, G. K.; Bhanuprakash,
K.; Jagadeesh, B. J. Org. Chem. 2008, 73, 9443.
(5) Gong, Y.; Sun, H.; Xie, J. Eur. J. Org. Chem. 2009, 6027.
(6) (a) Rodriguez, E. C.; Marcaurelle, L. A.; Bertozzi, C. R.
J. Org. Chem. 1998, 63, 7134. (b) Duléry, V.; Renaudet, O.;
Philouze, C.; Dumy, P. Carbohydr. Res. 2007, 342, 894.
(c) Chen, W.; Xia, C.; Cai, L.; Wang, P. G. Bioorg. Med.
Chem. Lett. 2010, 20, 3859.
(7) (a) Brask, J.; Jensen, K. J. J. Pept. Sci. 2000, 6, 290.
(b) Brask, J.; Jensen, K. J. Bioorg. Med. Chem. Lett. 2001,
11, 697. (c) Tofteng, A. P.; Hansen, T. H.; Brask, J.; Nielsen,
J.; Thulstrup, P. W.; Jensen, K. J. Org. Biomol. Chem. 2007,
5, 2225. (d) Jiménez-Castells, C.; de la Torre, B. G.;
Synthesis 2011, No. 17, 2761–2766 © Thieme Stuttgart · New York