Synthesis of glycoaminoxy acids as novel sugar building blocks

Article abstract of DOI:10.1055/s-0028-1083372

Glycoaminoxy acids, a new class of sugar building blocks bearing both aminoxy and carboxylic acid functional groups on the sugar ring, have been efficiently synthesized from α-C-allyl glycosides. These compounds can be easily used for the synthesis of an

Full text of DOI:10.1055/s-0028-1083372

888
SHORT PAPER
Synthesis of Glycoaminoxy Acids as Novel Sugar Building Blocks
Synthesis of
G
lyco
d
aminoxy Ac
e
ids line Malapelle, Romain Ramozzi, Juan Xie*
PPSM, ENS Cachan, Institut d’Alembert, CNRS, Universud, 61 av. Président Wilson, 94230 Cachan, France
Fax +33(1)47402454; E-mail: joanne.xie@ens-cachan.fr
Received 13 November 2008
of glycoamino acid, glycoaminoxy acid should represent
a new class of multifunctional synthetic building blocks
because both aminoxy and carboxylic acid functional
groups can be readily used for further derivatization. In
Abstract: Glycoaminoxy acids, a new class of sugar building
blocks bearing both aminoxy and carboxylic acid functional groups
on the sugar ring, have been efficiently synthesized from a-C-allyl
glycosides. These compounds can be easily used for the synthesis
of an N-oxy-amide-linked disaccharide and glycosyl amino acid mi- this paper, we report the synthesis of a glycoaminoxy acid
metics.
and its derivatization.
Key words: glycoaminoxy acids, glycopeptides, glycomimetics,
glycosides, oligosaccharides
HO2C
HO2C
OH
OH
O
O
n
n
NH2
ONH2
glycoaminoxy acid
The design and synthesis of new molecules with various
functions has attracted much attention from organic,
bioorganic, peptide, medicinal, as well as material chem-
istry. The creation of such cleverly functionalized mole-
cules has a large impact in designing bioactive molecules
and for drug discovery. Amino acids and carbohydrates
are two fundamental chiral building blocks in Nature,
generating diversity in biological systems. Recently, gly-
coamino acids or sugar amino acids, where amine and car-
boxylic acid functional groups were incorporated into the
sugar ring, have been widely employed as carbohydrate
scaffolds for preparing carbohydrate-based molecules
with various applications.1 In the meanwhile, aminoxy
acids, a class of unnatural amino acids where an aminoxy
function has been introduced in place of the amine group,
have emerged as very attractive scaffolds since the dis-
covery of turns and helices structures in peptides contain-
ing aminoxy acids.2 A new family of foldamers has been
developed from a-, b-, and g-aminoxy acids.3 Oligomeric
aminoxypeptides can also be prepared using solid phase
techniques.4 Thanks to the easy formation and stability of
the oxime bond, aminoxy-functionalized peptides and
proteins have been used as a tool in chemoselective liga-
tion to prepare glycosylated pseudopeptides,5 an antican-
cer vaccine,6 or for high-throughput protein glycomics.7
Through oxime ligation, peptide dendrimers,8 protein–
polymer conjugates,9 bifunctional chelating agents,10 and
an oxime-peptide library11 have also been synthesized.
glycoamino acid
Figure 1 Structure of glycoamino acids and glycoaminoxy acids
Aminoxy and carboxylic acid functions might be intro-
duced into the different positions of furanosyl or pyrano-
syl sugar rings. Continuing our efforts in the synthesis and
application of C-glycosyl building blocks,14 we decided to
prepare the first glucopyranosyl aminoxy acid from the
known C-allyl glucoside 114a (Scheme 1). The Mitsunobu
reaction of 1 with N-hydroxyphthalimide led to the pro-
tected aminoxy C-allyl glucoside 2 in 73% yield. The allyl
group was then oxidized to a carboxylic acid by the com-
bination of osmium tetroxide and Jones reagent;14a the
protected glycoaminoxy acid 3 was obtained in 60%
yield. The carboxylic acid function was then protected as
the tert-butyl ester to give 4 (t-BuOH, DCC, DMAP).
Cleavage of the phthalimido group was realized with hy-
drazine hydrate; the desired aminoxy ester 5 was obtained
in 77% yield.
The synthesized glycoaminoxy acid derivatives were then
tested as building blocks to generate oligosaccharide and
glycopeptide mimetics. Coupling of the N-phthalimi-
ONPhth
O
ONPhth
O
OH
BnO
BnO
a
BnO
BnO
b
BnO
BnO
O
BnO
BnO
BnO
CO2H
Aminoxy-functionalized saccharides have been reported
for glycoconjugate synthesis12 or as monosaccharide tem-
plates for the synthesis of ‘carboproteins’.13 However, to
the best of our knowledge, glycoaminoxy acids or sugar
aminoxy acids having both aminoxy and carboxy func-
tional groups incorporated into the sugar frameworks
have not previously been reported (Figure 1). As a ‘sister’
3
2
1
ONPhth
O
ONH2
O
c
BnO
BnO
d
BnO
BnO
BnO
BnO
CO2t-Bu
CO2t-Bu
4
5
SYNTHESIS 2009, No. 6, pp 0888–0890
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083372; Art ID: Z24708SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9
Scheme 1 Reagents and conditions: (a) PhthNOH, Ph3P, DIAD,
toluene, 73%; (b) OsO4, Jones reagent, 60%; (c) t-BuOH, DCC,
DMAP, CH2Cl2, 64%; (d) H2NNH2·H2O, MeOH, 77%.

SHORT PAPER
Synthesis of Glycoaminoxy Acids
889
J = 11.0 Hz, 1 H, OCH2Ph), 4.99 (d, J = 11.5 Hz, 1 H, OCH2Ph),
5.00–5.09 (m, 2 H, H2), 5.72–5.80 (m, 1 H, H1), 7.27–7.30 (m, 15
H, Ph), 7.72–7.80 (m, 4 H, Phth).
13C NMR (100 MHz, CDCl3): d = 30.0 (C3), 70.1, 70.8 (CH), 73.1
(CH2), 73.8 (CH), 75.0, 75.2, 76.5 (CH2), 77.2, 79.5, 82.1 (CH),
116.8 (C1), 123.5 (Phth), 127.6, 127.8, 127.9, 128.1, 128.4, 128.5,
128.6, 128.9, 129.0, 129.3, 129.9 (Ph), 134.4 (Phth), 135.8 (C2),
138.2, 138.3, 138.7 (Cipso), 163.2 (C=O).
doglycoaminoxy acid 3 with the glycoaminoxy ester 5
furnished the first N-oxy-amide-linked disaccharide 6 in
71% yield (Scheme 2). The coupling reagent diethyl
cyanophosphonate (DEPC), which we have previously
used to prepare oligomers of glycoamino acids,14c,d prov-
en to be efficient in this coupling. Reaction of the gly-
coaminoxy ester 5 with Boc-Gly-OH in the presence of
diethyl cyanophosphonate/triethylamine led to the glyco-
sylated amino acid 7 in 92% yield.
HRMS (ESI): m/z [M + H]+ calcd for C38H38NO7: 620.2648; found:
620.2641.
ONPhth
2-(2,3,4-Tri-O-benzyl-6-O-phthalimido-a-D-glucopyrano-
syl)ethanoic Acid (3)
BnO
BnO
O
OsO4 (4%) in t-BuOH(1.08 mL) and Jones reagent (4.8 mL) were
added to a magnetically stirred soln of 2 (2.55 g, 4.1 mmol) in anhyd
acetone (22 mL). The soln was stirred for 24 h and then a mixture
of H2O–EtOAc (1:1) was added. The organic phase was washed
with brine, dried (Na2SO4), filtered, and evaporated. Purification by
flash chromatography (EtOAc–PE, 2:8 to 1:1) afforded 3 as a col-
orless oil; yield: 1.6 g (60%).
1H NMR (400 MHz, CDCl3): d = 2.75–2.78 (m, 2 H, H2), 3.75–3.89
(m, 4 H), 4.37 (m, 2 H, H6¢), 4.59–4.65 (m, 3 H, H1¢, OCH2Ph), 4.79
(d, J = 11.0 Hz, 1 H, OCH2Ph), 4.81 (d, J = 11.0 Hz, 1 H, OCH2Ph),
4.90 (d, J = 11.0 Hz, 1 H, OCH2Ph), 4.91 (d, J = 11.0 Hz, 1 H,
OCH2Ph), 7.27–7.30 (m, 15 H, Ph), 7.72–7.80 (m, 4 H, Phth).
BnO
a
CONH O
BnO
3 + 5
O
71%
BnO
6
BnO
CO2t-Bu
O
O
NH
NHBoc
BnO
BnO
O
a
5 + Boc-Gly-OH
92%
BnO
CO2t-Bu
7
Scheme 2 Reagents and conditions: (a) DEPC, Et3N, THF.
13C NMR (100 MHz, CDCl3): d = 32.2 (C1), 71.1 (C1¢), 72.1 (CH),
73.4, 75.1, 75.3, 76.6 (CH2), 76.8, 78.6, 81.6 (CH), 123.6 (Phth),
127.8, 127.9, 128.2, 128.5, 128.6, 129.0 (Ph), 134.5 (Phth), 137.8,
138.1, 138.5 (Cipso), 164.4, 175.6 (C=O).
HRMS (ESI): m/z [M + H]+ calcd for C37H36NO9: 638.2390; found:
638.2415.
In summary, from readily available C-allyl glycoside 1,
we have succeeded in the synthesis of first C-glyco-
aminoxy acids, which can be readily converted into oligo-
saccharide or glycopeptide mimetics. These novel
multifunctional sugar derivatives should find wide appli-
cations for chemoselective ligation of carbohydrate and
peptides/proteins or as building blocks for the synthesis of
various glycoconjugates.
tert-Butyl 2-(2,3,4-Tri-O-benzyl-6-O-phthalimido-a-D-glucopy-
ranosyl)ethanoate (4)
t-BuOH (260 mL, 2.719 mmol) and DMAP (66 mg, 0.54 mmol)
were successively added to a magnetically stirred soln of 3 (856 mg,
1.34 mmol) in anhyd CH2Cl2 (8 mL). The mixture was stirred and
cooled to 0 °C and DCC (361 mg, 1.750 mmol) was added. After 6
h, a mixture of H2O–CH2Cl2 (2:3) was added and the organic phase
was washed with brine, dried with (Na2SO4), and evaporated to dry-
ness. Flash chromatography (EtOAc–PE, 2:8 to 3:7) gave 4 as a col-
orless oil; yield: 594 mg (64%).
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 9 H, t-Bu), 2.62–2.64 (m,
2 H, H2), 3.71–3.82 (m, 3 H), 3.92 (dd, J = 8.7, 10.1 Hz, 1 H), 4.37
(dd, J = 2.3, 11.0 Hz, 1 H, H6¢), 4.42 (dd, J = 3.7, 11.0 Hz, 1 H,
H6¢¢), 4.55 (td, J = 5.5, 8.7 Hz, 1 H, H1¢), 4.65 (s, 2 H, OCH2Ph),
4.82 (d, J = 11.0 Hz, 1 H, OCH2Ph), 4.90 (d, J = 11.0 Hz, 2 H,
OCH2Ph), 4.95 (d, J = 11.0 Hz, 1 H, OCH2Ph), 7.30–7.32 (m, 15 H,
Ph), 7.72–7.81 (m, 4 H, Phth).
13C NMR (100 MHz, CDCl3): d = 28.1 (t-Bu), 33.7 (C1), 71.6 (CH),
71.8 (C1¢), 73.3, 75.2, 75.4 (CH2), 76.1 (C6¢), 77.3 (Cq), 78.9, 80.9,
81.2 (CH), 123.6 (Phth), 127.7, 127.9, 128.2, 128.5, 128.6, 129.0
(Ph), 134.5 (Phth), 137.8, 138.1, 138.5 (Cipso), 163.2, 170.5 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C41H43NNaO9: 716.2938;
found: 716.2830.
All air-sensitive reactions were carried out under N2. Column chro-
matography was performed on E. Merck Silica Gel 60 (230–400
mesh). Petroleum ether = PE. Analytical TLC was performed on E.
Merck aluminum pre-coated plates of Silica Gel 60F-254 with de-
tection by UV and by spraying with 3 M H2SO4 and heating at 300
°C for ~2 min. NMR spectra were recorded at r.t. with Jeol DX 400
spectrometers in CDCl3. HRMS spectra were measured by the
Service de Spectrométrie de Masse de l’Université Pierre et Marie
Curie-Paris 6.
3-(2,3,4-Tri-O-benzyl-6-O-phthalimido-a-D-glucopyrano-
syl)propene (2)
To a soln of 3-(2,3,4-tri-O-benzyl-a-D-glucopyranosyl)propene (1,
2 g, 4.2 mmol) in toluene (6 mL) was added successively at r.t. un-
der N2, Ph3P (1.7 g, 6.72 mmol), PhthNOH (822 mg, 5.04 mmol).
After cooling to 0 °C, DIAD (1.24 mL, 6.30 mmol) was then added.
The mixture was stirred for 24 h, H2O–CH2Cl2 (2:3) was added, and
the aqueous phase was extracted with CH2Cl2 (20 mL). The com-
bined organic phases were washed with brine, dried (Na2SO4), fil-
tered, and evaporated. Flash chromatography (EtOAc–PE, 1:9)
gave 2 as a colorless oil; yield: 1.9 g (73%).
tert-Butyl 2-(6-O-Amino-2,3,4-tri-O-benzyl-a-D-glucopyrano-
syl)ethanoate (5)
1H NMR (400 MHz, CDCl3): d = 2.45–2.47 (m, 2 H, H3), 3.72–3.74
(m, 2 H), 3.81 (t, J = 7.8 Hz, 1 H), 3.90 (dd, J = 8.2, 9.6 Hz, 1 H),
4.05–4.07 (m, 1 H, H1¢), 4.35 (dd, J = 1.8, 10.6 Hz, 1 H, H6¢), 4.41
(dd, J = 3.2, 10.6 Hz, 1 H, H6¢¢), 4.59 (d, J = 11.5 Hz, 1 H,
OCH2Ph), 4.68 (d, J = 11.5 Hz, 1 H, OCH2Ph), 4.82 (d, J = 11.0 Hz,
1 H, OCH2Ph), 4.91 (d, J = 11.5 Hz, 1 H, OCH2Ph), 4.93 (d,
A suspension of 4 (300 mg, 0.43 mmol) in MeOH (1.5 mL) was
treated with H2NNH2·H2O (64%, 65 mL). The resulting mixture was
stirred at r.t. for 2 h. The progress of the reaction was monitored by
TLC (EtOAc–PE, 3:7). The mixture was diluted with Et2O and was
washed with sat. aq Na2CO3 soln. The aqueous layer was extracted
with Et2O (3 ×). The combined organic layers were dried (Na2SO4),
Synthesis 2009, No. 6, 888–890 © Thieme Stuttgart · New York

890
A. Malapelle et al.
SHORT PAPER
filtered, and evaporated. The residue was purified by flash chroma-
tography (EtOAc–PE, 3:7) to afford 5 as a colorless oil; yield: 190
mg (77%).
HRMS (ESI): m/z [M + Na]+ calcd for C40H52N2NaO10: 743.3622;
found: 743.3514.
1H NMR (400 MHz, CDCl3): d = 1.43 (s, 9 H, t-Bu), 2.62–2.64 (m,
2 H, H2), 3.46–3.49 (m, 1 H), 3.69–3.72 (m, 3 H), 3.82–3.83 (m, 2
H, H6¢, H6¢¢), 4.53–4.56 (m, 1 H, H1¢), 4.61 (d, J = 11.0 Hz, 1 H,
OCH2Ph), 4.66 (s, 2 H, OCH2Ph), 4.80 (d, J = 11.0 Hz, 1 H,
OCH2Ph), 4.84 (d, J = 11.0 Hz, 1 H, OCH2Ph), 4.90 (d, J = 11.0 Hz,
1 H, OCH2Ph), 7.28–7.30 (m, 15 H, Ph).
13C NMR (100 MHz, CDCl3): d = 28.2 (t-Bu), 33.6 (C1), 71.4 (CH),
71.8 (C1¢), 73.2 (CH2), 74.7 (C6¢), 75.2, 75.6 (CH2), 78.1, 79.3
(CH), 80.9 (Cq), 82.3 (CH), 127.9, 128.5, 128.6 (Ph), 138.0, 138.2,
138.6 (Cipso), 170.6 (C=O).
References
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HRMS (ESI): m/z [M + H]+ calcd for C33H42NO7: 564.2883; found:
564.2950.
tert-Butyl 2-(2,3,4-Tri-O-benzyl-6-O-{[(2,3,4-tri-O-benzyl-6-O-
phthalimido-a-D-glucopyranosyl)carbonyl]amino}-a-D-glu-
copyranyl)ethanoate (6)
To a soln of 5 (190 mg, 0.35 mmol) in THF (4 mL), were added 3
(217 mg, 0.35 mmol), DEPC (79 mL, 0.35 mmol), and Et3N (145
mL, 1.05 mmol). The mixture was stirred overnight under N2 and
then diluted with EtOAc–H2O (1:1) and separated. The aqueous
layer was extracted with EtOAc. The combined organic layers were
then washed with brine, dried (Na2SO4), filtered, concentrated, and
purified by chromatography (EtOAc–PE, 3:7) to afford 6 as a col-
orless oil; yield: 291 mg (71%).
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 9 H, t-Bu), 2.55 (m, 2 H,
CH2), 2.63 (m, 2 H, CH2), 3.47 (t, J = 8.2 Hz, 1 H, H1), 3.67–3.77
(m, 4 H), 3.84–3.86 (m, 2 H, CH2), 3.99 (dd, J = 6.4, 11.9 Hz, 1 H),
4.09–4.19 (m, 2 H), 4.30 (dd, J = 4.6, 14.2 Hz, 1 H), 4.34–4.37 (m,
1 H), 4.46–4.53 (m, 1 H), 4.56–4.91 (m, 13 H), 7.26–7.28 (m, 30 H,
Ph), 7.68–7.78 (m, 4 H, Phth), 9.61 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 28.2 (t-Bu), 30.8, 33.5 (C1), 71.2,
71.4, 71.5, 72.1 (CH), 72.9, 73.2, 74.8, 75.10, 75.14, 75.4 (CH2),
76.8 (CH), 77.2 (CH2), 78.0, 78.3, 79.2, 81.2 (CH), 81.4 (Cq), 81.9
(CH), 123.7 (Phth), 127.7, 127.9, 128.1, 128.2, 128.5, 128.9 (Ph),
134.5 (Phth), 138.0, 138.1, 138.5 (Cipso), 163.5, 167.8, 171.4 (C=O).
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HRMS (ESI): m/z [M + Na]+ calcd for C70H74N2NaO15: 1205.5089;
found: 1205.4981.
tert-Butyl 2-(2,3,4-Tri-O-benzyl-6-O-{[2-(tert-butoxycarbonyl-
amino)acetyl]amino}-a-D-glucopyranosyl)ethanoate (7)
To a soln of 5 (203 mg, 0.36 mmol) in THF (5 mL) were added Boc-
Gly-OH (63 mg, 0.35 mmol), DEPC (82 mL, 0.54 mmol), and Et3N
(152 mL, 1.08 mmol). The mixture was stirred overnight under N2
and then diluted with EtOAc–H2O (1:1) and separated. The aqueous
layer was extracted with EtOAc. The combined organic layers were
then washed with brine, dried (Na2SO4), filtered, concentrated, and
purified by chromatography (EtOAc–PE, 3:7) to afford 7 as a col-
orless oil; yield: 240 mg (92%).
1H NMR (400 MHz, CDCl3): d = 1.43 (s, 9 H, t-Bu), 1.44 (s, 9 H, t-
Bu), 2.64–2.67 (m, 2 H, CH2), 3.33 (m, 1 H), 3.67–3.88 (m, 6 H),
4.10 (m, 1 H), 4.44 (m, 1 H), 4.62–4.90 (m, 6 H), 5.18 (s, 1 H, NH),
7.24–7.30 (m, 15 H, Ph), 9.66 (s, 1 H, NH).
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13C NMR (100 MHz, CDCl3): d = 28.2, 28.4 (t-Bu), 33.5, 42.1
(CH2), 70.9, 71.6 (CH), 73.4, 75.2, 75.5, 75.8 (CH2), 78.0, 79.1
(CH), 81.8 (Cq), 81.9 (CH), 128.0, 128.7 (Ph), 137.6, 137.8, 138.3
(Cipso), 155.9, 166.4, 171.7 (C=O).
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Synthesis 2009, No. 6, 888–890 © Thieme Stuttgart · New York