Use of the p-nitrobenzyloxycarbonyl group as an orthogonal amine protecting group in the synthesis of β-GlcNAc terminating glycosides

Article abstract of DOI:10.1039/a700549k

The p-nitrobenzyloxycarbonyl group serves as a participating group in the stereoselective formation of 2-amino-β-glucosides and as an N-protecting group which can be readily removed either by hydrogenolysis or by reaction with sodium dithionite under neut

Full text of DOI:10.1039/a700549k

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Use of the p-nitrobenzyloxycarbonyl group as an orthogonal amine protecting
group in the synthesis of b-GlcNAc terminating glycosides
Xiangping Qian and Ole Hindsgaul*
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
The p-nitrobenzyloxycarbonyl group serves as a participat-
ing group in the stereoselective formation of 2-amino-
b-glucosides and as an N-protecting group which can be
readily removed either by hydrogenolysis or by reaction with
sodium dithionite under neutral conditions.
with the less reactive 4-OH groups of 10 and 11 also gave b-(1
? 4) linked disaccharides 12† and 13 in good yields (79 and
75%,¶ respectively) (Scheme 4). These results indicate that the
combination of the PNZ moiety with anomeric trichloro-
acetimidate activation can afford b-glycosides in high yield
with high stereoselectivity.
b-d-Glycosides of N-acetyl-2-amino-2-deoxy sugars are widely
distributed in living organisms where they constitute building
blocks of glycoconjugates.1 The synthesis of such glycosides
requires glycosyl donors where the amino group is protected.
The phthalimido (Phth) and azido groups have been the most
widely used.2,3
More recently, the carbamate functionality has been used for
protection of the amino group in peptide, protein and carbohy-
drate synthesis.4–7 Boullanger et al. conducted a systematic
study on the glycosylation of simple acceptor alcohols with
various N-alkoxycarbonyl derivatives of glucosamine, includ-
ing the p-nitrobenzyloxycarbonyl (PNZ) group.8 It was found
that b-glycosides were obtained stereoselectively in good yield
without the formation of an oxazolidinone when the b-acetate of
these carbamate derivatives was used as glycosyl donor in the
presence of a Lewis acid. The 2,2,2-trichloroethyl and allyl
carbamates have since been effectively applied in the synthesis
of glycoconjugates containing 2-acetamido glycosides.7,9 These
can be deprotected with zinc dust in acetic acid7 and with Pd0
complexes,9 respectively.
We chose to investigate the potential of the p-nitrobenzyl
carbamates of 2-amino sugars since this group should be
selectively cleavable by the reduction of the electron-with-
drawing nitro group to the electron-donating amine substituent
followed by 1,6-elimination4 (Scheme 1). As there are many
methods for reducing the aromatic nitro group, mild and
chemoselective deprotection methods should be readily avail-
able. Furthermore, unlike the 2,2,2-trichloroethyl or allyl
carbamates, the p-nitrobenzyl carbamate can be removed by
hydrogenolysis at the end of a synthesis along with the standard
O-benzyl protecting groups.
As shown in Scheme 2, treatment of glucosamine hydro-
chloride 1 with 1 equiv. of NaOMe in MeOH, followed by
p-nitrobenzyl chloroformate–Et3N and O-acetylation gave 2.
The trichloroacetimidate 3† was formed by regioselective
deacetylation at O-1 with benzylamine followed by treatment of
the reducing sugar with CCl3CN in the presence of K2CO3.10
Imidate 3 was evaluated as a glycosyl donor in CH2Cl2 using
BF3·Et2O as a promoter.‡§ The octyl b-glycoside 4 was formed
in 82% yield.¶ Glycosylation of 5 gave the b-(1 ? 6) linked
disaccharide 6 in 91% yield (Scheme 3).†,¶ The reaction of 3
A major disadvantage of using the N-phthalimido group in
oligosaccharide synthesis is that its deprotection requires
vigorous conditions, and esters usually do not survive.11
Recently, the more reactive tetrachlorophthaloyl (TCP) group
was applied as an amine protecting group.12,13 The TCP group
can be removed under milder conditions than the Phth group,
either by a slight excess of ethylenediamine at 60 °C or by
NaBH4 reduction. Although the extent of cleavage of carbox-
ylate ester groups is significantly reduced under these condi-
tions, yields are still moderate especially in the presence of
3-OAc and 6-OAc groups when using ethylenediamine.12b
Ketone or aldehyde functionalities may also be reduced by
NaBH4 during the removal of the TCP group. Clearly,
chemoselective removal of the PNZ group under conditions
where esters are inert would enhance its utility.
Methods for the removal of the PNZ group were examined
using the simple glycoside 4 as a model compound. Removal of
the PNZ group and acetylation of the resulting amine can be
directly achieved in one step by hydrogenolysis using 10% Pd–
C under H2 flow in the presence of Ac2O, yielding 9 in 83%
yield.¶ As shown in Scheme 3, the free amine 8 could also be
isolated (76%¶) when the hydrogenolysis was performed in the
absence of Ac2O.
Attempted reduction with stannous chloride14 in non-acidic
and non-aqueous media (EtOH or EtOAc) was ineffective.
p-Nitrobenzyl esters can, however, be reductively cleaved by
sodium dithionite (Na2S2O4) under neutral or slightly alkaline
conditions.15 We found that sodium dithionite was a very
OAc
OH
O
O
i–iii
AcO
AcO
HO
HO
OAc
OH
NH2•HCl
NH
PNZ
2
1
iv, v
OAc
O
OAc
O
vi
AcO
AcO
AcO
AcO
OC8H17
HN
NH
O
PNZ
PNZ
C
NH
4
O
CCl3
Na2S2O4
3
R
C
NO2
RNH2
O
C
N
H
O
NO2
PNZ =
O
Scheme 2 Reagents and conditions: i, NaOMe (1 equiv.), MeOH, 10 min;
ii, p-nitrobenzyl chloroformate (1 equiv.), Et3N (1 equiv.), 0 °C to room
temp; iii, Ac2O, pyridine, 16 h, 78% (3 steps); iv, BnNH2 (1.1 equiv.), THF,
16 h; v, CCl3CN (10 equiv.), K2CO3, CH2Cl2, 7 h, 75% (2 steps); vi,
BF3·Et2O (0.5 equiv.), octanol (0.7 equiv.), 4 Å molecular sieves, CH2Cl2,
230 to 0 °C, 2 h, 82% (based on octanol)
O
C
R
NH2
N
H
O
Scheme 1
Chem. Commun., 1997
1059

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effective reducing agent even in the absence of base. The PNZ
group can be readily removed quickly in quantitative yield. As
shown in Scheme 4, deacetylation of 12 using NaOMe in MeOH
followed by cleavage of PNZ and re-acetylation with Ac2O–
pyridine gave 16.† When disaccharide 12 was treated directly
with sodium dithionite in MeCN–EtOH–H2O solution, fol-
lowed by N-acetylation using Ac2O in MeOH, disaccharide 16
was obtained, demonstrating the stability of the three O-acetate
groups to the reduction conditions. The free amine group can
also be transformed into the acetamido group in ‘one pot’ by
simply adding Ac2O directly to the reaction mixture. Disaccha-
ride 16 was thus formed in a ‘one pot’ reaction in 86%
yield.¶
In summary, we have demonstrated that the PNZ group
functions as a good participating group for the formation of
2-amino-b-glucosides. This N-protecting group can be conve-
niently removed either by hydrogenolysis along with O-benzyl
ethers or selectively by sodium dithionite under neutral
conditions where carboxylate esters remain stable. Since
O-acetyl groups can be removed by treatment with NaOMe–
MeOH in the presence of the PNZ group, this group is
effectively an orthogonal protecting group and should thus find
unique application in oligosaccharide synthesis.
We gratefully acknowledge the Natural Sciences and Engi-
neering Research Council of Canada for financial support and
Drs J. C. McAuliffe and Z. G. Wang for helpful suggestions.
Footnotes
* E-mail: ole.hindsgaul@ualberta.ca
† Selected data for 3: 1H NMR (CDCl3) d 8.75 (s, 1 H, CNNH), 6.39 (d, 1
H, J1,2 3.6 Hz, H-1). For 6: JC1H1 168.5 Hz, JC1AH1A 160.4 Hz; HR-ESMS for
C48H54N2O17Na (M + Na+): calc. 953.3320, found 953.3348. For 12: JC1H1
160.0 Hz, JC1AH1A 158.1 Hz; HR-ESMS for C54H58N2O17Na (M + Na+): calc.
1029.3633, found 1029.3634. For 15: HR-ESMS for C40H47NO10Na (M +
Na+): calc. 724.3098, found 724.3119. For 16: 1H NMR (CDCl3) d 4.55 (d,
1 H, J1,2 8.4 Hz, H-1), 4.45 (d, 1 H, J1A,2A 7.6 Hz, H-1A); JC1H1 161.8 Hz,
JC1AHA 159.2 Hz.
‡ Typical procedure of glycosylation: compound 3 (236 mg, 0.375 mmol),
5 (116 mg, 0.25 mmol) and powdered 4 Å molecular sieves (250 mg) in dry
CH2Cl2 (5 ml) were stirred for 10 min at 230 °C under nitrogen. Then
BF3·Et2O (15 ml, 0.125 mmol) in dry CH2Cl2 (0.75 ml) was added, and the
reaction mixture was stirred for a further 2 h below 0 °C. After
neutralization with Et3N, the reaction mixture was filtered through Celite,
washed with CH2Cl2 and concentrated. Column chromatography (3:2,
hexane–EtOAc) gave disaccharide 6 (211 mg, 91%).
OAc
O
OH
O
AcO
AcO
BnO
BnO
O
i
O
NH
BnO
BnO
BnO
OMe
1
§ The H NMR spectra of most disaccharides containing the PNZ moiety
PNZ
5
BnO
gave broad peaks which make assignments difficult. The b-linkage of the
disaccharides was confirmed by 13C–1H HMQC experiments and NMR
data for the N-acetyl disaccharide obtained by N-acetylation after the
reductive cleavage step.
¶ Yields were calculated based on the weight of pure compounds isolated by
column chromatography.
OMe
6
ii
OH
O
HO
HO
O
O
NH
BnO
BnO
PNZ
BnO
References
OMe
7
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iii
v
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OH
OH
O
O
HO
HO
HO
HO
O
O
iv
O
O
HO
HO
NHAc
NH2
HO
HO
OH
OMe
OH
OMe
9
8
Scheme 3 Reagents and conditions: i, BF3·Et2O (0.5 equiv.), 3 (1.5 equiv.),
4 Å molecular sieves, CH2Cl2, 230 to 0 °C, 2 h, 91%; ii, NaOMe, MeOH,
2.5 h, 93%; iii, H2, 10% Pd–C, MeOH, 76%; iv, Ac2O, EtOH, 1 h, 87%; v,
H2, 10% Pd–C, MeOH, Ac2O, 83%
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R
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i
HO
BnO
AcO
AcO
BnO
OBn
OBn
O
O
R
NH
PNZ
OBn
10 R = OBn
11 R = NHAc
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13 R = NHAc
ii
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OH
OBn
O
v
O
HO
HO
BnO
O
OBn
NH
OBn
OAc
O
OBn
O
PNZ
AcO
14
BnO
O
OBn
AcO
iii
NHAc
OBn
OH
O
OBn
16
iv
HO
HO
BnO
O
OBn
O
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NH2
OBn
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15
Scheme 4 Reagents and conditions: i, BF3·Et2O (0.5 equiv.), 3 (1.5 equiv.),
4 Å molecular sieves, CH2Cl2, 230 to 0 °C, 2 h, 79% for 12, 75% for 13;
ii, NaOMe, MeOH, 3.5 h, quant.; iii, Na2S2O4 (8 equiv.), EtOH–H2O, 10
min, quant.; iv, Ac2O, pyridine, 16 h, 93%; v, Na2S2O4 (8 equiv.), MeCN–
EtOH–H2O, 1 h; then Ac2O, 10 min, 86%
Received in Corvallis, OR, USA, 23rd January 1997; Com.
7/00549K
1060
Chem. Commun., 1997