One-step synthesis of N-protected glycosylamines from sugar hemiacetals

Article abstract of DOI:10.1016/j.carres.2007.11.022

Protected pentofuranose, hexofuranose and hexopyranose hemiacetals were found to react efficiently with amines carrying a deactivating group (alkoxycarbonyl, tosyl or phosphoryl group) in the presence of a Lewis acid to give the corresponding, stable glyc

Full text of DOI:10.1016/j.carres.2007.11.022

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 2111–2117
One-step synthesis of N-protected glycosylamines from
sugar hemiacetals
,
*
Virginie Liautard, Christelle Pillard, Valerie Desvergnes and Olivier R. Martin*
´
Institut de Chimie Organique et Analytique, University of Orle´ans, CNRS-UMR 6005,
Rue de Chartres, F-45067 Orle´ans, France
Received 3 September 2007; received in revised form 15 November 2007; accepted 20 November 2007
Available online 28 January 2008
Presented at Eurocarb 14th Lubeck, Germany, September 2007
¨
Abstract—Protected pentofuranose, hexofuranose and hexopyranose hemiacetals were found to react efficiently with amines carry-
ing a deactivating group (alkoxycarbonyl, tosyl or phosphoryl group) in the presence of a Lewis acid to give the corresponding,
stable glycosylamines. Such glycosylamine derivatives are useful substrates for further elaboration into nitrogen-containing natural
products and carbohydrate mimetics.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Sugar hemiacetal; N-Glycosylamines; Lewis acid; Amination
1. Introduction
Kobayashi and co-workers have recently demonstrated
that N-alkoxycarbonylated glycosylamines6 as well as
model cyclic hemiaminals7 could be prepared in one step
from glycosyl acetates and benzyl carbamate, and that
these compounds were substrates for the Lewis acid-
catalysed additions of various silylated nucleophiles. In
the course of our work on pyrrolidine galactofuranose
mimics,8,9 we have investigated the scope of the forma-
tion of N-protected glycosylamines from ‘deactivated’
amines and found that, under Lewis acidic conditions,
these glycosylamines could be reached directly from
the free hemiacetal form of the starting carbohydrate
derivative. We report in this article the results of our
studies on the synthesis of N-protected glycosylamines
from diverse furanoid and pyranoid hemiacetals.
In addition to their fundamental importance as precur-
sors of N-linked glycoconjugates,1 glycosylamines have
useful properties as synthetic equivalents of the Schiff
bases of aldehydo-sugars; for example, in chain-exten-
sion reactions the addition of organometallic reagents
to N-benzyl2 and N,N-dibenzyl3 glycosylamines and to
related compounds4 provides indeed the corresponding
open-chain products, often with a good degree of stere-
oselectivity. This reaction has been used as the key step
in the synthesis of diverse iminosugars and of carbo-
hydrate-like natural products.2–4 However, just like free
glycosylamines,5 these N-alkyl glycosylamines are not
stable and are very sensitive to hydrolysis, thus regener-
ating the starting aldoses. By contrast, glycosylamines
carrying a deactivating group at nitrogen (acyl, alkoxy-
carbonyl, etc.) are stable and can be easily isolated.
2. Results and discussion
The synthesis of N-alkoxycarbonyl D-glucofuranosyl-
amines such as 2a, which we use as the starting material
for the synthesis of 1,4-dideoxy-1,4-imino-D-galactitol
derivatives,8 was initially performed from the acetate
of 2,3,5,6-tetra-O-benzyl-D-glucofuranose, under the
*
Corresponding authors. E-mail addresses: v.desvergnes@ism.u-
bordeaux1.fr; olivier.martin@univ-orleans.fr
Present address: Universite´ Bordeaux 1, Institut des Sciences Mole´-
´
culaires, UMR 5255, 351 Cours de la Liberation, F-33405 Talence,
France. Tel.: +33 540006287; fax: +33 540006286.
0008-6215/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.11.022

2112
V. Liautard et al. / Carbohydrate Research 343 (2008) 2111–2117
Table 1. Reactions of 1 with benzyl carbamate under different conditionsa
OBn
OBn
BnO
O
NH2CO2Bn
Lewis acid
O
O
OH
OBn
NHCO2Bn
+
O
OBn
BnO
OBn
BnO
OBn
2a
4 A MS, solvent
RT
BnO
OBn
1
11
Entry
Lewis acid (2 equiv)
Reaction time
Conversionb (%)
Yieldc (2a) (%)
Fraction of 11 (%)
1
2
3
4
5
6
7
8
9
TMSOTf
TMSOTf
6 h 30 min
30 min
30 min
100
93
20
56
58
13
45
50
48
—
53
7
ꢀ20
n.d.d
n.d.
n.d
14
18
—
24
—
TMSOTf (0.1 equiv)
TMSOTf (MeCN)
BF3ꢁEt2O
30 min
81
6 h 30 min
6 h 30 min
24 h
6 h 30 min
24 h
100
100
Near 0
100
n.d.e
0
HNTf2
Sc(OTf)3
Bi(OTf)3
Zn(OTf)2
MgBr2
10
24 h
—
—
a All reactions were performed using 1 equiv of Lewis acid except entry 3 (0.1 equiv), with 2 equiv of benzyl carbamate, and in dichloromethane
except entry 5 (acetonitrile).
b % Conversion from NMR analysis of crude mixtures.
c Isolated yields.
d n.d.: not determined.
e Sluggish reaction and degradation products formed.
conditions described by Kobayashi and co-workers.6
We rapidly found out, however, that the conversion of
1 into its acetate was not necessary, and that the amina-
tion could be performed directly onto the free sugar
hemiacetal 1.8,10 Investigations to determine the best
reaction conditions are reported in Table 1. While no
reaction between 1 and benzyl carbamate takes place
even after several days (RT, CH2Cl2), the addition of tri-
methylsilyl triflate promotes a rapid reaction and leads
to the expected N-Z glycosylamine 2a (entries 1 and
2). With 1 equiv of Lewis acid and 2 equiv of Z-NH2,
the conversion is complete and the glycosylamine
isolated in a yield of 56%, together with a fraction
containing 2a and the internal anhydride 118 (amount
estimated: ꢀ20%). This by-product, resulting from the
participation of the 6-O-benzyloxy group with con-
comitant debenzylation,11 could not be completely
eliminated.
hemiacetals in the D-arabino- and D-ribo-pentofuranose
series (3 and 5), and in the D-gluco- and D-galacto-hexo-
pyranose series (7 and 9). All the reactions were
performed using either TMSOTf or BF3ꢁEt2O as activa-
tors in dichloromethane, with 2 equiv of amine reagent.
The results are reported in Table 2. Using benzyl carb-
amate, all of these hemiacetals were converted nearly
quantitatively into the corresponding N-glycosyl benzyl
carbamates. The products (2a, 4a,6 6a,6 8a6 and 10a)
were isolated in yields ranging from 39% to 91%, the
lower yields being due to difficulties of separation during
their purification by chromatography (silica gel or deac-
tivated silica gel). No by-product arising from benzyloxy
group participation was observed in these cases. The N-
tosyl glycofuranosylamines (2b, 4b, 6b) were obtained in
excellent yields from 1, 3 and 5, respectively (70–96%),
and the corresponding pyranosylamines (8b and 10b)
in 49% and 69% yields from 7 and 9. The pyranoid
derivatives 8b and 10b were more difficult to purify than
the furanoid glycosylamines. In addition, we were
pleased to find that the same process could be applied
to the N-glycosylation of a dialkyl phosphoramidate,
although the yields were not as good as with the other
amine reagents (products 2c, 8c, 10c). The reaction led
to N-glycosyl phosphoramidates, a little known class
of compounds which are of interest as mimics of glyco-
syl phosphates.12
Notably, the two anomers of 2a, 2aa and 2ab, could
be separated by flash chromatography and fully charac-
terised. With
a catalytic amount of Lewis acid
(0.1 equiv), the reaction was incomplete (entry 3), and
with acetonitrile as the solvent, a substantial amount
of the (1?1)-linked disaccharide formed by condensa-
tion of 1 with itself was formed (about 20%) (entry 4).
Satisfactory yields of 2a were also obtained using boron
trifluoride etherate, triflimide or bismuth triflate (entries
5, 6 and 8) as activators, whereas no reaction or complex
mixtures were observed with scandium or zinc triflate,
and with magnesium bromide.
As the formation of these glycosylamines involves a
reaction of free hemiacetals, the question arises as to its
mechanism: is the C–N bond formed by the way of the
N-acylated Schiff base of the starting aldose or by the
way of an SN1-type mechanism resembling a glycosyla-
tion process? The reactions with the benzyl carbamate
This study was then extended to other ‘deactivated’
amines, including p-toluenesulfonamide and diethyl
phosphoramidate, and to a series of protected aldose

V. Liautard et al. / Carbohydrate Research 343 (2008) 2111–2117
Table 2. Reactions of aldose hemiacetals with protected aminesa
2113
O
OH
O
NH2R
NHR
TMSOTf
( )1,2
( )1,2
BnO
BnO
4 A MS, solvent
RT
Entry
Substrate
Protected amine
Reaction time (h)
Product #
Yield (%)
BnO
1
NH2CO2Bn
NH2SO2Tol
NH2PO(OEt)2
0.5
12
5
2a
2b
2c
58
70
32c
O
OH
OBn
2b
3
BnO
BnO
1
O
OH
BnO
BnO
4
NH2CO2Bn
NH2SO2Tol
NH2PO(OEt)2
0.75
2
24
4ad
4b
91
96
—
5b
6
OBn
4c
3
O
OH
7
BnO
BnO
NH2CO2Bn
NH2SO2Tol
NH2PO(OEt)2
5
15
20
6ad
6b
39
88
—
8b
9
OBn
6c
5
BnO
O
OH
10
NH2CO2Bn
NH2SO2Tol
NH2PO(OEt)2
22
8
8
8ad
8b
80
49
26
11b
12
7
BnO
OBn
8c
OBn
O
BnO
OH
13
14
15
NH2CO2Bn
NH2SO2Tol
NH2PO(OEt)2
22
8
8
10a
10b
10c
48
69
42
9
BnO
OBn
OBn
a Conditions: TMSOTf, 1 equiv; NH2R, 2 equiv in CH2Cl2.
b In this case, the reaction was performed using BF3ꢁEt2O.
c The formation of several by-products was observed.
d Identical to the compounds reported by Kobayashi and co-workers.6
of benzylamine (BnNHCOOBn) as amine reagent may
provide a hint: all of the hemiacetals described did react
with this reagent to provide the expected N-benzyl N-carb-
amoylated glycosylamines. The products issued from 7
and 9 were isolated in 56% and 46%, respectively,
whereas the furanosylamines could not be obtained in
a pure form. Since the formation of an N-alkylated, N-
acylated Schiff base (iminium salt) from the open-chain
form of the aldoses would be very unlikely with this
reagent, these results suggest that the N-glycosylation
reported herein occur by the way of an SN1-type reaction
involving an oxocarbenium ion intermediate and thus
are related to O-glycosylation processes.
corresponding glycosylamines readily. As shown by us
and others, these protected glycosylamines consti-
tute useful substrates for further elaboration into nitro-
gen-containing natural products and carbohydrate
mimetics of biological interest such as iminosugars. In
addition, N-glycosylated sulfamides were recently found
to have significant activities as carbonic anhydrase
inhibitors.15
3. Experimental
3.1. General methodsà
Finally, we also investigated the reaction using amides
as nucleophiles: the direct N-glycosylation of amides is a
notoriously difficult reaction and few solutions have
been reported so far.13,14 The desired N-glycosylated
amides, however, were not formed under the conditions
reported in this article.
Unless otherwise stated, all reactions requiring anhy-
drous conditions were carried out using oven-dried
glassware under an atmosphere of dry Ar. THF and
diethyl ether were freshly distilled from sodium/
benzophenone under Ar prior to use. Dichloromethane
In conclusion, we have shown that the reaction of
protected aldose hemiacetals with deactivated amines
(N-alkoxycarbonyl-, N-sulfonyl- or N-phosphoryl-
amines) in the presence of a Lewis acid provides the
à Editor’s note: According to authors, a number of new compounds are
unstable and the required combustion analyses could not be
performed. Pertinent NMR spectra run at high sensitivity have then
been provided in the Supplementary data section.

2114
V. Liautard et al. / Carbohydrate Research 343 (2008) 2111–2117
and MeCN was distilled from calcium hydride. All
reagent-grade chemicals were obtained from commercial
suppliers and were used as received, unless otherwise
stated.
Infrared spectra were recorded on a Perkin–Elmer
Paragon 1000 PC FT-IR spectrometer either as neat
films on NaCl windows or as KBr pellets. Low-resolu-
tion mass spectra were recorded with a Perkin–Elmer
hyd CH2Cl2 (substrate concentration 1 M). The mixture
was stirred at room temperature during the time indi-
cated in Table 2. Solids were removed by filtration over
Celite and saturated aq phase NaHCO3 (2 mL) was
added to the filtrate. The organic phase was separated
and the aq phase extracted with ethyl acetate. The or-
ganic phases were dried then concentrated under dimin-
ished pressure. The crude product was purified by flash
chromatography on silica gel.
Sciex API 3000 in the ESI mode, or with
Finnigan MAT 95 XL in the CI mode. High resolution
mass spectra (HRESIMS) were recorded with
Micromass ZABSpec TOF spectrometer at the Centre
a
a
3.4. N-Benzyloxycarbonyl 2,3,5,6-tetra-O-benzyl-a,b-D-
glucofuranosylamine (2a)
´
Re´gional de Mesures Physiques de l’Ouest (Universite
de Rennes).
Compound 2a (58% yield) was obtained from 110
(38 mg, 0.07 mmol). Purification by flash chromato-
graphy (99.5:0.5 toluene–acetone + eEt3N) afforded
compound 2a (27.2 mg, 58%). The anomers of 2a
(ꢀ1:1) could be separated by careful flash chromato-
graphy and fully characterised.
1H and 13C NMR spectra were recorded at 25 °C on a
Bruker DPX 250 Avance (250 MHz) or on Bruker
Avance 400 or 500 MHz spectrometers. Chemical shifts
are given in ppm (d) and are referenced to the internal
solvent signal or to TMS as internal standard. J values
are quoted in Hz. Carbon multiplicities were assigned
by distortionless enhancement by polarisation transfer
(DEPT) experiments 31P NMR spectra were recorded
25
Compound 2aa: colourless oil; ½aꢂD +8 (c 0.79,
CHCl3); IR (NaCl); m 3432, 3066, 3017, 1727, 1498,
1454, 1359, 1215, 1057 cmꢃ1
;
1H NMR (CDCl3,
1
with H decoupling.
500 MHz): d 3.68 (dd, 1H, J ꢀ 5.25 Hz, J ꢀ 10.5 Hz,
H6a), 3.82 (d, 1H, J ꢀ 3.75 Hz, H2), 3.88 (dd, 1H,
J ꢀ 10.75 Hz, J ꢀ 1.25 Hz, H6b), 3.94–3.99 (m, 1H,
H5), 4.07 (d, 1H, J ꢀ 3 Hz, H3), 4.25 (dd, 1H,
J ꢀ 9.25 Hz, J ꢀ 3 Hz, H4), 4.36–4.55 (m, 7H,
OCH2Ph), 4.78 (d, 1H, J ꢀ 11.5 Hz, OCH2Ph), 5.12 (br
s, 2H, OCH2Ph), 5.78–5.93 (m, 2H, NH and H1), 7.23–
7.33 (m, 25H, CHAr’s); 13C NMR (CDCl3, 125 MHz): d
67.03 (OCH2Ph), 71.02 (C6), 72.49, 72.77 and 73.42
(OCH2Ph), 76.08 (C5), 78.33 (C4), 80.05 (C2), 80.66
(C3), 82.60 (C1), 127.5–128.7 (CHAr’s), 136.28, 136.90,
137.66, 138.68 and 138.91 (CqAr), 155.69 (C@O); (+)
ESIMS: m/z 691.5 [M+NH4]+, 696.0 [M+Na]+.
Specific rotations were measured at room temperature
(20 °C) in a 1 dm cell with a Perkin–Elmer 341 polari-
meter. Analytical thin layer chromatography was
performed using Silica Gel 60F254 precoated plates
(E. Merck) with visualisation by ultraviolet light, phos-
phomolybdate solution (2% in H2SO4–EtOH 1:7)
and/or exposure to I2 vapors. Flash chromatography
was performed on Silica Gel 60 (230–400 mesh) with
EtOAc and petroleum ether (PE) as eluants, unless
otherwise indicated.
3.2. General procedure for glycosylamines 2a, 2b, 2c, 8a,
8b, 8c, 10a, 10b, 10c
25
Compound 2ab: colourless oil; ½aꢂD ꢃ32 (c 0.96,
CHCl3); IR (NaCl); m 3415, 3062, 3030, 2925, 2863,
In a dry flask (10 mL), under Ar, the Lewis acid
(TMSOTf; BF3ꢁEt2O for 2b, 8b and 10b) (1 equiv) was
added by portion to a mixture of substrate 1, 7 or 9
1731, 1504, 1495, 1453, 1207, 1059 cmꢃ1 1H NMR
;
(CDCl3, 500 MHz):
d
3.68 (dd, 1H, J ꢀ 5.5 Hz,
J ꢀ 10.5 Hz, H6a), 3.86 (br s, 1H, H2), 3.90 (d, 1H,
J ꢀ 10.5 Hz, H6b), 4.00 (ddd, 1H, J ꢀ 9 Hz, J ꢀ 5.5 Hz,
J ꢀ 1.5 Hz, H5), 4.07 (d, 1H, J ꢀ 3.5 Hz, H3), 4.25 (dd,
1H, J ꢀ 9.5 Hz, J ꢀ 3 Hz, H4), 4.66–4.72 (m, 7H,
OCH2Ph), 4.82 (d, 1H, J ꢀ 11.5 Hz, OCH2Ph), 5.10
(AB, 2H, J ꢀ 12 Hz, OCH2Ph), 5.66–5.72 (m, 2H, H1
and NH), 7.16–7.34 (m, 25H, CHAr’s); 13C NMR
(CDCl3, 125 MHz): d 66.90 (OCH2Ph), 71.46 (C6),
71.69, 72.52, 72.70 and 73.58 (OCH2Ph), 76.69 (C5),
80.57 (C4), 80.84 (C3), 84.37 (C2), 86.08 (C1), 127.52–
128.58 (CHAr’s), 136.37, 137.27, 137.35, 138.62 and
138.95 (CqAr), 155.02 (C@O); (+) MALDI-TOFMS:
m/z 696.3 [M+Na]+, 712.2 [M+K]+; HRESIMS m/z:
[M+Na]+ calcd for C42H43NO7Na, 696.2937; found,
696.2940. Anal. (mixture of 2aa and 2ab) Calcd for
C42H43NO7: C, 74.87; H, 6.43; N, 2.08. Found: C,
75.10; H, 6.46; N, 2.02.
˚
(1 equiv), amine reagent (2 equiv) and 4 A molecular
sieves, in anhyd CH2Cl2 (substrate concentration 1 M).
The orange mixture was stirred at room temperature
during the time indicated in Table 2. After quenching
by the addition of triethylamine, filtration over Celite
and rinsing with EtOAc, the solvent was evaporated to
provide a yellow oily product. The crude product was
then purified by flash chromatography on silica gel.
3.3. General procedure for pentofuranosylamines 4a, 4b,
6a, 6b
In a dry flask (10 mL), under Ar, the Lewis acid
(TMSOTf; BF3ꢁEt2O for 4b and 6b) (1 equiv) was added
dropwise to a mixture of substrate 3 or 5 (1 equiv),
˚
amine reagent (2 equiv) and 4 A molecular sieves, in an-

V. Liautard et al. / Carbohydrate Research 343 (2008) 2111–2117
2115
3.5. N-p-Tolylsulfonyl 2,3,5,6-tetra-O-benzyl-a,b-D-
glucofuranosylamine (2b)
162 MHz): d 5.51 (s), 6.65 (s); (+) ESIMS: m/z 676.5
[M+H]+, 698.5 [M+Na]+; HRESIMS m/z: [M+Na]+
calcd for C38H46NO8NaP, 698.2858; found, 698.2843.
Compound 2b was obtained from
1
(132 mg,
0.245 mmol). After purification by flash chromatogra-
phy (9:1 petroleum ether–EtOAc) compound 2b
(119 mg, 70%) was obtained as a colourless oil and as
an equimolar mixture of a/b anomers.
3.7. N-Benzyloxycarbonyl 2,3,5-tri-O-benzyl-a,b-D-
arabinofuranylamine (4a)
Compound 4a was obtained from 316 (50 mg,
0.12 mmol) after purification by flash chromatography
(9:1?4:1 petroleum ether–EtOAc) as a colourless oil
(60 mg, 91%) (1:1 mixture of a/b anomers).
NMR spectral data identical to those reported by
Kobayashi and co-workers.6 (+) HRESIMS m/z:
[M+Na]+ calcd for C34H35NO6Na, 576.23621; found,
576.2361.
IR (NaCl); m 3253, 3063, 3031, 2249, 1725, 1599, 1496,
1454, 1343, 1209, 1165 cmꢃ1
.
1H NMR (CDCl3,
500 MHz); d 2.33 (s, 1.5H, CH3), 2.36 (s, 1.5H, CH3),
3.04 (dd, 0.5H, J ꢀ 15 Hz, J ꢀ 5.2 Hz, H6a), 3.27–3.34
(m, 1H, H6b, H60 ), 3.53–3.58 (m, 1H, H60 , H5), 3,82–
a
b
3,85 (m, 0.5H, H50), 3.89 (d, 0.5H, J ꢀ 5 Hz, H20),
3.95 (s, 0.5H, H2), 3.98 (d, 0.5H, J ꢀ 5 Hz, H3), 4.00–
4.05 (m, 1H, H30, H4), 4.18 (dd, 0.5H, J ꢀ 9.5 Hz,
J ꢀ 5 Hz, H40), 4.34–4.58 (m, 7H, OCH2Ph), 4.69 (d,
0.5H, J ꢀ 10 Hz, OCH2Ph) and 4.71 (d, 0.5H,
J ꢀ 10 Hz, OCH2Ph), 5.39 (d, 0.5H, J ꢀ 11 Hz, H1),
5.56–5.67 (m, 1.5H, H10 and NH), 7.14–7.38 (m, 22H,
CHAr’s), 7.69 (d, 1H, J ꢀ 10 Hz, CHAr’s), 7.76 (d, 1H,
J ꢀ 10 Hz, CHAr’s); 13C NMR (CDCl3, 125 MHz): d
21.59 (CH3), 21.64 (CH3), 70.12 (C6), 71.22 (C6),
71.87, 72.15, 72.52, 72.58, 73.08, 73.26, 73.43 and
73.47 (OCH2Ph), 75.68 (C5), 76.26 (C5), 78.54 (C4),
80.30 (C3), 80.34 (C3), 80.79 (C2 and C4), 84.41 (C1
or C2), 84.44 (C1 or C2), 88.02 (C1), 127.35–129.48
(CHAr’s), 136.66, 136.82, 137.09, 137.48, 138.56,
138.66, 138.70, 138.84, 138.97, 139.01, 143.08 and
143.18 (CqAr); (+) ESIMS: m/z 702 [M+NH4]+; HR-
ESIMS m/z: [M+Na]+ calcd for C41H43NO7SNa,
716.26579; found, 716.2660.
3.8. N-p-Tolylsulfonyl 2,3,5-tri-O-benzyl-a,b-D-arabino-
furanosylamine (4b)
Compound 4b was obtained from 315 (50 mg,
0.12 mmol) after purification by flash chromatography
(petroleum ether–EtOAc 4:1 then 7:3). The colourless
oil (65 mg, 96%) was obtained as a 1:1 mixture of a/b
anomers.
IR (NaCl); 3282, 3029, 2924, 2867, 1496, 1454 cmꢃ1
;
1H NMR (CDCl3, 250 MHz): d 2.37 (s, 1.5H, CH3),
2.38 (s, 1.5H, CH3), 3.31–3.43 (m, 2H, H5), 3.87–4.01
(m, 3H, H2, H3, H4), 4.36–4.56 (m, 6H, OCH2Ph),
5.43–5.54 and 5.75–5.82 (2AB, 2H, J ꢀ 10.8 Hz, H1,
NH), 7.19–7.34 (m, 17H, CHAr’s), 7.74 and 7.77 (2d,
2H, J ꢀ 8.5 Hz, CHAr’s); 13C NMR (CDCl3,
62.5 MHz): d 21.7 (CH3), 69.9 (C5), 70.0 (C5), 71.7,
71.9, 72.0, 72.3, 73.3 and 73.5 (OCH2Ph), 80.9, 81.3,
82.3, 82.6, 82.7, 83.9 (C1), 85.2, 87.8 (C1), 127.2–129.6
(CHAr’s), 136.9 (2 C), 137.1, 137.6, 137.7, 138.1, 138.6,
138.8, 143.3 and 143.4 (CqAr); (+) ESIMS: m/z 591
[M+NH4]+, 596 [M+Na]+; (+) HRESIMS m/z:
[M+Na]+ calcd for C33H35NO6SNa, 596.20773; found,
596.20712.
3.6. N-Diethylphosphoryl 2,3,5,6-tetra-O-benzyl-a,b-D-
glucofuranosylamine (2c)
Compound 2c was obtained from
1
(137 mg,
0.253 mmol) after purification by flash chromatography
(9:1 petroleum ether–EtOAc). The colourless oil (54 mg,
32%) was obtained as a 3:2 mixture of a/b anomers.
IR (NaCl); 3385, 2981, 2927, 1724, 1454, 1269, 1097,
3.9. N-Benzyloxycarbonyl 2,3,5-tri-O-benzyl-a-D-ribo-
furanosylamine (6a)
1
1027, 977 cmꢃ1; H NMR (CDCl3, 400 MHz): d 1.26
(t, 6H, J ꢀ 7.2 Hz, CH3), 3.62–3.68 (m, 1H, H6a),
3.75–4.11 (m, 9H, H6b, H2, H3, H5, CH3CH2, NH),
4.22 (dd, 1H, J ꢀ 3.6 and 9.6 Hz, H4), 4.39–4.62 (m,
7H, OCH2Ph), 4.79 and 4.83 (2d, 1H, J ꢀ 11.6,
2OCH2Ph), 5.06 (dd, 0.4H, J ꢀ 7.2 and 12 Hz, H1b),
5.27–5.32 (m, 0.6H, H1a), 7.11–7.43 (m, 20H, CHAr’s);
13C NMR (CDCl3, 100 MHz): d 16.18–16.37 (m,
CH3), 62.50–62.59 (m, CH2CH3), 71.37 (OCH2Ph),
71.62 (C6), 72.52, 72.61, 72.90, 72.93, 73.57 and 73.60
(OCH2Ph), 76.11 (C5), 77.36 (C5), 78.07 (C4), 80.34
(d, C4), 80.41 (C2), 80.69 (C3), 80.75 (C3), 84.18 (d,
C1a), 85.30 (d, C2), 87.78 (C1b), 127.56–128.76
(CHAr’s), 137.02, 137.25, 137.42, 137.78, 138.56,
138.63, 138.95 and 138.98 (CqAr); 31P NMR (CDCl3,
Compound 6a6 was obtained from 517 (200 mg,
0.48 mmol) as a ꢀ1:1 mixture of a/b anomers (1H
NMR of crude product). Purification of the mixture
by flash chromatography (9:1?17:3?4:1 petroleum
ether–EtOAc) yielded only the 6ab anomer (100 mg,
39%) as a colourless oil.
25
Compound 6ab: ½aꢂD +53 (c 1.7, CHCl3); IR (NaCl);
3418, 3014, 2925, 2865, 1734, 1508, 1454 cmꢃ1 1H
;
NMR (CDCl3, 250 MHz): d 3.42–3.45 (m, 2H, H5),
3.96 (m, 1H, H2), 4.04 (br t, 1H, H3), 4.23–4.68 (s and
2 AB, 7H, H4, OCH2Ph), 5.11 (s, 2H, OCH2Ph), 5.71
(dd, 1H, J ꢀ 5.4 Hz J ꢀ 9.5 Hz, H1), 6.35 (d, 1H,
J ꢀ 9.5 Hz, NH), 7.20–7.33 (m, 20H, CHAr’s); 13C

2116
V. Liautard et al. / Carbohydrate Research 343 (2008) 2111–2117
NMR (CDCl3, 62.5 MHz): d 66.8 (OCH2Ph), 70.1 (C5),
72.6 and 73.6 (OCH2Ph), 76.6 and 77.9 (C2 and C3),
81.2 (C1), 81.3 (C4), 127.6–128.5 (CHAr’s), 136.4,
137.4, 137.7 and 137.9 (CqAr), 156.0 (C@O); (+)
ESIMS: m/z 554 [M+H]+, 571 [M+NH4]+, 576
[M+Na]+; (+) HRESIMS m/z: [M+Na]+ calcd for
C34H35NO6Na, 576.23566; found, 576.23490.
H6a), 3.26–3.75 (m, 5.5H), 4.27–4.53 (m, 4H, OCH2Ph),
4.62–4.90 (m, 4.5H, OCH2Ph and H1), 5.20 (d, 0.5H,
J ꢀ 10 Hz, NH), 5.32–5.36 (m, 0.5H, H1), 5.51 (d,
0.5H, J ꢀ 3 Hz, NH), 7.07–7.36 (m, 22H, CHAr’s),
7.72–7.81 (m, 2H, CHAr’s); 13C NMR (CDCl3,
62.5 MHz): d 21.60 (CH3), 67.37 (C6), 68.32 (C60),
70.48 (CH), 72.67, 73.51, 73.66, 75.01, 75.17, 75.77
and 75.87 (OCH2Ph), 76.47 (C2), 76.97 (CH), 77.33
(C2), 79.68 (C1), 80.59 (CH), 82.01 (CH), 84.33 (C1),
85.67 (CH), 127.37–129.56 (CHAr’s), 136.94, 137.39,
137.68, 137.94, 137.97, 138.11, 138.16, 138.41, 138.46,
138.63, 143.38 and 143.71 (CqAr); HRESIMS m/z:
[M+Na]+ calcd for C41H43NO7SNa, 716.26579; found,
716.2670.
3.10. N-(p-Toluenesulfonyl) 2,3,5-tri-O-benzyl-a,b-D-
ribofuranosylamine (6b)
Compound 6b was obtained from 516 (60 mg,
0.14 mmol) as a colourless oil (70 mg, 88%) (2:1 mixture
of anomers) after flash chromatography (petroleum
ether–EtOAc 4:1 then 7:3).
IR (NaCl); 3271, 3028, 2924, 2867, 1724, 1599, 1496,
3.13. N-Diethylphosphoryl 2,3,4,6-tetra-O-benzyl-a,b-D-
glucopyranosylamine (8c)
1454 cmꢃ1
;
1H NMR (CDCl3, 250 MHz): d 2.36 (s,
2H, 3 ꢄ 0.67H, CH3 M), 2.38 (s, 1H, 3 ꢄ 0.33H, CH3
m), 3.27–3.43 (m, 2H, H5), 3.90–4.08 (several m, 3H,
H2, H3, H4), 4.30–4.72 (m, 6H, OCH2Ph), 5.28 (dd,
0.33H, J ꢀ 2.2 Hz, J ꢀ 9.1 Hz, H1 m), 5.46–5.56 (m,
1H, H1 M, NH m), 6.25 (d, 0.67H, J ꢀ 9.1 Hz, NH
M), 7.18–7.33 (m, 17H, CHAr’s), 7.62 (d, 0.66H, J
8.2 ꢀ Hz, CHAr’s), 7.78 (d, 1.34H, J ꢀ 8.2 Hz, CHAr’s);
13C NMR (CDCl3, 62.5 MHz): d 21.6 (CH3), 68.7
(C5), 69.9 (C5), 72.2, 72.4, 72.9, 73.5 and 73.7
(OCH2Ph), 76.1, 76.9, 77.7, 81.1, 81.2, 81.6, 83.3 (C1
M), 87.6 (C1 m), 127.0–129.5 (CHAr’s,), 137.1, 137.3,
137.5, 137.6, 137.9, 138.1, 139.3, 143.0 and 143.4 (CqAr);
(+) ESIMS: m/z 574 [M+H]+, 596 [M+Na]+.
Compound 8c was obtained from
7
(100 mg,
0.185 mmol). After purification by flash chromato-
graphy (1:1 petroleum ether–EtOAc) compound 8c
(32 mg, 26%) was obtained as a colourless oily product
and as the b-anomer predominantly.
IR (NaCl); 3422, 3185, 2924, 2857, 1725, 1453, 1234,
1161, 1093, 1028, 973 cmꢃ1
;
1H NMR (CDCl3,
500 MHz): d 1.19 (m, 6H, CH3), 3.28 (t, 1H, J ꢀ 10 Hz,
H2), 3.41–3.48 (m, 2H, NH, H3 or H4), 3.61–3.70 (m,
4H, H3 or H4, H5, 2H6), 4.03–4.10 (m, 4H, CH2CH3),
4.33 (dt, 1H, J ꢀ 8.5, J ꢀ 8.5, J ꢀ 11.5 Hz, H1), 4.44–
4.63 (m, 3H, OCH2Ph), 4.70–4.92 (m, 5H, OCH2Ph),
7.15–7.35 (m, 20H); 13C NMR (CDCl3, 62.5 MHz): d
16.14 (CH3), 16.26 (CH3), 62.72–62.85 (several d,
POCH2CH3), 68.73 (C6), 72.91, 75.08, 75.22 and 75.84
(OCH2Ph), 76.16 (CH), 77.92 (CH), 82.46 (d, C2),
83.76 (C1), 86.05 (d, CH), 127.81–128.55 (CHAr’s),
137.99, 138.04, 138.19 and 138.53 (CqAr); 31P NMR
(CDCl3, 202 MHz): d 6.12 (s); (+) ESIMS: m/z 676.5
[M+H]+, 698.5 [M+Na]+.
3.11. N-Benzyloxycarbonyl 2,3,4,6-tetra-O-benzyl-a,b-D-
glucopyranosylamine (8a)
Compound 8a was prepared from commercial tetra-O-
benzyl-D-glucopyranose 7 (100 mg, 0.185 mmol). After
purification by flash chromatography (17:3 petroleum
ether–EtOAc) compound 8a (100 mg, 80%) was ob-
tained as a colourless oil (1:1 mixture of anomers).
NMR spectral data identical to those reported by
Kobayashi and co-workers.6 (+) ESIMS: m/z 691.5
[M+NH4]+, 696.5 [M+Na]+. HRESIMS m/z:
[M+Na]+ calcd for C42H43NO7Na, 696.29372; found,
696.2941.
3.14. N-Benzyloxycarbonyl 2,3,4,6-tetra-O-benzyl-a,b-D-
galactopyranosylamine (10a)
Compound 10a was prepared from commercial tetra-O-
benzyl-D-galactopyranose
9
(100 mg, 0.185 mmol).
After purification by flash chromatography (4:1 petro-
leum ether–EtOAc) compound 10a (60.4 mg, 48%) was
obtained as a colourless oily product (1:1 mixture of
anomers).
3.12. N-p-Toluenesulfonyl 2,3,4,6-tetra-O-benzyl-a,b-D-
glucopyranosylamine (8b)
Compound 8b was prepared from
7
(100 mg,
IR (NaCl); 3415, 3063, 3030, 2869, 1731, 1522, 1454,
1
0.185 mmol). After purification by flash chromato-
graphy (4:1 petroleum ether–EtOAc) compound 8b
(63 mg, 49%) was obtained as a colourless oily product
(1:1 mixture of anomers).
1265, 1100, 1043 cmꢃ1; H NMR (CDCl3, 250 MHz):
d 3.47–3.72 (m, 4H), 3.82–4.16 (m, 2H), 4.33–4.49 (m,
2H), 4.49–4.74 (m, 4H), 4.76–4.95 (m, 2H), 4.99–5.19
(m, 2.5H), 5.53–5.61 (m, 0.5H), 7.11–7.46 (m, 25H);
13C NMR (CDCl3, 62.5 MHz): d 67.08 (CH2), 67.21
(CH2), 68.08 (CH2), 68.15 (CH2), 72.75 (CH2), 73.03
(CH2), 73.06 (CH2), 73.54 (CH), 73.59 (CH2), 74.06
IR (NaCl); 3055, 2987, 2306, 1422, 1265, 1069,
896 cmꢃ1 1H NMR (CDCl3, 250 MHz): d 2.31 (s,
;
1.5H, CH3), 2.32 (s, 1.5H, CH3), 2.90–3.02 (m, 0.5H,

V. Liautard et al. / Carbohydrate Research 343 (2008) 2111–2117
2117
(CH2), 74.49 (CH2), 74.66 (CH), 74.87 (CH), 75.12
Supplementary data
(CH), 75.17 (CH), 77.36 (CH), 78.19 (CH), 82.12
(CH), 83.59 (CH), 127.59–128.64 (CHAr’s), 136.18,
136.31, 137.72, 137.86, 138.12, 138.26, 138.37, 138.55
and 138.59 (CqAr), 155.75 (C@O), 156.23 (C@O); (+)
ESIMS: m/z 691.5 [M+NH4]+, 696.5 [M+Na]+; HR-
ESIMS m/z: [M+Na]+ calcd for C42H43NO7Na,
696.29372; found, 696.2944.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2007.11.022.
References
1. Garg, H. G.; von dem Bruch, K.; Kunz, H. Adv.
Carbohydr. Chem. Biochem. 1994, 50, 277–310.
3.15. N-p-Toluenesulfonyl 2,3,4,6-tetra-O-benzyl-a,b-D-
galactopyranosylamine (10b)
2. (a) Lay, L.; Nicotra, F.; Paganini, A.; Pangrazio, C.;
Panza, L. Tetrahedron Lett. 1993, 34, 4555–4558; (b)
Cipolla, L.; Lay, L.; Nicotra, F.; Pangrazio, C.; Panza, L.
Tetrahedron 1995, 51, 4679–4690; (c) Cipolla, L.; La Ferla,
B.; Peri, F.; Nicotra, F. Chem. Commun. 2000, 1289–1290;
(d) Cipolla, L.; Palma, A.; La Ferla, B.; Nicotra, F. J.
Chem. Soc., Perkin Trans. 1 2002, 2161–2165; (e) Behr, J.
B.; Erard, A.; Guillerm, G. Eur. J. Org. Chem. 2002, 1256–
1262; (f) Behr, J. B.; Guillerm, G. Tetrahedron: Asymmetry
2002, 13, 111–113; (g) Yoda, H.; Yamazaki, H.; Kiwauchi,
M.; Takabe, K. Tetrahedron: Asymmetry 1995, 11, 2669–
2672; (h) Yoda, H.; Katoh, H.; Takabe, K. Tetrahedron
Lett. 2000, 41, 7661–7665; (i) Bosco, M.; Bisseret, P.;
Constant, P.; Eustache, J. Tetrahedron Lett. 2007, 48, 153–
157.
Compound 10b was prepared from
9 (100 mg,
0.185 mmol). After purification by flash chromatogra-
phy (4:1 petroleum ether–EtOAc) compound 9 (88 mg,
69%) was obtained as a colourless oily product (1:1 mix-
ture of anomers).
IR (NaCl); 3423, 3063, 3030, 2915, 2970, 1496, 1454,
1330, 1164, 1096, 1076, 896 cmꢃ1 13C NMR (CDCl3,
;
62.5 MHz): d 21.55 (CH3), 68.11 (CH2), 73.07 (CH2),
73.46 (CH2), 73.52 (CH2), 74.76 (CH2), 74.84 (CH),
74.88 (CH), 75.27 (CH), 77.73 (CH), 83.29 (CH), 84.64
(CH), 127.36–129.59 (CHAr’s), 137.9–138.7 (CqAr),
143.25 (CqAr); (+) ESIMS: m/z 711.5 [M+H]+, m/z
716.5 [M+Na]+.
3. Nagai, M.; Gaudino, J. J.; Wilcox, C. S. Synthesis 1992,
163–168.
4. (a) Bortolussi, M.; Cinquin, C.; Bloch, R. Tetrahedron
Lett. 1996, 37, 8729–8732; (b) Dondoni, A.; Perrone, D.
Tetrahedron 2003, 59, 4261–4273.
3.16. N-Diethylphosphoryl 2,3,4,6-tetra-O-benzyl-a,b-D-
galactopyranosylamine (10c)
´
5. Monsigny, M.; Quetard, C.; Bourgerie, S.; Delay, D.;
Pichon, C.; Midoux, P.; Mayer, R.; Roche, A. C.
Biochimie 1998, 80, 99–108.
6. Sugiura, M.; Hagio, H.; Kobayashi, S. Helv. Chim. Acta
2002, 85, 3678–3691.
7. Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J.
Am. Chem. Soc. 2001, 123, 12510–12517.
8. Liautard, V.; Desvergnes, V.; Martin, O. R. Org. Lett.
2006, 8, 1299–1302.
9. Liautard, V.; Christina, A. E.; Desvergnes, V.; Martin, O.
R. J. Org. Chem. 2006, 71, 7337–7345.
Compound 10c was obtained from
9
(100 mg,
0.185 mmol). After purification by flash chromatogra-
phy (1:1 petroleum ether–EtOAc) compound 10c
(52 mg, 42%) was obtained as a colourless oily product
and as the b-anomer predominantly.
IR (NaCl); 3385, 2869, 2924, 1724, 1454, 1237, 1272,
1
1097, 1027, 979 cmꢃ1; H NMR (CDCl3, 500 MHz): d
1.19 (t, 6H, J ꢀ 7.5 Hz, CH3), 3.40 (t, 1H, J ꢀ 11 Hz,
H2), 3.50–3.65 (m, 5H, H4, H3, 2H6 and NH), 3.92–
4.09 (m, 5H, CH2CH3 and H5), 4.30 (dt, 1H, J ꢀ 8,
J ꢀ 8.5, J ꢀ 11.5 Hz, H1), 4.41 (AB, 2H, J ꢀ 11.7 Hz,
OCH2Ph), 4.60 (d, 1H, OCH2Ph), 4.71 (AB, 2H,
J ꢀ 11.5, OCH2Ph), 4.80 (d, 1H, J ꢀ 11 Hz, OCH2Ph),
4.89 (d, 1H, J ꢀ 11 Hz, OCH2Ph), 4.94 (d, 1H,
J ꢀ 11 Hz, OCH2Ph), 7.25–7.34 (m, 20H); 13C NMR
(CDCl3, 62.5 MHz): d 16.09 (CH3), 16.22 (CH3), 62.53–
62.67 (m, POCH2CH3), 68.76 (CH2), 72.91 (CH2),
73.58 (2C, CH), 74.63 (CH), 74.84 (CH2), 75.44 (CH2),
79.5 (d, CH), 83.76 (d, CH), 84.09 (CH), 127.66–128.54
(CHAr’s), 137.90, 137.26, 137.32 and 137.56 (CqAr); 31P
NMR (CDCl3, 202 MHz): d 6.26 (s), 7.54 (s); (+) ESIMS:
m/z 676.5 [M+H]+, 698.5 [M+Na]+.
`
10. Ferrieres, V.; Bertho, J. N.; Plusquellec, D. Carbohydr.
Res. 1998, 311, 25–35.
11. Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org.
Chem. 1989, 54, 1346–1353.
12. Paulsen, H.; Pries, M.; Lorentzen, J.-P. Liebigs Ann.
Chem. 1994, 389–397.
13. Kahne, D.; Walker, S.; Cheng, Y.; van Engen, D. J. Am.
Chem. Soc. 1989, 111, 6881–6882.
14. Tanaka, H.; Iwata, Y.; Takahashi, D.; Adachi, M.;
Takahashi, T. J. Am. Chem. Soc. 2005, 127, 1630–1631.
15. Colinas, P. A.; Bravo, R. D.; Vullo, D.; Scozzafava, A.;
Supuran, C. T. Bioorg. Med. Chem. Lett. 2007, 17, 5086–
5090.
16. Tejima, S.; Fletcher, H. G., Jr. J. Org. Chem. 1963, 28,
2999–3004.
17. Barker, R.; Fletcher, H. G., Jr. J. Org. Chem. 1961, 26,
4605–4609.