One-step synthesis of β-C-glycosidic ketones in aqueous media: The case of 2-acetamido sugars

Article abstract of DOI:10.1055/s-2005-861816

The one step synthesis of β-D-C-glycosidic ketones by condensation of pentane-2,4-dione with unprotected N-acetyl-D-gluco-, manno-, and galactosamine in alkaline aqueous media has been explored. N-Acetyl-D-gluco- and mannosamine gave, in good yield, a mixture of the two gluco and manno C-glycosidic ketones, which were separated by crystallization after acetylation, whereas N-acetyl-D-galactosamine afforded the galacto C-glycosidic ketone which was isolated as its acetylated derivative in 50% yield.

Full text of DOI:10.1055/s-2005-861816

8
14
PAPER
One-Step Synthesis of b-C-Glycosidic Ketones in Aqueous Media: The Case of
-Acetamido Sugars
2
S
N
ynthesis of
C
-
Gly
i
cosidic
c
K
etones olas Bragnier, Marie-Christine Scherrmann*
Laboratoire de Chimie Organique Multifonctionnelle, Bat. 420, Université de Paris XI, 91405 Orsay, France
Fax +33(1)69154715; E-mail: mcscherr@icmo.u-psud.fr
Received 18 October 2004; revised 24 November 2004
Dedicated to Prof. Alessandro Dondoni (University of Ferrara, Italy) for his 70th birthday
OH
(CH2)nCH3
O
Abstract: The one step synthesis of b-D-C-glycosidic ketones by
condensation of pentane-2,4-dione with unprotected N-acetyl-D-
gluco-, manno-, and galactosamine in alkaline aqueous media has
been explored. N-Acetyl-D-gluco- and mannosamine gave, in good
yield, a mixture of the two gluco and manno C-glycosidic ketones,
which were separated by crystallization after acetylation, whereas
N-acetyl-D-galactosamine afforded the galacto C-glycosidic ketone
which was isolated as its acetylated derivative in 50% yield.
RO
HO
O
NaHCO3
+
O
OH
OH
(CH2)nCH3
R = H
R = α-D-Glc
n = 0, 5, 8
OH
RO
HO
O
Key words: asymmetric synthesis, carbohydrates, condensation,
C-glycosides, ketones
(CH2)nCH3
OH
O
Scheme 1
C-Glycosides, the carbon-linked analogues of naturally
The case of 2-acetamido sugars as substrates of this reac-
tion was challenging since the Fessner group reported that
the condensation of pentane-2,4-dione with N-acetyl-D-
glucosamine (GlcNAc) gave a 1:1 mixture of a- and b-C-
glycosidic ketones in poor yield (36%). We report herein
our results on the reaction involving unprotected N-
acetyl-D-gluco-, manno- and galactosamine as substrates.
occurring sugars, are the subject of great interest in carbo-
1
hydrate chemistry and biochemistry since they are stable
toward both enzymatic and chemical hydrolysis, and since
2
3
their biological properties are similar and even better
5
c
than those of the parent O-glycosides. Many efforts have
4
been made to achieve their synthesis, and particularly the
5
use of water as solvent has stimulated recent work in this
field. In fact, in this medium, known to promote many or- We first carried out the condensation of pentane-2,4-dione
6
ganic reactions, carbohydrates can be used directly with- (2 equiv) with N-acetyl-D-glucosamine in water in the
out the need for tedious protection-deprotection presence of NaHCO (4 equiv) and we obtained, after 24
3
9
sequences. The stereocontrolled creation of a carbon-car- h, in 41% yield, an inseparable mixture of the known C-
bon bond at the anomeric position of carbohydrates is a glycosidic ketone 1 and its epimer at C-2 2 in a 1:1 ratio
key step in the synthesis of complex C-glycosides. The as judged by 13C NMR analysis (Scheme 2). The two
group of Nicotra has recently developed a method to pre- products were separated by crystallization after acetyla-
7
8
pare C-glycopeptides from C-glycosidic ketones in turn tion to give 3 and 4, respectively, and fully characterized.
obtained from commercially available tetrabenzyl-glu- The latter compounds were then individually deacetylated
cose.
to afford pure samples of triols 1 and 2.
1
The quantitative one-step synthesis of b-D-C-glycosidic The H NMR spectrum of 3 notably exhibited a large cou-
ketones by condensation of pentane-2,4-dione with un- pling constant for the H-1¢ signal (J1¢,2¢ = 11.5 Hz), indicat-
protected sugars in alkaline aqueous media has been ex-
5
a
plored in our laboratory. Further studies on the use of
other 1,3-dicarbonyl compounds as nucleophiles have
OH
HO
HO
O
O
O
NaHCO3, H O
5
c
2
been reported by Riemann et al. The synthesis is based
on a Knoevenagel condensation between the carbanion of
a b-diketone and the formyl group of an unprotected sug-
ar. We have also described an extension of this work for
the preparation of glucose and maltose derivatives bearing
a C-linked hydrophobic residue of 8 or 11 carbon atoms5f
+
AcHN
41%
OH
OR
NHAc
O
OR
O
RO
RO
RO
RO
+
AcHN
(
Scheme 1).
O
O
1
: 1
1
R = H
2
4
R = H
Ac2O
Pyridine
Ac2O
Pyridine
3
R = Ac
R = Ac
SYNTHESIS 2005, No. 5, pp 0814–0818
x
x
.
x
x
.2
0
0
5
100%
100%
Advanced online publication: 14.02.2005
DOI: 10.1055/s-2005-861816; Art ID: T12004SS
Georg Thieme Verlag Stuttgart · New York
Scheme 2 For optimized conditions, see Table 1.
©

PAPER
Synthesis of C-Glycosidic Ketones
815
ing a trans-diaxial orientation of H-1¢ and H-2¢ as
1
expected for a b-D-configured glucopyranose moiety
4
–CH COONa
3
adopting a C conformation. The synthesis of 1 was also
1
5
c
1
claimed by Fessner and coworkers, however the H
NMR data reported were not compatible with the assigned
structure. In particular, the vicinal coupling constant
J2¢,3¢ = 2.3 Hz and J3¢,4¢ = 4.0 Hz suggested a glucofurano
rather than a glucopyrano configuration. Moreover, also
the other product isolated by these authors,5c i.e. the a-
anomer of 1 appeared to be a glucofurano derivative since
the above mentioned coupling constant values were 1.2
Hz and 3.9 Hz, respectively. Unfortunately, the physical
data of both anomers were missing, preventing further
comparison.
OH
OH
_
O
+
O
O
NaHCO3
H2O
O Na
HO
HO
O
HO
HO
CH3
CH3
+
–
AcHN
AcHN
OH
O
5
OH
NHAc
OH
NHAc
_
+ O
O Na
_
O
O
+
HO
HO
HO
HO
O Na
CH3
CH3
CH3
CH3
1
The H NMR analysis of 2 indicated a mannopyrano con-
O
7
2
6
figuration. In fact, the signal of axial H-3¢ (d = 3.69 ppm)
showed a large coupling constant (10.0 Hz) with H-4¢ and
a small one (4.5 Hz) with H-2¢, consistent with an axial
orientation of the 2-acetamido group. Unfortunately, the
very small coupling constant (1.5 Hz) observed between
H-1¢ and H-2¢, did not allow establishing the anomeric
configuration of 2. However, the b-D-manno configura-
–CH COONa
3
Scheme 3
tion of 2 was assigned by the significant NOEs (C D ) be-
6
6
Table 1 Conditions and Results for the Condensation of GlcNAc
tween H-1¢, H-3¢, and H-5¢ on one side and between H-4¢ with Pentanedione (2 equiv) in the Presence of NaHCO (4 equiv) at
3
and NH on the other side, showed by the triacetate deriv- 90 °C
ative 4 (Figure 1). It is worth noting that the manno-con-
figured ketone 2 was described several years ago10 as a
Entry
Solvent
Time
24 h
Yield (%) 1:2 Ratio
side product of the decarboxylation of a 6-acetamido-de-
culopyranosic acid derivative. However, its configuration
could not be firmly established by those authors.
1
2
3
4
5
H O–EtOH (2:1)
60
50
43
83
36
1:1
4:6
3:7
4:6
7:3
2
H O–pentanedione (2:1) 24 h
2
H O–CH CN (2:1)
24 h
24 h
3 d
2
3
H O–THF (2:1)
H4' OAc
NHAc
2
H O–THF (2:1)
AcO
AcO
O
2
H5'
H3'
O
H1'
All the co-solvents we tested increased the yield of the re-
action with the exception of CH CN, which gave a yield
3
4
comparable to that obtained in pure water, but a better se-
lectivity for the manno ketone. The best yield (83%) was
obtained when THF was used as the co-solvent, where, af-
ter 24 hours we isolated by flash chromatography 1 and 2
as a 4:6 mixture, whereas a longer reaction time (3 d) gave
rise to a 7:3 mixture in only 36% yield. In this case we ob-
served (TLC analysis) the formation of some unidentified
products. Considering these results, we postulated that 1
and 2 were not stable in the reacting mixture and in fact,
when a 1:1 mixture of 1 and 2 was heated for 15 hours at
Figure 1 Nuclear Overhauser effects observed in peracetate 4.
The formation of the N-acetyl-D-mannosamine ketone 2
could be rationalized considering that N-acetyl-D-man-
nosamine (ManNAc) can be obtained by alkaline epimer-
ization of GlcNAc. In addition, the intermediate 5 can
undergo an epimerization to 7 (Scheme 3) through the for-
mation of its regioisomer 6 before giving rise to the
Michael addition, as observed by Wen and Hulting in the
9
0 °C in a solution of NaHCO in H O–THF (2:1), 1 and
3 2
1
1
preparation of C-linked glycophosphonates.
2
were recovered in 48% yield as a 6:4 mixture showing
We checked that under our conditions [NaHCO (4 that the mannose derivatives decomposed more rapidly
3
equiv), H O, 90 °C] pure GlcNAc gave, after 12 hours, a than its gluco isomer. A shorter (< 24 h) reaction time did
2
1
3
13
GlcNAc/ManNAc mixture in a 4:1 ratio ( C NMR anal- not lead to better results. Indeed, examination by
C
ysis) but, in the reaction with pentanedione, we were un- NMR of the crude reaction mixture obtained after 1.5
able to observe the formation of the intermediates 5, 6, or hours, revealed the presence of 1 and 2 in a 3:7 ratio to-
7
. Having characterized the products formed during the gether with two other C-glycosidic ketones in a 2:1 ratio.
condensation, we turned to the use of co-solvents in order The ketones are presumably the intermediate furanosidic
ketones by analogy with previous results of our group.5
The starting GlcNAc (together with some ManNAc) was
a
to improve the yield of the reaction (Table 1).
Synthesis 2005, No. 5, 814–818 © Thieme Stuttgart · New York

8
16
N. Bragnier, M.-C. Scherrmann
PAPER
present at less than 10%, whereas the ratio of the pyrano- Gel 60 F254 with detection by charring with sulfuric acid. Melting
points were determined with a Buchi B 545 capillary apparatus and
sidic ketones 1 and 2 vs the furanosidic ketones could be
1
3
are uncorrected. Optical rotations were determined using a Jasco
DIP-370 digital polarimeter. NMR spectra were recorded at r.t. at
estimated at 7:3 ( C NMR analysis). A longer reaction
time (24 h) allowed the complete conversion of the fura-
nosides to the pyranosides. Then we tried to perform the
reaction with N-acetyl-D-mannosamine using the best
1
13
2
50 MHz ( H) and 90 MHz ( C). Mass spectrometry was recorded
on a MAT 95S instrument. Elemental analyses were performed at
the C.N.R.S. Microanalytical Laboratory (Gif sur Yvette, France).
conditions found for GlcNAc [pentanedione (2 equiv), IR spectra were recorded with a Bruker IFS 66 spectrometer.
NaHCO (4 equiv), H O–THF (2:1), 90 °C, 24 h] and we
3
2
Reactions Between Unprotected Sugars and 2,4-Pentanedione;
General Procedure
obtained a mixture of the manno ketone 2 and the gluco
ketone 1 in a 3:1 ratio and 40% yield. This poor yield can
be explained by the instability of 2 in the reaction mixture
but it was not improved by reducing the reaction time.
To a solution of the sugar (GlcNAc, ManNAc, Gal or GalNAc, 0.15
M) in H O–THF (2:1) were added NaHCO (4 equiv) and 2,4-pen-
2
3
tanedione (2 equiv). The reaction mixture was stirred at 90 °C for
4 h (72 h in the case of GalNAc), then cooled to r.t. and treated
2
Before extending the above methodology to the N-acetyl-
D-galactosamine (GalNAc), we decided to apply our pro-
tocol to galactose (Gal) and we were pleased to observe a
clean reaction, which allowed us to isolate the ketone 8 in
+
with Dowex 50 X-8 200 H to reach pH 5. The resin was filtered and
the solution was washed with CH Cl and concentrated. The residue
2
2
was treated as described below.
9
0% yield (Scheme 4). This represents a significant im-
Acetylation; General Procedure
provement in the preparation of this compound since, the A solution of the sugar (0.5 mmol) in pyridine (10 mL) and acetic
5
c
conditions previously described by others [pentanedione anhydride (5 mL) was kept at r.t. overnight and then concentrated.
The residue was suspended in CH Cl (50 mL) and washed with wa-
(
1.2 equiv), NaHCO (1.2 equiv), H O, 80 °C, 5 h] afford-
2
2
3
2
ter (50 mL); the organic layer was dried (MgSO ) and concentrated.
4
ed a yield of only 47%. Then we turned to the reaction of
GalNAc using our procedure, and observed after 3 days
the formation of 10 together with some other side-prod-
ucts, which made the isolation of 10 troublesome. There-
Deacetylation; General Procedure
A solution of the acetylated compound (0.9 mmol) in CH OH–
3
Et N–H O (8:1:1, 20 mL) was kept at r.t. overnight and then con-
3
2
fore the crude reaction mixture was acetylated and pure 11 centrated. The residue was dissolved in water and the solution was
could be isolated in 50% yield. The anomeric configura- concentrated; this procedure was repeated several times until the
1
odourless solid residue (free from triethyl ammonium salts) reached
a constant weight.
tion of compounds 8 and 10 was assigned by H NMR on
the basis of the large J1¢,2¢ values (9.5 Hz and 10.5 Hz, re-
spectively) indicating a trans-diaxial arrangement of the
H-1¢ and H-2¢ atoms.
1
-C-(2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-b-D-glucopyrano-
syl)-propan-2-one (3) and 1-C-(2-Acetamido-2-deoxy-3,4,6-tri-
O-acetyl-b-D-mannopyranosyl)-propan-2-one (4)
HO
HO
OH
HO
HO
OH
Prepared from 2-acetamido-2-deoxy-D-glucopyranose (904 mg,
4.05 mmol). Flash chromatography of the residue [EtOAc–MeOH
(4:1)] afforded 1 and 2 as an inseparable 4:6 mixture (877 mg,
83%). The mixture was acetylated and crystallization of the residue
from EtOAc–cyclohexane (2:1) gave 1-C-(2-acetamido-2-deoxy-
O
O
O
NaHCO3
O
+
R
R
OH
O
Gal R = OH
GalNAc R = NHAc
8
R = OH 90%
10 R = NHAc
3
2
,4,6-tri-O-acetyl-b-D-glucopyranosyl)-propan-2-one (3) (352 mg,
7%); white crystals [EtOAc–cyclohexane (2:1)]; mp 211–212 °C;
2
8
[
a]D –35 (c = 1, CHCl3).
–
1
IR (KBr): 3321, 1742 cm .
AcO
AcO
OAc
Ac2O
Pyridine
1
H NMR (250 MHz, CDCl ): d = 5.50 (d, J = 9.0 Hz, 1 H, NH),
2¢,NH
3
O
5.08 (dd, J3¢,4¢ = J4¢,5¢ = 9.5 Hz, 1 H, H-4¢), 4.99 (dd, J = 9.5 Hz, 1
H, H-3¢), 4.22 (dd, J
(
2¢,3¢
R
= 5.0 Hz, J
= 12.5 Hz, 1 H, H-6¢a), 4.06
O
5¢,6¢a
6¢a,6¢b
ddd, J = 11.5 Hz, 1 H, H-2¢), 4.05 (dd, J5¢,6¢b = 2.5 Hz, 1 H, H-
1¢,2¢
9
1
R = OAc 100%
R = NHAc 50% (2 steps)
6
1
¢b), 3.86 (ddd, J1a,1¢ = 7.0 Hz, J1b,1¢ = 4.5 Hz, 1 H, H-1¢), 3.62 (ddd,
H, H-5¢), 2.84 (dd, J1a,1b = 17.5 Hz, 1 H, H-1a), 2.68 (dd, 1 H, H-
1
Scheme 4
1b), 2.16, 2.08, 2.04, 2.05, 1.91 (5 × s, 15 H, 5 × Ac).
1
3
C NMR (90 MHz, CDCl ): d = 20.5, 20.6, 23.0, 30.8 (COCH ),
3
3
3
7
1.0 (C3), 45.8 (C1), 53.4 (C2¢), 62.1 (C6¢), 68.3 (C4¢), 74.1 (C3¢),
In conclusion, the one step methodology leading to b-D-
C-glycosidic ketones, i.e. the aqueous condensation of
pentane-2,4-dione with unprotected carbohydrates, has
been applied to 2-acetamido sugars. Our protocol gave a
straightforward entry to N-acetyl-D-gluco-, manno- and
galactosamine C-glycosidic ketones. The acetylation-
deacetylation procedure allowed an easy purification of
the products.
5.0 (C1¢), 75.6 (C5¢), 169.3, 170.3, 170.6, 171.4 (COCH ), 206.2
3
(
C2).
HRMS (ESI): m/z calcd for C H NO Na: 410.1422; found:
1
7
25
9
4
10.1430.
Anal. Calcd for C H NO : C, 52.71; H, 6.50; N, 3.62; O, 37.17.
17 25
9
Found: C, 52.59; H, 6.66; N, 3.52; O, 37.07.
Flash chromatography [EtOAc–cyclohexane (9:1)] of the residue
obtained from the mother liquor of 3 afforded 1-C-(2-acetamido-2-
deoxy-3,4,6-tri-O-acetyl-b-D-mannopyranosyl)-propan-2-one (4)
(726 mg, 56%); white crystals [EtOAc–cyclohexane (1:10)]; mp
Flash column chromatography was performed on Silica Gel 60A
C.C. (6–35 mm, SDS). Reactions were monitored by TLC on Silica
2
8
142–143 °C; [a]D –39 (c = 1, CHCl3).
Synthesis 2005, No. 5, 814–818 © Thieme Stuttgart · New York

PAPER
Synthesis of C-Glycosidic Ketones
817
–
1
IR (KBr): 3379, 1750 cm .
1
mg, 90%); white crystals from EtOAc–MeOH (3:1); mp 175–176
2
8
°C; [a]
20 (c = 1, H O).
2
D
H NMR (250 MHz, CDCl ): d = 5.79 (d, J2¢,NH = 9.5 Hz, 1 H, NH),
.13–5.00 (m, 2 H, H-3¢, H-4¢), 4.58 (ddd, J2¢,3¢ = 3.5 Hz, J1¢,2¢ = 1.5
3
–
1
5
IR (KBr): 3285, 1709 cm .
Hz, 1 H, H-2¢), 4.26 (dd, J5¢,6¢a = 5.5 Hz, J6¢a,6¢b = 12.5 Hz, 1 H, H-
¢a), 4.20 (ddd, J1a,1¢ = 8.5 Hz, J1b,1¢ = 4.5 Hz, 1 H, H-1¢), 4.00 (dd,
J5¢,6'b = 2.5 Hz, 1 H, H-6¢b), 3.67 (ddd, J4¢,5¢ = 10.0 Hz, 1 H, H-5¢),
1
H NMR (250 MHz, D O): d = 3.93 (dd, J = 3.5 Hz, J4¢,5¢ = 0.5
2
3¢,4¢
6
Hz, 1 H, H-4¢), 3.73 (dd, J2¢,3¢ = 9.0 Hz, 1 H, H-3¢), 3.69–3.61 (m, 3
H, H-5¢, H-6¢a, H-6¢b), 3.62 (ddd, J1b,1¢ = J = 9.5 Hz, J
= 3.5
1¢,2¢
1a,1¢
2
2
1
.74 (dd, J1a,1b = 17.5 Hz, 1 H, H-1a), 2.50 (dd, 1 H, H-1b), 2.16,
.11, 2.10, 2.06, 2.00 (5 × s, 15 H, 5 × Ac).
Hz, 1 H, H-1¢), 3.42 (dd, J = J2¢,3¢ = 9.5 Hz, 1 H, H-2¢), 3.00 (dd,
1
¢,2¢
J
= 16.5 Hz, 1 H, H-1a), 2.71 (dd, 1 H, H-1b), 2.25 (s, 3 H, 3 ×
1
a,1b
H NMR (250 MHz, C D ): d = 5.44 (d, J = 9.5 Hz, 1 H, NH),
2¢,NH
H-3).
13
6
6
5
1
.32 (dd, J3 = J = 10.0 Hz, 1 H, H-4¢), 5.12 (dd, J2¢,3¢ = 4.5 Hz,
¢,4¢
4¢,5¢
C NMR (90 MHz, D O): d = 30.2 (C3), 46.1 (C1), 61.5 (C6¢), 69.5
2
H, H-3¢), 4.68 (ddd, J1¢,2¢ = 1.5 Hz, 1 H, H-2¢), 4.35 (dd, J5¢,6¢a = 5.0
(
C4¢), 70.8 (C2¢), 74.2 (C3¢), 76.0 (C1¢), 78.9 (C5¢), 213.7 (C2).
Hz, J6¢a,6¢b = 12.5 Hz, 1 H, H-6¢a), 3.92 (dd, J5¢,6¢b = 2.5 Hz, 1 H, H-
HRMS (ESI): m/z calcd for C H O Na: 243.0839; found:
2
6
1
1
¢b), 3.81 (ddd, J1a,1¢ = 9.0 Hz, J1b,1¢ = 3.5 Hz, 1 H, H-1¢), 3.20 (ddd,
H, H-5¢), 2.27 (dd, J1a,1b = 17.5 Hz, 1 H, H-1a), 1.78 (dd, 1 H, H-
b), 1.83, 1.76, 1.62, 1.61, 1.42 (5 × s, 15 H, 5 × Ac).
9
16
6
43.0848.
Anal. Calcd for C H O : C, 49.09; H, 7.32; O, 43.59. Found: C,
48.85; H, 7.33, O, 43.86.
9
16
6
1
3
C NMR (90 MHz, CDCl ): d = 20.6, 23.1 (COCH ), 30.4 (C3),
3
3
4
7
4.4 (C1), 50.0 (C2¢), 62.6 (C6¢), 65.9 (C4¢), 72.4 (C3¢), 73.4 (C1¢),
1
-C-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-propan-2-
6.5 (C5¢), 169.8, 170.0, 170.4, 170.5 (COCH ), 204.3 (C2).
3
one (9)
HRMS (ESI): m/z calcd for C H NO Na: 410.1422; found:
1
7
25
9
Compound 8 (150 mg, 0.68 mmol) was acetylated to give 9 (264
mg, 100%); white crystals from cyclohexane; mp 91–92 °C; [a]D
6 (c = 1, CHCl3).
4
10.1429.
28
Anal. Calcd for C H NO : C, 52.71; H, 6.50; N, 3.62; O, 37.17.
1
7
25
9
Found: C, 52.48; H, 6.49; N, 3.53; O, 37.17.
IR (KBr): 1740 cm–1.
1
H NMR (250 MHz, CDCl ): d = 5.43 (dd, J = 3.0 Hz, J4¢,5¢ = 0.5
1
-C-(2-Acetamido-2-deoxy-b-D-glucopyranosyl)-propan-2-one
3
3¢,4¢
Hz, 1 H, H-4¢), 5.10 (dd, J = 10.0 Hz, J2¢,3¢ = 9.5 Hz, 1 H, H-2¢),
5
H-6¢a), 4.03 (dd, J5¢,6¢b = 6.0 Hz, 1 H, H-6¢b), 3.97 (ddd, J1a,1¢ = 9.0
Hz, J1b,1¢ = 3.0 Hz, 1 H, H-1¢), 3.91 (ddd, 1 H, H-5¢), 2.80 (dd,
J1a,1b = 16.5 Hz, 1 H, H-1a), 2.50 (dd, 1 H, H-1b), 2.19, 2.16, 2.04,
(
1)
1¢,2¢
.04 (dd, 1 H, H-3¢), 4.10 (dd, J6¢a,6¢b = 11.0 Hz, J5¢,6¢a = 7.0 Hz, 1 H,
Compound 3 (325 mg, 0.84 mmol) was deacetylated to give 1 in
quantitative yield (219 mg); white crystals (EtOAc–MeOH); mp
9
28
1
{
78–179 °C (Lit. mp 135–137 °C); [a]
= –7 (c = 1, MeOH)
D
9
Lit. [a] –8.1 (c = 1, MeOH)}.
D
2
1
.03, 1.98 (5 × s, 15 H, 5 × Ac).
–
1
IR (KBr): 3280, 1714, 1655 cm .
H NMR (250 MHz, C D ): d = 5.46 (dd, J = 3.5 Hz, J4¢,5¢ = 1.0
6
6
3¢,4¢
HRMS (ESI): m/z calcd for C H NO Na: 284.1105; found:
2
1
1
19
6
Hz, 1 H, H-4¢), 5.38 (dd, J = J2¢,3¢ = 10.0 Hz, 1 H, H-2¢), 5.14 (dd,
1
¢,2¢
84.1111.
1
H, H-3¢), 4.06 (dd, J6¢a,6¢b = 11.0 Hz, J5¢,6¢a = 7.0 Hz, 1 H, H-6¢a),
4.00 (dd, J5¢,6¢b = 6.5 Hz, 1 H, H-6¢b), 3.90 (ddd, J1a,1¢ = 8.5 Hz,
J1b,1¢ = 3.5 Hz, 1 H, H-1¢), 3.29 (ddd, 1 H, H-5¢), 2.48 (dd, J1a,1b
6.0 Hz, 1 H, H-1a), 2.27 (dd, 1 H, H-1b), 1.73, 1.64, 1.63, 1.62,
Anal. Calcd for C H NO ·1.2H O: C, 46.70; H, 7.62; N, 4.95; O,
4
11
19
6
2
0.72. Found: C, 46.83; H, 7.24; N, 4.81; O, 40.73.
=
1
1
-C-(2-Acetamido-2-deoxy-b-D-mannopyranosyl)-propan-2-
1.61 (5 × s, 15 H, 5 × Ac).
one (2)
13
C NMR (90 MHz, CDCl ): d = 20.5, 20.6 (COCH ), 30.9 (C3),
3
3
Compound 4 (325 mg, 0.84 mmol) was deacetylated to afford 2
4
7
5.3 (C1), 61.3 (C2¢), 67.5 (C6¢), 68.8 (C4¢), 71.7 (C3¢), 74.1 (C1¢),
(219 mg, 100%); white crystals (EtOAc–MeOH); mp 162–163 °C;
4.2 (C5¢), 169.9, 169.9, 170.0, 170.2 (COCH ), 205.1 (C2).
28
10
3
[
a]D = –62 (c = 1, MeOH) {Lit. [a] –28.5 (c = 0.45, H O)}.
D
2
HRMS (ESI): m/z calcd for C H NO Na: 411.1262; found:
–
1
17 24
10
IR (KBr): 3394, 1712, 1680 cm .
4
11.1268.
1
H NMR (250 MHz, CD OD): d = 4.30 (dd, J = 1.5 Hz, J2¢,3¢ = 4.5
3
1¢,2¢
Anal. Calcd for C H O : C, 52.57; H, 6.23; O, 41.20. Found: C,
1
7
24 10
Hz, 1 H, H-2¢), 4.03 (ddd, J1a,1¢ = 7.5 Hz, J1b,1¢ = 5.5 Hz, 1 H, H-1¢),
.77 (d, J5¢,6¢ = 3.5 Hz, 2 H, 2 × H-6¢), 3.69 (dd, J3¢,4¢ = 10.0 Hz, 1 H,
H-3¢), 3.49 (dd, J4¢,5¢ = 9.5 Hz, 1 H, H-4¢), 3.22 (dt, 1 H, H-5¢), 2.69
5
2.66; H, 6.15; O, 41.16.
3
1
-C-(2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-b-D-galactopyra-
(
(
1
dd, J1a,1b = 17.5 Hz, 1 H, H-1a), 2.54 (dd, 1 H, H-1b), 2.14 and 2.05
2 × s, 6 H, 2 × Ac).
nosyl)-propan-2-one (11)
Prepared from 2-acetamido-2-deoxy-D-galactopyranose (443 mg,
2.00 mmol). The crude mixture was acetylated. Flash chromatogra-
phy of the residue (EtOAc) afforded 11 (437 mg, 50%); white crys-
tals (cyclohexane–EtOAc); mp 219–220 °C; [a] = –25 (c = 1,
CHCl ).
3
3
C NMR (90 MHz, CD OD): d = 22.6 (COCH ), 30.4 (C3), 45.8
3
3
(
(
1
C1), 54.0 (C2¢), 62.2 (C6¢), 68.2 (C5¢), 74.8 (C3¢), 75.0 (C1¢), 82.2
2
8
C4¢), 174.4 (COCH ), 208.6 (C2).
3
D
3
C NMR (90 MHz, D O): d = 24.5 (COCH ), 32.5 (C3), 47.1 (C1),
2
3
–
1
5
5.4 (C2¢), 63.2 (C6¢), 69.4 (C5¢), 78.1 (C1¢, C3¢), 82.8 (C4¢), 177.8
IR (KBr): 3258, 1742 cm .
(
COCH ), 214.5 (C2).
1
3
H NMR (250 MHz, CDCl ): d = 5.63 (d, J
= 9.5 Hz, 1 H, NH),
3
2¢,NH
HRMS (ESI): m/z calcd for C H NO Na: 284.1105; found:
2
5.36 (dd, J = 3.5 Hz, J = 0.5 Hz, 1 H, H-4¢), 4.96 (dd, J2¢,3¢ =
1
1
19
6
3¢,4¢ 4¢,5
84.1115.
11.0 Hz, 1 H, H-3¢), 4.24 (ddd, J = 9.5 Hz, 1 H, H-2¢), 4.08 (dd,
¢,2¢
1
J
= 5.0 Hz, J
= 9.0 Hz, 1 H, H-6¢a), 4.04 (dd, J5¢,6¢b = 12.0
6¢a,6¢b
5
¢,6¢a
Anal. Calcd for C H NO : C, 50.57; H, 7.33; N, 5.36; O, 36.74.
Found: C, 50.34; H, 7.11; N, 5.08; O, 37.01.
1
1
19
6
Hz, 1 H, H-6¢b), 3.86 (ddd, 1 H, H-5¢), 3.86 (ddd, J1b,1¢ = 7.5 Hz,
J1a,1¢ = 4.5 Hz, 1 H, H-1¢), 2.86 (dd, J1a,1b = 17.5 Hz, 1 H, H-1a), 2.70
(
1
dd, 1 H, H-1b), 2.18, 2.16, 2.03, 2.01, 1.93 (5 × s, 15 H, 5 × Ac).
1
-C-(b-D-Galactopyranosyl)-propan-2-one (8)
3
Prepared from D-galactopyranose (500 mg, 2.78 mmol). Flash chro-
C NMR (90 MHz, CDCl ): d = 20.7, 23.2 (COCH ), 31.0 (C3),
3
3
matography of the residue [EtOAc–MeOH (5:1)] afforded 8 (550
46.1 (C1), 49.8 (C2¢), 61.6 (C6¢), 67.0 (C4¢), 71.6 (C3¢), 74.3 (C1¢),
7
5.6 (C5¢), 170.2, 170.4, 170.5, 171.0 (COCH ), 206.5 (C2).
3
Synthesis 2005, No. 5, 814–818 © Thieme Stuttgart · New York

8
18
N. Bragnier, M.-C. Scherrmann
PAPER
HRMS (ESI): m/z calcd for C H NO Na: 410.1422; found:
(2) (a) Xin, Y.-C.; Zhang, Y.-M.; Mallet, J.-M.; Glaudemans, C.
1
7
25
9
4
10.1429.
P. J.; Sinaÿ, P. Eur. J. Org. Chem. 1999, 471.
(
b) Glaudemans, C. P. J. Chem. Rev. 1991, 91, 25.
Anal. Calcd for C H NO : C, 52.71; H, 6.50; N, 3.62. Found: C,
17
25
9
(
(
3) Yang, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Angew.
5
2.62; H, 6.62; N, 3.51.
Chem. Int. Ed. 2004, 43, 3818.
4) (a) Postema, M. H. D. C-Glycosides Synthesis; CRC Press:
Boca Raton, 1995. (b) Levy, D. E.; Tang, C. The Chemistry
of C-Glycosides; Elsevier: Oxford, 1995. (c) Beau, J.-M.;
Gallagher, T. Top. Curr. Chem. 1997, 187, 1. (d) Beau, J.-
M.; Vauzeilles, B.; Skrydstrup, T. In Glycoscience,
Chemistry and Chemical Biology, Vol. 3; Fraser-Reid, B.;
Tatsuta, K.; Thiem, J., Eds.; Springer-Verlag: Heidelberg,
1
-C-(2-Acetamido-2-deoxy-b-D-galactopyranosyl)-propan-2-
one (10)
Compound 11 (200 mg, 0.51 mmol) was deacetylated to afford 10
(
133 mg, 100%).
Alternatively, 10 can be obtained from 2-acetamido-2-deoxy-D-glu-
copyranose (666 mg, 3.00 mmol). Flash chromatography of the res-
idue [EtOAc–MeOH (5:1)] afforded 10 (235 mg, 30%); white
2
001, 2679. (e) Dondoni, A.; Marra, A. Chem. Rev. 2000,
2
8
crystals (EtOAc–MeOH (3:1)]; mp 197–198 °C; [a]D 17 (c = 1,
100, 4395.
MeOH).
(
5) (a) Rodrigues, F.; Canac, Y.; Lubineau, A. Chem. Commun.
2000, 2049. (b) Lubineau, A.; Canac, Y.; Le Goff, N. Adv.
Synth. Catal. 2002, 344, 319. (c) Riemann, I.;
Papadopoulos, M. A.; Knorst, M.; Fessner, W.-D. Aust. J.
Chem. 2002, 55, 147. (d) Peters, S.; Lichtenthaler, F. W.;
Lindner, H. J. Tetrahedron: Asymmetry 2003, 2475.
–
1
IR (KBr): 1740 cm .
1
H NMR (250 MHz, CD OD): d = 3.92 (dd, J1¢,2¢ = J2¢,3¢ = 10.5 Hz,
3
1
H, H-2¢), 3.87 (dd, J3¢,4¢ = 3.5 Hz, J4¢,5¢ = 0.5 Hz, 1 H, H-4¢), 3.70
(
ddd, J1a,1¢ = 8.5 Hz, J1b,1¢ = 3.5 Hz, 1 H, H-1¢), 3.66 (d, J5¢,6¢ = 6.0
Hz, 2 H, 2 × H-6¢), 3.53 (dd, 1 H, H-3¢), 3.44 (dt, 1 H, H-5¢), 2.73
dd, J1 = 16.5 Hz, 1 H, H-1a), 2.61 (dd, 1 H, H-1b), 2.16 (s, 3 H,
(e) Misra, A. K.; Agnihotri, G. Carbohydr. Res. 2004, 339,
(
a,1b
1
381. (f) Hersant, Y.; Abou-Jneid, R.; Canac, Y.; Lubineau,
3
× H-3), 1.96 (s, 3 H, Ac).
A.; Philippe, M.; Semeria, D.; Radisson, X.; Scherrmann,
M.-C. Carbohydr. Res. 2004, 339, 741. (g) Sato, S.; Akiya,
T.; Suzuki, T.; Onodera, J. Carbohydr. Res. 2004, 339, 2611.
1
3
C NMR (90 MHz, D O): d = 24.50 (COCH ), 32.15 (C3), 48.27
2
3
(
(
C1), 54.00 (C2¢), 63.60 (C6¢), 70.57 (C5¢), 74.22 (C3¢), 76.90
C1¢), 80.94 (C4¢), 177.12 (COCH ), 215.07 (C2).
3
(6) (a) Lubineau, A.; Augé, J.; Queneau, Y. Synthesis 1994,
41. (b) Organic Reactions in Aqueous Media; Li, C.-J.;
Chan, T.-H., Eds.; Wiley-Interscience: New York, 1997.
c) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie:
7
HRMS (ESI): m/z calcd for C H NO Na: 284.1105; found:
1
1
19
6
2
84.1117.
(
Anal. Calcd for C H NO ·0.2H O: C, 49.88; H, 7.38; N, 5.29; O,
11
19
6
2
London, 1998. (d) Aqueous-Phase Organometallic
Catalysis; Cornils, B.; Herrmann, W. A., Eds.; Wiley-VCH:
Weinheim, 1998. (e) Lubineau, A.; Augé, J. Modern
Solvents in Organic Synthesis, In Topics in Current
Chemistry, Vol. 206; Knochel, P., Ed.; Springer-Verlag:
Berlin, 1999, 1.
3
7.45. Found: C, 49.83; H, 7.29; N 5.07; O, 37.75.
Acknowledgment
This work was supported by the Ministère de l'Education Nationale,
de l'Enseignement Supérieur et de la Recherche and the CNRS. We
thank Prof. A. Lubineau for helpful discussions.
(
7) (a) Peri, F.; Cipolla, L.; Rescigno, M.; La Ferla, B.; Nicotra,
F. Bioconjugate Chem. 2001, 12, 325. (b) Cipolla, L.;
Rescigno, M.; Leone, A.; Peri, F.; La Ferla, B.; Nicotra, F.
Bioorg. Med. Chem. 2002, 10, 1639.
References
(8) Cipolla, L.; La Ferla, B.; Lay, L.; Peri, F.; Nicotra, F.
Tetrahedron: Asymmetry 2000, 295.
9) Peri, F.; Cipolla, L.; La Ferla, B.; Dumy, P.; Nicotra, F.
(
1) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Lee, Y. C.; Lee,
R. T. Acc. Chem. Res. 1995, 28, 321. (c) Dwek, R. A.
Chem. Rev. 1996, 96, 683. (d) Bertozzi, C. R.; Kiessling, L.
L. Science 2001, 291, 2357. (e) Witczack, Z. J. Curr. Med.
Chem. 1995, 1, 392. (f) Sears, P.; Wong, C.-H. Chem.
Commun. 1998, 1161. (g) Lis, H.; Sharon, N. Chem. Rev.
(
Glycoconjugate J. 1999, 16, 399.
10) Hagedorn, H.-W.; Merten, H.; Brossmer, R. Carbohydr.
Res. 1992, 236, 89.
11) (a) Wen, X.; Hultin, P. G. Tetrahedron Lett. 2004, 45, 1773.
(
(
(b) Wen, X.; Hultin, P. G. Tetrahedron Lett. 2004, 45, 4809.
1998, 98, 637.
Synthesis 2005, No. 5, 814–818 © Thieme Stuttgart · New York