Stereoselective entry into the d-GalNAc series starting from the d-Gal one: a new access to N-acetyl-d-galactosamine and derivatives thereof

Article abstract of DOI:10.1016/j.carres.2008.11.018

A new stereoselective preparation of N-aceyl-d-galactosamine (1b) starting from the known p-methoxyphenyl 3,4-O-isopropylidene-6-O-(1-methoxy-1-methylethyl)-β-d-galactopyranoside (10) is described using a simple strategy based on (a) epimerization at C-2

Full text of DOI:10.1016/j.carres.2008.11.018

Carbohydrate Research 344 (2009) 298–303
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Stereoselective entry into the D-GalNAc series starting from the D-Gal one:
a new access to N-acetyl-D-galactosamine and derivatives thereof q
*
Lorenzo Guazzelli, Giorgio Catelani , Felicia D’Andrea, Alessia Giannarelli
Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno, 33-I-56126 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2008
Received in revised form 10 November 2008
Accepted 28 November 2008
Available online 10 December 2008
A new stereoselective preparation of N-aceyl-
phenyl 3,4-O-isopropylidene-6-O-(1-methoxy-1-methylethyl)-b-
using a simple strategy based on (a) epimerization at C-2 of 10 via oxidation–reduction to give the talo
derivative 11, (b) amination with configurational inversion at C-2 of 11 via a SN2-type reaction on its 2-
D
-galactosamine (1b) starting from the known p-methoxy-
D-galactopyranoside (10) is described
imidazylate, (c) anomeric deprotection of the p-methoxyphenyl b-D-galactosamine glycoside 14, (d)
complete deprotection. Applying the same protocol to 2,3:5,6:30,40-tri-O-isopropylidene-60-O-(1-meth-
oxy-1-methylethyl)-lactose dimethyl acetal (4), directly obtained through acetonation of lactose, the
Keywords:
N-Acetyl-D-galactosamine
Amination with inversion
Epimerization
Lactose
disaccharide b-
D
-GalNAcp-(1?4)-
D-Glcp (1a) was obtained with complete stereoselectivity in good
(40%) overall yield from lactose.
Ó 2008 Elsevier Ltd. All rights reserved.
b-D-Galactopyranosides
1. Introduction
-Galactosamine (
hydro-b-
used the azidonitration of tri-O-acetyl-
of some 2-azido-2-deoxy- -galactopyranose derivatives and free
-GalNAc (1b). After this key paper, several addition reactions to
D
-talopyranoside. A few years later, Lemieux and Ratcliffe9
-galactal for the synthesis
D
D
D
-GalNH2) is, after
D
-glucosamine, the second
D
most abundant natural aminosugar, isolated first in 1914 by Le-
D
D
vene and La Forge2 from chondroitin, a mucopolysaccharide in
-galactal derivatives have been proposed to obtain
D-GalNAc
which
sulfate,3 as its acetamido derivative (2-acetamido-2-deoxy-
galactopyranose, -GalNAc, 1b). -GalNAc is also a constituent of
D-GalNH2 is present, as in the structurally related dermatan
and its glycosides, as the Danishefsky’s sulfamidoglycosylation,10
D
-
the Gin’s acetamidoglycosylation.11 Furthermore, specific synthe-
D
D
ses of
tose13 have been proposed.
In the frame of a general project on the synthesis of b-
aminyl-(1?4)-
-Glcp disaccharides,14 we considered the synthesis
of b- -GalNAcp-(1?4)- -Glcp (1a), a natural disaccharide present
D-GalNH2 starting from L D-taga-
-lyxose12 and, very recently,
several complex glycoproteins, as for examples: (i) the monosac-
charide ‘core’ of mucines,4 (ii) oligosaccharide determinants of hu-
man blood group antigens,5 (iii) anti-freeze glycoproteins of
D
-hexos-
D
anthartic fishes.5 Furthermore,
D
-GalNAc has been recently recog-
nised as one of the strongest agonist of the NKR-P1 rat Natural Kill-
er cells receptor.6 Owing to the biological relevance of
-GalNAc,
D
D
in minute amount in the bovine colostrum.15 The sole reported syn-
thesis of 1a is based on an enzymatic glycosylation involving a b-
(1?4)-N-acetylgalactosaminyltransferase.16 However, the above
synthesis does not appear suitable for preparative purposes. Pre-
sented herein is a new efficient chemical method for the preparation
of the disaccharide 1a starting from lactose, involving a two-step
amination with overall retention of configuration at C-20 (Chart 1),
D
several approaches to its synthesis in the free form and/or to the
synthesis of its derivatives have been proposed, using different car-
bohydrate starting materials. The two most exploited synthetic
channels to
C-4 epimerization of the largely and cheaply available
mimicking thus the biosynthetic pathway; and (b) the amination
D-GalNAc and its derivatives are those based on (a)
D
-GlcNAc,7
through the formation of a b-
2. The potentiality of the method has also been demonstrated in the
case of a monosaccharide b- -galactopyranoside, that has been
transformed into a known precursor of free -GalNAc (1b) and of
some 2-azido-2-deoxy- -galactopyranoside glycosyl donors.
D-talopyranoside intermediate of type
at C-2 of
The first
D
-galactose with formal retention of configuration.8–11
D-Gal to
D
-GalNAc transformation was described in
D
19768 by Paulsen and co-workers using as key reaction the sodium
D
azide opening of the epoxide ring of the intermediate 1,6:2,3-dian-
D
2. Results and discussion
q
Part 25 of the series ‘chemical valorisation of milk-derived carbohydrates’. For
part 24, see Ref. 1.
* Corresponding author. Tel.: +39 0502219700; fax: +39 0502219660.
E-mail address: giocate@farm.unipi.it (G. Catelani).
A straightforward route to b-D-GalNAcp-(1?4)-D-Glcp (1a) was
envisaged (Scheme 1) taking advantage of the easy availability of
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.11.018

L. Guazzelli et al. / Carbohydrate Research 344 (2009) 298–303
299
OH
OP
OP
3
OH
HO
OP
PO
OP
PO
OH
O
O
O
X
OR
OR
NHAc
OH
1a: X = 4-O-D-glucopyranosyl
2
1b: X = OH
Chart 1. Retrosynthetic approach for transforming a b-
D-galactopyranoside unit into a
D-GalNAc one.
O
O
O
O
OMIP
OH
O
OMIP
OSO2Im
O
CMe2
O
CMe2
CMe2
O
OMIP
O
O
O
O
O
a
Me2C
Me2C
Me2C
Ref. 17
(92%)
O
O
O
O
O
O
OH
O
O
O
(MeO)2CH
(MeO)2CH
5
(MeO)2CH
4
CMe2
CMe2
CMe2
O
O
O
6
b
O
OMIP
CMe2
O
OH
O
CMe2
RO
RO
OR
O
O
OR
O
c
O
O
Me2C
Me2C
RO
O
OR
d
O
O
O
O
O
N3
NHAc
(MeO)2CH
8
NHAc
O
O
OR
1a: R = H
9: R = Ac
(MeO)2CH
7
CMe2
CMe2
e
O
O
MIP = -C(OMe)Me2
Scheme 1. Synthesis of b-
D
-GalNAcp-(1?4)-
D
-Glcp disaccharide from lactose. Reagents and conditions: (a) Im2SO2, NaH, DMF, ꢀ30 °C, 4 h (86%); (b) NaN3, DMF, 100 °C, 1.2 h
(94%); (c) (1) NiCl2ꢁ6H2O, NaBH4, MeOH, 0 °C, rt, 2 h; (2) Ac2O, MeOH, rt, 2 h (86%); (d) 80% aq AcOH, 80 °C, 4 h (90%); (e) Ac2O, Py, rt, 18 h (95%).
the tetraacetonide 5,17 prepared from its C-20 lactose epimer (4)
through a completely stereoselective, high yielding (92%) oxida-
tion–reduction sequence.17 The activation of 5 was made by treat-
ment with imidazyl sulfate (Im2SO2) and NaH in DMF at ꢀ30 °C,
resulting in the corresponding imidazylate 6, isolated pure by flash
chromatography in 86% yield. Compound 6 was then subjected to a
SN2 substitution reaction, with NaN3 in DMF at 100 °C, which gave,
after flash chromatography, the azido derivative 7 in 94% yield.
This result confirms the usefulness of the imidazylate leaving
group for performing efficient substitution in position 2 of a pyran-
oside, where other aryl and alkyl sulfonates are known to give
unsatisfactory results.18
The reduction of the azido group of 7, employing nickel chlo-
ride hexahydrate and sodium borohydride, afforded a single prod-
uct which was directly submitted to N-acetylation (Ac2O in
MeOH). In the slightly acidic reaction conditions, the labile 60-
mixed acetal group was removed and compound 8 was obtained
in 86% yield, after chromatographic purification. The target com-
pound 1a was instead prepared by complete deprotection of 8
using 80% aq AcOH at 80 °C: the reaction involves the O-deisopro-
pylidenation and the C-1 aldehydo group exposition with con-
comitant six-membered ring closure. The structure of 1a as well
as its anomeric composition (a/b ratio about 2:3) was established
on the basis of its NMR spectra. In particular, the 1H NMR spec-
trum was identical to the reported one,15 while the 13C NMR sig-
nals, which have not yet been reported, were assigned by
comparison (see Table 1) with those of
the gluco portion, and with those of methyl 2-acetamido-2-
deoxy-b-
-galactopyranoside20 (not shown). NMR analysis of the
a
- and b-lactose,19 for
D
acetylated disaccharide 9, obtained by treatment of 1a with Ac2O
in pyridine for 18 h, further confirmed the parent compound struc-
ture. It is worthy of note that the transformation of lactose into the
20-aminated analogue is obtained with a seven-step process involv-
ing common reagents and simple manipulations in a very good
overall yield (40%), certainly not easily achieved through chemical
means starting from the two deprotected monosaccharide compo-
nents. On the basis of this positive result, the same protocol of
C-2 amination with retention of configuration was applied (Scheme
2) to p-methoxyphenyl 3,4-O-isopropylidene-6-O-(1-methoxy-1-
methylethyl)-b-
commercial penta-O-acetyl-b-
sequence.21 Also in this case, the introduction of the azido group
D-galactopyranoside (10), easily obtainable from
D-galactopyranose through a simple
Table 1
13C NMR chemical shifts of - and b-1a and related compoundsa
a
Compound
-Lactose
b-Lactose
Me b- -GalNAcp
-1a
C-10
C-20
C-30
C-40
C-50
C-60
C-1
C-2
C-3
C-4
C-5
C-6
a
103.6
103.6
103.1
104.5
104.5
72.0
72.0
53.0
55.4
55.4
73.5
73.5
71.9
73.5
73.5
69.5
69.5
68.6
70.5
70.5
76.2
76.2
75.8
78.2
78.2
62.0
62.0
61.7
63.8
63.8
92.7
96.6
72.2
74.8
72.4
75.3
79.3
79.2
71.0
75.6
61.0
61.1
D
a
94.6
98.5
74.3
76.5
73.8
82.1
81.9
72.6
62.9b
63.0b
b-1a
77.4b
77.3b
a
Spectra taken in D2O. Internal reference: 1,4-dioxane for lactose (Ref. 19) and Me b-D-GalNAc (Ref. 20), TMSP for 1a.
Assignments may be reversed.
b

300
L. Guazzelli et al. / Carbohydrate Research 344 (2009) 298–303
OMIP
OSO2Im
OMIP
O
OMIP
O
O
O
OH
a
b
O
O
Me2C
Me2C
Me2C
OMP
OMP
OMP
O
O
O
OH
10
11
12
MP= p-methoxyphenyl
c
AcO
OAc
AcO
OMIP
O
OAc
O
O
O
e
d
Me2C
OMP
OR
OMP
AcO
AcO
O
N3
N3
N3
15: R = H
16: R=Ac
14
13
f
Scheme 2. Formal synthesis of D-GalNAc and of 2-deoxy-2-azido-D-galactopyranosyl glycosyl donors. Reagents and conditions: (a) (1) TPAP, NMO, CH2Cl2, rt, 2 h; (2) NaBH4,
MeOH, 0 °C, 2 h (81% overall); (b) Im2SO2, NaH, DMF, ꢀ30 °C, 20 min (92%); (c) NaN3, DMF, 100 °C, 2 h (96%); (d) (1) 80% aq AcOH, 80 °C, 2 h; (2) Ac2O, Py, rt, 2 h (97% overall);
(e) CAN, 3:1 Me2CO–H2O, 0 °C, rt, 30 min (81%); (f) Ac2O, Py, rt, 15 h (95%).
in position 2 was achieved by a high yielding double stereoselec-
tive inversion sequence, providing first the preparation of the talo
derivative 11 through an oxidation at C-2 (TPAP-NMO) followed
by reduction of the crude uloside with NaBH4 in MeOH. The stere-
oselectivity of the reduction was again complete leading to the
exclusive formation of 11 (81% isolated yield) due to the b face
shielding of the acetonide bridge, which completely inhibits the
hydride attack on the same face. The axial hydroxyl function was
then activated as sulfonyl imidazole (Im2SO2, and NaH in DMF at
ꢀ30 °C) and 12 was obtained in 92% yield after chromatographic
purification. The second inversion–amination was performed, as
described for the disaccharide analogue, by treatment with NaN3
in DMF at 100 °C, resulting in the desired azido derivative 13 in
96% yield. The two consecutive inversions of configuration were
easily checked by 1H NMR spectroscopy, on the basis of J1,2 and
J2,3 values (2.1 and 4.5 Hz, respectively, for the talo derivative 11,
and 8.6 and 7.5 for the galacto one 13).
tosylation followed by its C-2 amination with retention of
configuration.
3. Experimental
3.1. General methods
General methods are those reported in Ref. 1. 1H and 13C NMR
spectra were recorded with an Avance II 250 spectrometer operat-
ing at 250.13 MHz (1H) and 62.9 MHz (13C) in the reported solvent
(internal standard Me4Si) and the assignments were made, when
possible, with DEPT, HETCOR and COSY experiments. Compounds
517 and 1021 were prepared according to the reported procedures.
3.2. 4-O-[2-O-(1-Imidazolylsulfonyl)-3,4-O-isopropylidene-6-O-
(1-methoxy-1-methylethyl)-b-
D-talopyranosyl]-2,3:5,6-di-O-
isopropylidene-aldehydo- -glucose dimethyl acetal (6)
D
Although some reported methods22 allow the direct transfor-
mation of the anomeric p-methoxyphenyl into other more reactive
leaving groups, our next target was the known azido derivative
1523 and its peracetylated derivative 16.24
To a suspension of NaH in mineral oil (60%, 632 mg, 15.8 mmol)
pre-washed with hexane under argon atmosphere and cooled to
0 °C, a soln of 517 (1.84 g, 3.17 mmol) in dry DMF (55 mL) was
slowly added. The mixture was stirred at 0 °C for 30 min, cooled
to ꢀ30 °C, treated with Im2SO2 (940 mg, 4.74 mmol) and further
stirred until TLC analysis (EtOAc) revealed the complete disappear-
ance of the starting material (4 h). The reaction mixture was then
cooled to ꢀ40 °C, excess of NaH was destroyed by addition of
MeOH (0.5 mL) followed by 10 min stirring, and partitioned be-
tween Et2O (50 mL) and crushed iced-water. The organic phase
was separated, and the aq layer extracted with Et2O (4 ꢂ 50 mL).
The collected organic phases were dried (MgSO4), filtered and con-
centrated under diminished pressure. The flash chromatographic
purification over silica gel of the reaction product (1:3 hexane–
This goal was achieved by removing first the acetal functions
with 80% aq AcOH and acetylation of the crude residue
(Ac2O–Py), resulting in 14 in almost quantitative yield (97%) after
chromatographic purification. Removal of the anomeric p-methoxy-
phenyl group was performed with CAN, resulting in 15 (81% yield),
which was quantitatively transformed into the peracetate 16 by
routine acetylation.
Transformation of
described by Lemieux,9 while 15 constitutes the key precursor of
a series of 2-azido-2-deoxy-
-galactopyranosyl donors.25
In conclusion, we have performed an easy -galactose to
-galactosamine transformation with complete stereoselectivity
avoiding thus difficult diastereoisomeric separations. Using this
new methodology, the first chemical synthesis of the b- -Gal-
NAcp-(1?4)- -Glcp disaccharide has been achieved with excellent
yield starting from lactose, while in the monosaccharide series, a
new synthesis of -GalNAc and of some 2-azido-2-deoxy- -galac-
a-16 into D-GalNAc hydrochloride has been
D
D
D
EtOAc + 0.1% Et3N) gave pure 6 (1.93 g, 86%) as a syrup; ½a D
ꢃ
+2.7
(c, 1.06, CHCl3); Rf 0.33 (1:3 hexane–EtOAc); 1H NMR (CD3CN): d
7.98 (dd, 1H, J2,4 1.3 Hz, J2,5 0.9 Hz, Im-H-2), 7.44 (dd, 1H, J4,5
D
D
0
0
1.7 Hz, Im-H-4), 7.05 (dd, 1H, Im-H-5), 4.92 (dd, 1H, J1 ,2 1.0 Hz,
J2 ,3 5.7 Hz, H-20), 4.82 (d, 1H, H-10), 4.40 (dd, 1H, J3 ,4 5.8 Hz, H-
0
0
0
0
30), 4.36 (d, 1H, J1,2 6.0 Hz, H-1), 4.27 (dd, 1H, J2,3 7.7 Hz, H-2),
D
D
topyranosyl donors has been accomplished, complementing thus
the existing approaches. This strategy of amination with overall
retention of configuration (double inversion) gave good results in
both the mono- and disaccharide series and seems to have general
applicability and good potentiality in the construction of complex
0
0
4.15 (dt, 1H, J4,5 5.9 Hz, J5,6a = J5,6b 6.1 Hz, H-5), 4.12 (dd, 1H, J4 ,5
2.7 Hz, H-40), 4.04 (dd, 1H, J3,4 1.9 Hz, H-3), 3.94 (dd, 1H, J6a,6b
8.6 Hz, H-6b), 3.85 (dd, 1H, H-6a), 3.84 (ddd, 1H, J5 ,6 a 6.5 Hz,
0
0
J5 ,6 b 6.3 Hz, H-50), 3.83 (dd, 1H, H-4), 3.63 (dd, 1H, J6 a,6 b 9.6 Hz,
H-60b), 3.55 (dd, 1H, H-60a), 3.41, 3.40 (2s, each 3H, 2 ꢂ OMe-1),
3.14 [s, 3H, C(OMe)Me2], 1.37, 1.36, 1.32, 1.30, 1.29, 1.28 (6s, each
3H, 3 ꢂ CMe2), 1.22, 1.20 [2s, each 3H, C(OMe)Me2]; 13C NMR
0
0
0
0
b-D-GalNAc containing oligosaccharides through a first b-galac-

L. Guazzelli et al. / Carbohydrate Research 344 (2009) 298–303
301
(CD3CN): d 138.1 (Im-C-2), 130.9 (Im-C-5), 120.1 (Im-C-4), 110.7,
110.3, 109.2 (3 ꢂ CMe2), 106.5 (C-1), 100.9 [C(OMe)Me2], 99.1 (C-
10), 79.9 (C-20), 78.5 (C-4), 77.9 (C-3), 77.1 (C-5), 76.3 (C-2), 73.5
(C-50), 71.9 (C-30), 71.1 (C-40), 66.5 (C-6), 60.3 (C-60), 56.6, 54.7
(2 ꢂ OMe-1), 48.9 [C(OMe)Me2], 27.3, 27.1, 27.0, 25.8, 25.4, 25.3
(3 ꢂ CMe2), 24.7, 24.6 [C(OMe)Me2]. Anal. Calcd for C30H50N2O15S:
C, 50.69; H, 7.09; N, 3.94. Found: C, 50.89; H, 7.43; N, 5.29.
4, C-2), 74.6 (C-40), 73.5 (C-50), 65.6 (C-6), 62.5 (C-60), 57.5, 54.6
(2 ꢂ OMe), 55.2 (C-20), 28.2, 27.4, 26.8, 26.4, 26.3, 24.8 (3 ꢂ CMe2),
23.3 (MeCON). Anal. Calcd for C25H43NO12: C, 54.63; H, 7.89; N,
2.55. Found: C, 54.72; H, 7.91; N, 2.58.
3.5. 4-O-(2-Acetamido-2-deoxy-b-D-galactopyranosyl]-a,b-D-
glucopyranose (1a)
3.3. 4-O-[2-Azido-2-deoxy-3,4-O-isopropylidene-6-O -(1-meth-
A soln of 8 (450 mg, 0.82 mmol) in 80% aq AcOH (15 mL) was
stirred at 80 °C for 4 h and then concentrated under diminished
pressure by co-evaporation with toluene (4 ꢂ 35 mL). The residue
was triturated with EtOAc to give an amorphous white solid
oxy-1-methylethyl)-b-
D-galactopyranosyl]-2,3:5,6-di-O-iso-
propylidene-aldehydo- -glucose dimethyl acetal (7)
D
A soln of 6 (3.85 g, 5.41 mmol) and NaN3 (707 mg, 10.9 mmol)
in dry DMF (100 mL) was stirred under argon atmosphere at
100 °C. After 1 h and 20 min, TLC analysis (EtOAc) revealed the
complete disappearance of the starting material, the mixture was
cooled to rt and partitioned between satd aq NaHCO3 (50 mL)
and Et2O (50 mL). The organic phase was separated and the aq
layer extracted with Et2O (3 ꢂ 50 mL). The organic extracts were
dried (MgSO4), filtered and concentrated under diminished pres-
sure. Purification of the residue by flash chromatography over sil-
ica gel (7:3 hexane–EtOAc + 0.1% of Et3N) gave pure 7 (3.08 g, 94%)
(283 mg, 90%) composed (13C NMR, D2O) by a 2:3
a
/b anomeric
mixture of 1a, as established on the basis of the integration of
the H-1 signals; ½a D1
+55.8 (c, 0.92, water); selected 1H NMR
(D2O) data of -1a: d 5.21 (d, 1H, J1,2 3.8 Hz, H-1), 4.52 (d, 1H,
J1 ,2 8.4 Hz, H-10); b-1a: d 4.65 (d, 1H, J1,2 8.4 Hz, H-1), 4.51 (d,
ꢃ
a
0
0
1H, J1 ,2 8.3 Hz, H-10), 3.27 (dd, 1H, J2,3 8.8 Hz, H-2); 13C NMR
(D2O) data of -1a and b-1a see Table 1 and d: 177.6 (MeCO),
0
0
a
25.0 (MeCO). Anal. Calcd for C14H25NO11: C, 43.86; H, 6.57; N,
3.65. Found: C, 43.95; H, 6.59; N, 3.66.
as a clear syrup; ½a D
ꢃ
ꢀ30.0 (c, 1.0, CHCl3); Rf 0.64 (EtOAc); 1H NMR
3.6. 4-O-(2-Acetamido-2-deoxy–3,4,6-tri-O -acetyl-b-
D-galacto-
(CD3CN): d 4.63 (d, 1H, J1 ,2 8.5 Hz, H-10), 4.34 (d, 1H, J1,2 6.0 Hz, H-
1), 4.32 (t, 1H, J2,3 6.0 Hz, H-2), 4.25 (dt, 1H, J4,5 4.7 Hz, J5,6a = J5,6b
pyranosyl]- ,b-1,2,3,6-tetra-O -acetyl- -glucopyranose (9)
a
D
0
0
6.4 Hz, H-5), 4.15 (dd, 1H, J3 ,4 5.4 Hz, J4 ,5 2.1 Hz, H-40), 4.09 (dd,
1H, J6a,6b 8.5 Hz, H-6b), 4.06 (dd, 1H, J3,4 1.3 Hz, H-3), 4.01 (dd,
Compound 1a (50 mg, 0.13 mmol) was dissolved in 2:1 pyri-
dine–Ac2O (3 mL) and the resulting soln was stirred at rt for 18 h
and then co-evaporated with toluene (3 ꢂ 5 mL) under diminished
pressure. Flash chromatographic purification, eluting with EtOAc,
0
0
0
0
1H, H-6a), 3.94 (dd, 1H, H-4), 3.90 (dd, 1H, J2 ,3 8.3 Hz, H-30), 3.84
0
0
(ddd, 1H, J5 ,6 a 6.2 Hz, J5 ,6 b 6.7 Hz, H-50), 3.61 (dd, 1H, J6 a,6 b
9.4 Hz, H-60b), 3.53 (dd, 1H, H-60a), 3.39, 3.38 (2s, each 3H,
2 ꢂ OMe), 3.30 (dd, 1H, H-20), 3.15 [s, 3H, C(OMe)Me2], 1.49, 1.40,
1.33, 1.32, 1.30, 1.29 (6s, each 3H, 3 ꢂ CMe2), 1.29, 1.30 [2s, each
0
0
0
0
0
0
afforded pure 9 (84 mg, 95%) as an 1:1
a/b anomeric mixture, as
established on the basis of the integration of the H-1 signals; syrup,
½
a D
ꢃ
+16.0 (c, 1.04, CHCl3); Rf 0.23 (EtOAc); 1H NMR (CD3CN) of
a
-9:
3H, C(OMe)Me2]; 13C NMR (CD3CN):
d
110.9, 110.7, 108.9
d 6.38 (d, 1H, J2 ,NH 9.3 Hz, NH), 6.12 (d, 1H, J1,2 3.8 Hz, H-1), 5.32
0
(3 ꢂ CMe2), 106.4 (C-1), 102.2 (C-10), 100.9 [C(OMe)Me2], 78.5 (C-
3), 77.9 (C-5), 77.8 (C-30), 76.7 (C-2), 76.2 (C-4), 73.8 (C-40), 73.0
(C-50), 67.3 (C-20), 66.0 (C-6), 60.4 (C-60), 56.3, 54.4 (2 ꢂ OMe),
48.9 [C(OMe)Me2]; 28.4, 27.6, 27.1, 26.7, 26.3, 25.2 (3 ꢂ CMe2),
24.7, 24.5 C(OMe)Me2]. Anal. Calcd for C27H47N3O12: C, 53.54; H,
7.82; N, 6.94. Found: C, 53.47; H, 7.62; N, 7.12.
(dd, 1H, J2,3 10.4 Hz, J3,4 8.7 Hz, H-3), 5.02 (dd, 1H, J2 ,3 11.3 Hz,
0
0
J3 ,4 3.5 Hz, H-30), 4.90 (dd, 1H, H-2), 4.58 (d, 1H, J1 ,2 8.4 Hz, H-
0
0
0
0
10), 1.82 (s, 3H, MeCON); b-9: d 6.36 (d, 1H, J2 ,NH 9.3 Hz, NH),
0
0
0
5.74 (d, 1H, J1,2 8.3 Hz, H-1), 5.24 (m, 1H, H-3), 5.03 (dd, 1H, J2 ,3
11.2 Hz, J3 ,4 3.5 Hz, H-30), 4.92 (dd, 1H, J2,3 9.7 Hz, H-2), 4.59 (d,
0
0
1H, J1 ,2 8.4 Hz, H-10), 1.83 (s, 3H, MeCON); cluster of signals for
both anomers: d 4.40–3.95 (m, 14H, H-4, H-5, H-6a, H-6b, H-50,
H-60a, H-60b), 3.86 (m 2H, H-20) 2.13, 2.08, 2.07, 2.06, 2.05, 2.04,
2.03, 2.02, 2.01, 2.00, 1.98, 1.97, 1.96, 1.90 (14s, each 3H,
0
0
3.4. 4-O-(2-Acetamido-2-deoxy-3,4-O-isopropylidene-b-
D-galac-
topyranosyl)-2,3:5,6-di-O-isopropylidene-aldehydo-
D-glucose
dimethylacetal (8)
14 ꢂ MeCOO); 13C NMR (CD3CN)
a
-9: d 102.1 (C-10), 89.6 (C-1),
76.1 (C-4), 71.3 (C-5, C-50), 71.2 (C-30), 70.6 (C-3), 70.2 (C-2), 67.5
(C-40), 62.4 (C-6), 62.1 (C-60), 51.4 (C-20); b-9: d 102.1 (C-10), 92.2
(C-1), 75.8, 74.3, 73.3 (C-3, C-4, C-5), 71.3 (C-50), 71.2 (C-30), 70.3
(C-2), 68.5 (C-40), 62.8 (C-6), 62.1 (C-60), 51.4 (C-20); cluster of sig-
nals for both anomers: d 171.4–169.9 (MeCO), 23.2 (MeCON), 21.2–
20.8 (MeCOO). Anal. Calcd for C28H39NO18: C, 49.63; H, 5.80; N,
2.07. Found: C, 49.65; H, 5.83; N, 2.08.
To a soln of 7 (1.40 g, 2.31 mmol) in MeOH (24 mL) cooled to
0 °C, NiCl2ꢁ6H2O (2.75 g, 11.5 mmol) and NaBH4 (699 mg,
18.4 mmol) were added. The soln was warmed to rt and stirred
for 2 h. To the mixture were then added brine (50 mL) and, after
10 min, water (50 mL) and CHCl3 (50 mL). The organic phase was
separated and the aq layer extracted with CHCl3 (4 ꢂ 50 mL). The
collected organic extracts were dried (MgSO4), filtered and concen-
trated at diminished pressure. The residue was dissolved in MeOH
(30 mL), Ac2O (7.5 mL) was added and the mixture was stirred at rt
for 2 h when TLC analysis (EtOAc) showed the formation of a new
product. The reaction mixture was repeatedly co-evaporated with
toluene (4 ꢂ 30 mL) under diminished pressure and purified by
flash chromatography over silica gel (49:1 CHCl3–MeOH) affording
3.7. 4-Methoxyphenyl 3,4-O-isopropylidene-6-O-(1-methoxy-1-
methylethyl)-b-D-talopyranoside (11)
A mixture of 1021 (320 mg, 0.803 mmol), pre-dried 4-methyl-
morpholine N-oxide (NMO, 165 mg, 1.41 mmol) and 4 Å powdered
molecular sieves (500 mg) in anhyd CH2Cl2 (15 mL) was stirred for
30 min at rt under argon atmosphere. Tetrapropylammonium per-
ruthenate (TPAP, 14.1 mg, 0.04 mmol) was then added and the
resulting mixture was stirred for 2 h at rt until TLC (9:1 CH2Cl2–
Me2CO) revealed complete oxidation of 10. The mixture was
filtered through a Celite-silica gel-Celite triple alternate pad, the
filter was washed with CH2Cl2 and then with EtOAc, and the organ-
ic phase was concentrated under diminished pressure. The residue
was dissolved in MeOH (15 mL), NaBH4 (121.4 mg, 3.21 mmol) was
added and the mixture was stirred at 0 °C. After 2 h, TLC analysis
pure 8 (1.09 g, 86%) as a clear syrup; ½a D
ꢃ
+8.15 (c, 1.46, MeOH); Rf
0.10 (EtOAc); 1H NMR (CD3CN): d 6.47 (d, 1H, J2 ,NH 8.9 Hz, NH),
0
4.58 (d, 1H, J1 ,2 8.6 Hz, H-10), 4.50 (dd, 1H, J1,2 6.9 Hz, J2,3 7.0 Hz,
H-2), 4.34 (d, 1H, H-1), 4.36–4.05 (m, 4H, H-5, H-30, H-60a, H-60b),
3.97–3.70 (m, 4H, H-50, H-3, H-6a, H-6b), 3.51 (m, 2H, H-2, H-4),
3.43, 3.42 (2s, each 3H, 2 ꢂ OMe), 1.90 (s, 3H, MeCON), 1.45,
1.40, 1.32, 1.31, 1.28, 1.26 (6s, each 3H, 3 ꢂ CMe2); 13C NMR
(CD3CN): d 170.6 (MeCO), 110.2, 110.0, 108.5 (3 ꢂ CMe2), 107.6
(C-1), 101.6 (C-10), 78.6 (C-3), 77.4, 77.3 (C-30, C-5), 75.7, 75.6 (C-
0
0

302
L. Guazzelli et al. / Carbohydrate Research 344 (2009) 298–303
(9:1 CH2Cl2–Me2CO) showed the complete disappearance of the 2-
uloside. Water (8 mL) was added and the resulting soln was stirred
for additional 30 min and then extracted with CH2Cl2 (3 ꢂ 30 mL).
The organic extracts were collected, dried (MgSO4), filtered and
concentrated under diminished pressure. Purification of the resi-
due by flash chromatography over silica gel (9:1 CH2Cl2–
Me2CO + 0.1% Et3N) afforded pure 11 (259.2 mg, 81%) as a clear
Rf 0.32 (7:3 hexane–EtOAc); 1H NMR (CD3CN): d 7.03, 6.92 (AA’XX’
system, 4H, Ar–H), 4.80 (d, 1H, J1,2 8.6 Hz, H-1), 4.19 (dd, 1H, J3,4
5.3 Hz, J4,5 2.0 Hz, H-4), 4.02 (ddd, 1H, J5,6a 7.0 Hz, J5,6b 5.2 Hz, H-5),
3.98 (dd, 1H, J2,3 7.5 Hz, H-3), 3.75 (s, 3H, OMe), 3.64 (dd, 1H, J6a,6b
10.0 Hz, H-6a), 3.63 (dd, 1H, H-2), 3.59 (dd, 1H, H-6b), 3.12 [s, 3H,
C(OMe)Me2], 1.52, 1.32 (2s, each 3H, CMe2), 1.31, 1.30 [2s, each 3H,
C(OMe)Me2]; 13C NMR (CD3CN): d 156.5, 151.8 (Ar–C), 119.1, 115.5
(Ar–CH), 111.1 (CMe2), 101.4 (C-1), 100.8 [C(OMe)Me2], 77.9 (C-3),
73.9 (C-4), 73.3 (C-5), 66.0 (C-2), 60.9 (C-6), 56.1 (OMe), 48.8
[C(OMe)Me2], 28.4, 26.4 (CMe2), 24.7, 24.6 [C(OMe)Me2]. Anal. Calcd
for C20H31N3O7: C, 56.46; H, 7.34; N, 9.88. Found: C, 56.48; H, 7.38; N,
9.91.
syrup; ½a D ꢀ49.5 (c, 0.99, CHCl3); Rf 0.43 (9:1 CH2Cl2–Me2CO);
ꢃ
1H NMR (CD3CN): d 7.02, 6.95 (AA’XX’ system, 4H, Ar–H), 5.08 (d,
1H, J1,2 2.1 Hz, H-1), 4.37 (dd, 1H, J3,4 7.0 Hz, J2,3 4.5 Hz, H-3),
4.30 (dd, 1H, J4,5 2.1 Hz, H-4), 3.84 (ddd, 1H, J5,6a 6.9 Hz, J5,6b
5.2 Hz, H-5), 3.82 (dd, 1H, H-2), 3.73 (s, 3H, OMe), 3.59 (dd, 1H,
J6a,6b 10.0 Hz, H-6a), 3.55 (dd, 1H, H-6b), 3.12 [s, 3H, C(OMe)Me2],
1.52, 1.32 (2s, each 3H, CMe2), 1.28 (s, 6H, C(OMe)Me2); 13C NMR
(CD3CN): d 155.9, 152.4 (Ar–C), 118.9, 115.3 (Ar–CH), 110.5
(CMe2), 100.8 [C(OMe)Me2], 99.5 (C-1), 73.9 (C-3), 72.8 (C-4),
72.1 (C-5), 67.0 (C-2), 61.4 (C-6), 56.1 (OMe), 48.8 [C(OMe)Me2],
25.8, 25.4 (CMe2), 24.7, 24.6 [C(OMe)Me2]. Anal. Calcd for
C20H30O8: C, 60.29; H, 7.59. Found: C, 60.47; H, 7.61.
3.10. 4-Methoxyphenyl 2-azido-2-deoxy-3,4,6-tri-O-acetyl-b-D-
galactopyranoside (14)
A soln of 13 (68 mg, 0.16 mmol) in 80% aq AcOH (3 mL) was stir-
red at 80 °C for 2 h, then concentrated under diminished pressure
and co-evaporated with toluene (3 ꢂ 8 mL). The residue was dis-
solved in 2:1 pyridine–Ac2O (3 mL) and the resulting soln was stir-
red at rt for 2 h and then co-evaporated with toluene (3 ꢂ 8 mL)
under diminished pressure. Flash chromatographic purification
over silica gel (7:3 hexane–EtOAc) afforded pure 14 (67.8 mg,
3.8. 4-Methoxyphenyl 2-O-(1-imidazolylsulfonyl)-3,4-O-isopro-
pylidene-6-O-(1-methoxy-1-methylethyl)-b-D-talopyranoside (12)
To a suspension of NaH in mineral oil (60%, 94 mg, 2.34 mmol)
pre-washed with hexane under argon atmosphere and cooled to
0 °C, a soln of 11 (186.8 mg, 0.469 mmol) in dry DMF (8 mL) was
added. The mixture was stirred at 0 °C for 30 min, cooled to
ꢀ30 °C, treated with Im2SO2 (139 mg, 0.703 mmol) and further stir-
red at ꢀ30 °C. After 20 min, TLC analysis (3:7 hexane–EtOAc) re-
vealed the complete disappearance of the starting material. The
reaction mixture was then cooled to ꢀ40 °C, excess of NaH was de-
stroyed by addition of MeOH (0.5 mL) followed by 10 min stirring,
then partitioned between Et2O (16 mL) and crushed iced-water.
The organic phase was separated, and the aq layer extracted with
Et2O (2 ꢂ 16 mL). The collected organic phases were dried (MgSO4),
filtered and concentrated under diminished pressure. Flash chro-
matographic purification over silica gel of the reaction product
(2:3 hexane–EtOAc + 0,1% of Et3N) gave pure 12 (226.6 mg, 92%)
97%) as a clear syrup; ½a D
ꢃ
+6.02 (c, 0.83, CHCl3); Rf 0.56 (2:3 hex-
ane–EtOAc); 1H NMR (CD3CN): d 7.03, 6.90 (AA’XX’ system, 4H,
Ar–H), 5.33 (dd, 1H, J3,4 3.4 Hz, J4,5 1.0 Hz, H-4), 5.00 (d, 1H, J1,2
8.1 Hz, H-1), 4.92 (dd, 1H, J2,3 10.8 Hz, H-3), 4.24–4.04 (m, 3H, H-
6a, H-6b, H-5), 3.98 (dd, 1H, H-2), 3.75 (s, 3H, OMe), 2.21, 2.00,
1.99 (3s, each 3H, 3 ꢂ MeCO); 13C NMR (CD3CN): d 171.2, 171.1,
170.7 (3 ꢂ MeCO), 156.6, 151.6 (Ar–C), 119.0, 115.6 (Ar–CH),
101.6 (C-1), 71.9 (C-5), 71.8 (C-3), 67.5 (C-4), 62.4 (C-6), 61.6 (C-
2), 56.1 (OMe), 20.8 (MeCO). Anal. Calcd for C19H23N3O9: C,
52.17; H, 5.30; N, 9.61. Found: C, 52.20; H, 5.33; N, 9.63.
3.11. 2-Azido-2-deoxy-3,4,6-tri-O-acetyl-a,b-D-galactopyranose
(15)
To a soln of 14 (67 mg, 0.153 mmol) in 3:1 Me2CO–water
(6 mL), CAN (587 mg, 1.07 mmol) was added at 0 °C, the soln was
warmed to rt and stirred for 30 min. It was then concentrated to
3 mL, diluted with CH2Cl2 (25 mL), washed with sat aq NaHCO3
(2 ꢂ 15 mL), dried (MgSO4), filtered and concentrated under
diminished pressure. Purification of the residue by flash chroma-
tography over silica gel (7:3 hexane–EtOAc) afforded known 1523
(41 mg, 81%) as a clear syrup composed (NMR, CDCl3) by a mixture
as a clear syrup; ½a D
ꢃ
+4.2 (c, 1.18, CHCl3); Rf 0.22 (2:3 hexane–
EtOAc); 1H NMR (CD3CN): d 8.07 (dd, 1H, J2,4 1.3 Hz, J2,5 0.8 Hz,
Im-H-2), 7.50 (dd, 1H, J4,5 1.7 Hz, Im-H-4), 7.10 (dd, 1H, Im-H-5),
6.83, 6.72 (AA’XX’ system, 4H, Ar–H), 5.03 (dd, 1H, J1,2 1.0 Hz, J2,3
5.5 Hz, H-2), 4.93 (d, 1H, H-1), 4.51 (dd, 1H, J3,4 5.8 Hz, H-3), 4.23
(dd, 1H, J4,5 2.7 Hz, H-4), 4.01 (ddd, 1H, J5,6a 7.4 Hz, J5,6b 4.7 Hz, H-
5), 3.71 (s, 3H, OMe), 3.65 (dd, 1H, J6a,6b 10.3 Hz, H-6a), 3.57 (dd,
1H, H-6b), 3.09 [s, 3H, C(OMe)Me2], 1.49, 1.33 (2s, each 3H, CMe2),
1.29, 1.28 [2s, each 3H, C(OMe)Me2]; 13C NMR (CD3CN): d 156.3,
151.3 (Ar–C), 138.3 (Im-C-2), 131.1 (Im-C-5), 120.0 (Im-C-4),
118.6, 115.2 (Ar–CH), 111.4 (CMe2), 100.8 [C(OMe)Me2], 97.3 (C-
1), 79.3 (C-2), 73.8 (C-5), 71.9 (C-3), 71.4 (C-4), 60.7 (C-6), 56.1
(OMe), 48.8 [C(OMe)Me2], 25.9, 25.4 (CMe2), 24.7, 24.6
[C(OMe)Me2]. Anal. Calcd for C23H32N2O10S: C, 52.26; H, 6.10; N,
5.30; S, 6.07. Found: C, 52.46; H, 6.18; N, 5.33; S, 6.11.
of
ative intensities of C-1 signals (d 92.3 and 96.3, respectively);
+61.7, ½a D1 +55.5 (c, 0.91, MeOH); Rf 0.20 (7:3 hexane–
EtOAc); 1H NMR (CDCl3) of
-15: d 5.43 (d, 1H, J1,2 3.3 Hz, H-1),
a- and b-anomers in a 3:2 ratio calculated on the basis of the rel-
½
a Dinitial
ꢃ
ꢃ
a
5.37 (dd, 1H, J2,3 10.0 Hz, J3,4 3.2 Hz, H-3), 4.47 (m, 1H, H-5), 3.74
(dd, 1H, H-2), 3.91 (bs, 1H, OH-1); b-15: d 4.83 (dd, 1H, J2,3
10.9 Hz, J3,4 3.3 Hz, H-3), 4.72 (dd, 1H, J1,2 7.8 Hz, J1,OH 5.3 Hz, H-
1), 3.91 (m, 1H, H-5), 3.67 (dd, 1H, H-2), 4.58 (d, 1H, OH-1); cluster
of signals for both anomers: d 5.45 (m, 1H, H-4), 4.08–4.22 (m, 2H,
3.9. 4-Methoxyphenyl 2-azido-2-deoxy-3,4-O-isopropylidene-
H-6a, H-6b); 2.20–1.97 (m, 9H, 3 ꢂ MeCO); 13C NMR (CDCl3)
a-15:
6-O-(1-methoxy-1-methylethyl)-b-
D
-galactopyranoside (13)
d 92.3 (C-1), 67.6 (C-4), 66.4, 66.3 (C-3, C-5), 57.9 (C-2); b-15: d
96.3 (C-1), 71.1 (C-3), 70.8 (C-5), 68.3 (C-4), 61.9 (C-2); cluster of
signals for both anomers: d 170.7–170.0 (MeCO), 61.7, 61.3 (C-6),
20.7–20.5 (MeCO). Anal. Calcd for C12H19N3O8: C, 43.24; H, 5.75;
N, 12.61. Found: C, 43.26; H, 5.76; N, 12.62.
A
soln of 12 (91.2 mg, 0.173 mmol) and NaN3 (22.5 mg,
0.345 mmol) in dry DMF (4 mL) was stirred at 100 °C under argon
atmosphere. After 2 h, the mixture was cooled to rt and partitioned
between satd aq NaHCO3 (8 mL)and Et2O (15 mL). The organicphase
was separated and the aq layer extracted with Et2O (3 ꢂ 15 mL). The
organic extracts were collected, dried (MgSO4), filtered and concen-
tratedunderdiminishedpressure. Purificationof theresidue byflash
chromatography over silica gel (7:3 hexane–EtOAc + 0.1% of Et3N)
gave pure 13 (71 mg, 96%) as a clear syrup; ½aꢃD +35.5 (c, 0.67, CHCl3);
3.12. 2-Azido-2-deoxy-1,3,4,6-tetra-O-acetyl-a,b-D-galactopyra-
nose (16)
A soln of 15 (32 mg, 0.10 mmol) in 2:1 pyridine-Ac2O (2 mL)
was stirred at rt for 15 h and then co-evaporated with toluene

L. Guazzelli et al. / Carbohydrate Research 344 (2009) 298–303
303
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purification over silica gel (1:1 hexane–EtOAc) afforded pure 16
(34 mg, 95%) as a clear syrup, composed (NMR, CDCl3) by a mixture
ˇ
ˇ
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+49.7 (c, 0.92, CHCl3); lit.24
- and b-anomers; NMR data were
a- and b-anomers in 1:1 ratio calculated on the basis of the rel-
ꢃ
½aꢃD
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a
in full accordance with those reported.24
ˇ
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Acknowledgement
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This research was supported by the Ministero dell’Università e
della Ricerca (MIUR, Rome, Italy) in the frame of the national pro-
ject COFIN 2006.
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