Synthesis of 4-C-sulfoaminosugar derivatives: Isomerization of 4-C-sulfogalactosamine to its gluco epimer

Article abstract of DOI:10.1016/j.tetasy.2003.10.004

Methyl 2-benzamido-3,6-di-O-benzoyl-2,4-dideoxy-α-D-glucopyranoside- 4-C-sulfonate sodium salt 9 and its galacto epimer 10 were prepared by oxidation with hydrogen peroxide in acetic acid of methyl 4-S-acetyl-2- benzamido-3,6-di-O-benzoyl-2-deoxy-4-thio-α

Full text of DOI:10.1016/j.tetasy.2003.10.004

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3761–3768
Synthesis of 4-C-sulfoaminosugar derivatives: isomerization of
4-C-sulfogalactosamine to its gluco epimer
Jose´ G. Ferna´ndez-Bolan˜os,a,* Salud Garc´ıa,a Jose´ Ferna´ndez-Bolan˜os,a Ma Jesu´s Dia´nez,b
Ma Dolores Estrada,b Amparo Lo´pez-Castrob and Simeo´n Pe´rez-Garridob
aDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de Sevilla, Apartado de Correos 553,
E-41071 Seville, Spain
bInstituto de Ciencias de Materiales de Sevilla and Departamento de F´ısica de la Materia Condensada,
C.S.I.C.—Universidad de Sevilla, Apartado de Correos 1065, E-41071 Seville, Spain
Received 30 July 2003; accepted 3 October 2003
Abstract—Methyl 2-benzamido-3,6-di-O-benzoyl-2,4-dideoxy-a-
epimer 10 were prepared by oxidation with hydrogen peroxide in acetic acid of methyl 4-S-acetyl-2-benzamido-3,6-di-O-benzoyl-
2-deoxy-4-thio-a- -glucopyranoside 7 and its galacto epimer 8, respectively. The 4-thioglucoside 7 was prepared from methyl
2-benzamido-3,6-di-O-benzoyl-2-deoxy-a- -glucopyranoside by double inversion through triflation, inversion at C-4 with NaNO2,
triflation of the resulting methyl 2-benzamido-3,6-di-O-benzoyl-2-deoxy-a- -galactopyranoside, followed by displacement with
potassium thioacetate. Deacylation of 9 with refluxing aqueous sodium hydroxide followed by deionisation yielded methyl
2-amino-2,4-dideoxy-a- -glucopyranoside-4-C-sulfonic acid 11. Deacylation of the galactopyranoside 10 under the same condi-
D-glucopyranoside-4-C-sulfonate sodium salt 9 and its galacto
D
D
D
D
tions also gave 11, due to base catalysed isomerisation of galacto to the more stable gluco configuration. The structure of 11,
crystallized as the monohydrate, was confirmed by X-ray crystallographic analysis. The asymmetric unit contains two sugar
molecules in two unique but similar conformations and two water molecules. The sulfo and the amino groups form a zwitterion,
with each ammonium group hydrogen bonded to the sulfonate groups of two other molecules related by symmetry.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
antitumoral11 and antiviral12 activities, has stimulated
their synthesis and the preparation of analogues that
have shown potent activity as DNA-polymerase
inhibitors and apoptosis inducer.13 SQDG analogues of
anomeric b-configuration were found to be potent
immunosuppressive agents without cytotoxic side
effects.14
Naturally occurring C-sulfonates, such as taurine (2-
aminoethanesulfonic acid),1,2
D
-cysteinolic acid,3 coen-
zyme M,4 and sulfoquinovosyldiacylglycerols (SQDGs)
1,5 are relatively few in number though involved in
important functions.6 SQDGs have been found in pho-
tosynthetic membranes of most photosynthetic bacteria
and all plants,7 and their biosynthesis have been exten-
sively studied.8 6-C-Sulfoquinovose, the carbohydrate
moiety of SQDGs, has recently been identified in the
oligosaccharide chain of a glycoprotein isolated from
the acidophilic archaeon Sulfolobus acidocaldarius,9 and
a 6-C-sulfohexosamine has been found in cell-wall
hydrolysates of extremely halophilic bacterium Halo-
coccus sp. strain 24.10
Syntheses of 6-C-sulfoquinovose,15 6-C-sulfofucose,16
6-C-sulfodisaccharides17 and the transformation of 6-
C-sulfosugars into alkyl sulfonates and N-
alkylsulfonamides18 have been reported. Several
2-amino-6-C-sulfohexoses,19,20 and 1-amino-6-C-sulfo-
The finding of natural SQDGs and SQMGs
(sulfoquinovosylmonoacylglycerols),
with
potent
* Corresponding author. Tel.: +34 95 4557151; fax: +34 95 4624960;
e-mail: bolanos@us.es
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.004

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J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 3761–3768
hexuloses,16 and
a
1-amino-4-C-sulfohexulose of
conditions to give the crystalline galactoside 5 in 52%
unknown configuration21 have also been described as
crystalline zwitterions. To our knowledge, no synthesis
of a 4-C-sulfohexose has been reported.
yield from 3. Treatment of 5 with triflic anhydride in
dichloromethane–pyridine at −18° gave the 4-O-triflate
6 which could be isolated (77%). The galacto configura-
tion of 5 and 6 is assigned from the NMR data of the
sugar rings (see Section 3). Thus, the J4,5 values was ca.
0 Hz as described for related galactopyranosides.28,29
Treatment of 6 with potassium thioacetate in acetone at
rt gave the methyl glucopyranoside 7 in 64% overall
yield from 5.
We report herein the preparation of amino sugar
derivatives bearing a C-sulfo group at C-4, and the
base catalyzed conversion of
tive 10 into the less sterically strained
derivative 9 (Scheme 1). The zwitterion sugar derived
sulfo-amino acid 11 can be considered as a homochiral
analogue of the amino acid homotaurine 2 which has
relevant physiological functions.22 Homotaurine and
N-acetylhomotaurine calcium salt (acamprosate) have
been used in the treatment of alcoholism.23
D
-galactosamine deriva-
-glucosamine
D
Oxidation of the thioacetate group of 7 and 8 with
hydrogen peroxide in acetic acid containing sodium
acetate (1 equiv.)17,19 at 80°C gave the sodium sul-
fonates 9 and 10 in 52 and 59% yield, respectively, after
purification by column chromatography on Biogel P2.
The vicinal coupling constants of the galacto derivative
4
10 indicates that is mainly in the C1 conformation in
2. Results and discussion
spite of the bulky sulfo group in axial position. The
calculated30,31 vicinal coupling constants for that con-
formation (J1,2 3.4 Hz, J2,3 11.1 Hz, J3,4 4.0 Hz, J4,5 1.7
Hz) are in good agreement with the observed constants
(J1,2 3.4 Hz, J2,3 11.1 Hz, J3,4 5.0 Hz, J4,5 2.4 Hz).
In the search of new thiosugar derivatives,24 we have
previously described25 the synthesis of the 4-thio-a-
D-
galactopyranoside derivative 8 from the partially O-
protected
D
-glucopyranoside 326 by nucleophilic
displacement of a sulfonyloxy group with potassium
thioacetate. We now describe the preparation of the
4-thio-a- -glucopyranoside derivative 7 by a double
inversion process.
Deacylation of the glucopyranoside 9 was accomplished
with refluxing in 2 M aq. sodium hydroxide. Subse-
quent acidification of the aq. solution with Amberlite
IR-120(H+) followed by chromatography on Biogel P2
afforded 11 in 90% yield. The same compound was
obtained in 63% yield from the more readily available
sulfonate 10 of galacto configuration, by the base cata-
lyzed epimerisation at C-4 that took place during the
hydrolysis of the amide group. This isomerization is
possible due to the acidity32 of the hydrogen at a-posi-
tion of the sulfonate group (Scheme 2). The steric
D
Treatment of 3 with triflic anhydride in dichloro-
methane containing pyridine gave the triflate 4, which
was used without further purification for the next step.
The introduction of the axial hydroxy group at C-4 was
carried out by treating 4 with sodium nitrite in
dimethylformamide at rt.27,28 The axial nitrite was not
isolated and underwent hydrolysis under the reaction
Scheme 1. Reagents and conditions: (i) Tf2O (2 equiv.), CH2Cl2/pyridine, −18°C; (ii) NaNO2 (10 equiv.), DMF, rt, 30 min; (iii)
KSAc (1.6 equiv.), acetone, rt, 1 h; (iv) aq. H2O2 (33% w/v, 9 equiv.), AcOH, NaOAc (1 equiv.), 80°C, 8 h; (v) 2 M aq. NaOH,
reflux, 24 h; (vi) Amberlite IR-120(H+).

J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 3761–3768
3763
Scheme 2.
,
requirements of the bulky axial sulfo group is responsi-
ble for the complete conversion of the galacto into the
gluco configuration via carbanions 13 and 14.
magnitudes for 11a are Q=0.587(4) A, ƒ=116(3)° and
ƒ=7.1(4)° for the sequence O5, C1, C2, C3, C4, C5,
and the asymmetry parameters39 are DCs (C2)=
0.011(2) and DC2 (C-2–C-1)=0.013(2); and for 11b are
,
Q=0.584(4) A, ƒ=105(7)° and q=2.8(4)°, and the
asymmetry parameters are DCs (C2%)=0.012(2) and DC2
2.1. Solid-state structure
(C-2%–C-1%)=0.004(2).
The structure of 11, crystallized as monohydrate, was
confirmed by X-ray crystallographic analysis. An
ORTEP33 view of the asymmetric unit, containing two
molecules of 11 in two unique but similar conforma-
tions 11a and 11b and two water molecules, together
with the atomic numbering is shown in Figure 1. The
lengths of the three SꢀO bonds are similar [1.441(2)–
The asymmetry of the endocyclic bonds [C-5–O-5
,
,
(1.445 A) and O-5–C-1 (1.408 A) for 11a and C-5%–O-5%
,
,
(1.447 A) and O-5%–C-1% (1.407 A) for 11b] are accord-
ing to the anomeric effect;37 and the glycosidic torsion
angles ƒ=O-5–C-1–O-1–C-11 (69.2°) and O-5%–C-1%–O-
1%–C11% (74.0°) are according to the exo-anomeric
effect.40 The torsional angles C-4–C-5–C-6–O-6 (61.1°)
and C-4%–C-5%–C-6%–O-6% (60.1°) correspond to the gg
conformation, one of the permitted conformations for
the exocyclic hydroxymethyl group of glucopyranose
derivatives.37
,
,
1.461(2) A for 11a and 1.454(2)–1.460(2) A for 11b],
−
indicating that the negative charge of the two SO3
groups are delocalized over the three oxygen atoms.
,
,
The mean SꢀO distance (1.451 A for 11a and 1.456 A
for 11b) is similar to that observed in 6-C-sulfo sugar
derivatives16,20,34,35 and is in agreement with the value
,
obtained (1.458 A) by ab initio SCF 6−31+G* calcula-
The structure is stabilized by an extensive system of
inter- and intra-molecular hydrogen bonds (Table 1).
The network of some of these hydrogen bonds is shown
in Figure 2. The hydroxy groups O-6–H and O-6%–H,
and the ammonium groups N–H-3 and NꢀH-3% are
involved in the unusual three- and four-center hydrogen
bonds,41 respectively. The sulfo and the amino groups
form a zwitterion structure, with the ammonium groups
hydrogen bonded to the sulfonate groups of two differ-
ent molecules related by symmetry through the hydro-
gen bonds N–H-1···O-43(i) and N–H-1%···O-43%(i), and
through N–H-3···O-42(ii) and N–H-3%···O-43(ii).
tions on methanesulfonate anion.36
The water molecules are involved in hydrogen bonds as
donor and as acceptor: OW acts as donor to O-5(0) and
O-43%(i), and as acceptor of OW%–H-2%···OW(iii) and
O-6···OW(0), while OW% acts as a donor to OW(iii) and
as an acceptor of O-6%···OW%(0). Extensive hydrogen
bond systems in which are involved crystallization
water have also be found for other 6-C-sulfoamino
sugars and C-sulfoamino poliols.16,20,35
3. Experimental
Figure 1. ORTEP view of 11 showing the atomic numbering.
The ellipsoids enclose 30% probability.
Melting points were determined on an Electrothermal
apparatus and are uncorrected. Optical rotations were
measured at 22°C with a Perkin–Elmer 241 polarimeter
and IR spectra (KBr discs) were recorded with a FT-IR
The geometry found for the pyranoid rings of 11a and
4
11b are consistent37 with the C1 (D) chair conforma-
1
Bomem MB-120 spectrophotometer. H (300 and 500
MHz) and 13C NMR spectra (75.5 and 125.7 MHz)
were recorded with a Bruker AMX-300 and AMX-500
for solutions in CDCl3 and MeOH-d4, using Me4Si as
internal standard, and for solutions in D2O, using
DOH (4.75 ppm) and 1,4-dioxane (67.4 ppm) as inter-
,
tion. The N atom in 11a is practically [0.062(4) A] at
the best plane defined by O5, C1, C2, C3, C4, and C5,
,
while that atom in 11b is at 0.170(4) A of the best plane
defined by O5%, C1%, C2%, C3%, C4%, and C5%. In terms of
ring-puckering coordinates,38 amplitude and phase

3764
J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 3761–3768
Table 1. Geometry of the hydrogen-bonding system and short contacts for 11
Acceptor symmetry codea
D···A (A)
DꢀH (A)
H···A (A)
DꢀH···A (°)
,
,
,
DonorꢀH···acceptor
Two-center
NꢀH-1···O-43
N%ꢀH-1%···O-43%
NꢀH-2···O-6
N%ꢀH-2%···O-6%
O-3···O-42
(i)
(i)
(i)
(i)
2.827(3)
2.978(3)
2.832(3)
2.680(3)
2.806(3)
2.806(3)
3.004(3)
2.955(3)
2.925(3)
1.00
1.00
0.99
0.99
0.94
1.00
0.90
0.97
0.95
1.92
2.11
2.20
2.10
1.97
2.01
2.36
2.19
2.18
149
145
121
116
146
135
129
134
134
(0)b
(0)
(0)
(i)
O-3%···O-42%
OWꢀH-1···O-5
OWꢀH-2···O-43%
OW%ꢀH-2%···OW
Three-center
O-6···OW
O-6···O-5
0-6%···OW%
O-6%···O-5%
(iii)
(0)
(0)
(0)
(0)
2.946(3)
2.728(2)
2.863(3)
2.745(3)
0.91
0.91
0.91
0.91
2.06
2.30
2.09
2.39
164
108
142
103
Four-center
NꢀH-3···O-3
NꢀH-3···O-42
NꢀH-3···O-3
N%ꢀH-3%···O-3%
N%ꢀH-3%···O-42%
N%ꢀH-3%···O-3%
(ii)
(ii)
(0)
(iii)
(iii)
(0)
2.859(3)
2.918(3)
2.772(3)
2.837(3)
2.876(3)
2.767(3)
1.01
1.01
1.01
1.00
1.00
1.00
2.13
2.30
2.41
2.12
2.33
2.39
127
119
100
127
113
101
a Symmetry code: (0) x, y, z; (i) x, y+1, z; (ii) −x+3/2, y+1/2, −z+1; (iii)=(ii+c).
b Intramolecular hydrogen bonds.
nal standard. The assignments of H and 13C signals
were confirmed by homonuclear COSY and heteronu-
clear 2D correlated spectra, respectively. Chemical
shifts are expressed in l (ppm) and coupling constants
(J) in Hz. FAB-mass spectra were taken on a Kratos
MS-80 RFA instrument. The samples were dissolved in
thioglycerol and NaI was added as cationising agent.
Ions were produced by a beam of Xe atoms with a
maximum energy of 8 keV, and the positive ions were
separated and accelerated over a potential of 7 kV. For
HR–FABMS spectra thioglycerol was used as matrix
and RbI was added as cationising agent. All reactions
were monitored by TLC on aluminum sheets coated
with Silica Gel 60 F254 (E. Merck) with visualization by
UV light and by charring with 10% H2SO4 in EtOH.
Preparative TLC was carried out using Silica Gel 60
HF254 (E. Merck). Gel-filtration chromatography was
performed on Biogel P2 (47×3.5 cm column), with 1:1
MeOH–H2O as eluent. Microanalyses were performed
at ‘Instituto Qu´ımico de Sarria´’, Barcelona, Spain.
After 30 min TLC (CH2Cl2–MeOH, 40:1) showed com-
plete conversion of 4 (Rf 0.74) into the major product 5
(Rf 0.30). Insoluble material was collected and washed
with CH2Cl2; the combined filtrate and washings were
washed with water, dried (MgSO4), and evaporated.
The residue was crystallized from EtOH to give 5 (2.4
g, 52%); mp 208–210°C; [h]2D0=+105 (c 1.0, CH2Cl2); IR
wmax 3556, 3491, 3288 (OH, NH), 2835 (MeO), 1724,
1707 (CꢁO, benzoate), 1638 (Amide I), 1537 (Amide II),
1600, 1580, 1450, 710 cm−1 (phenyl); 1H NMR (300
MHz, CDCl3): l 8.06–7.26 (m, 15H, Ar-H), 6.50 (d,
1H, J2,NH 9.6 Hz, NH), 5.51 (dd, 1H, J2,3=11.1 Hz,
1
J
3,4=2.8 Hz, H-3), 5.14 (td, 1H, J1,2=3.5 Hz, H-2),
4.98 (d, 1H, H-1), 4.68 (dd, 1H, J5,6a=5.6 Hz, J6a,6b
11.4 Hz, H-6a), 4.60 (dd, 1H, H-6b), 4.34 (m, 1H, J4,5
=
0
Hz, H-4), 4.29 (dd, 1H, J5,6b=6.9 Hz, H-5), 3.44 (s, 3H,
OMe), 3.20 (s, 1H, OH-4); 13C NMR (75.5 MHz,
CDCl3): l 167.60 (CON), 166.80, 166.40 (COO),
133.60, 133.03, 132.85, 131.35, 129.80, 129.56, 129.08,
128.53, 128.43, 127.07 (18C Ar), 98.80 (C-1), 71.81
(C-3), 68.17 (C-5), 67.49 (C-4), 63.53 (C-6), 55.29
(OMe), 47.99 (C-2); FABMS: m/z 528 ([M+Na]+,
100%), 173 ([M−2Bz−BzOH]+, 80). Anal. calcd for
C28H27NO8: C, 66.52; H, 5.38; N, 2.77. Found: C,
66.80; H, 5.41; N, 2.91.
3.1. Methyl 2-benzamido-3,6-di-O-benzoyl-2-deoxy-a-D-
galactopyranoside 5
To a stirred solution of trifluoromethanesulfonic anhy-
dride (3 mL, 18.5 mmol) in CH2Cl2 (30 mL) at −18°C
was added dropwise pyridine (3 mL) diluted with
CH2Cl2 (1 mL), and then a solution of methyl 2-benz-
3.2. Methyl 2-benzamido-3,6-di-O-benzoyl-2-deoxy-4-O-
trifluoromethylsulfonyl-a-D-galactopyranoside 6
amido-3,6-di-O-benzoyl-2-deoxy-a- -glucopyranoside 3
D
(4.7 g, 9.3 mmol) in CH2Cl2 (45 mL). After 30 min, the
mixture was diluted with CH2Cl2, washed with 2 M
HCl, satd aq NaHCO3 and with water, dried (MgSO4),
and evaporated. The residue containing the 4-O-triflate
derivative 4 was treated with NaNO2 (7 g, 101 mmol) in
DMF (12 mL) under stirring at room temperature.
To a stirred solution of trifluoromethanesulfonic anhy-
dride (1.28 mL, 7.9 mmol) in CH2Cl2 (16 mL) at −18°C
was added dropwise pyridine (1.3 mL) diluted with
CH2Cl2 (1 mL), and then a solution of compound 5
(1.98 g, 3.92 mmol) in CH2Cl2 (20 mL). After 30 min,
the mixture was diluted with CH2Cl2, washed with 2 M

J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 3761–3768
3765
Figure 2. The packing for 11 viewed down the b axis. Hydrogen bonds are indicated by dashed lines.
HCl, satd aq NaHCO3 and with water, dried (MgSO4),
and evaporated to give 6 (2.5 g) that could be used for
the next step. A sample (0.2 g) was purified by prepara-
tive TLC (80:1 CHCl3–MeOH) yielding pure 6 (153 mg,
77%) as an amorphous solid; [h]2D0=+72 (c 1.0, CHCl3);
Rf 0.47 (80:1 CHCl3–MeOH); 1H NMR (300 MHz,
CDCl3): l 8.09–7.33 (m, 15H, Ar-H), 6.34 (d, 1H, J2,NH
9.1 Hz, NH), 5.65 (dd, 1H, J2,3=10.9 Hz, J3,4=2.7 Hz,
H-3), 5.52 (d, 1H, J4,50 Hz, H-4), 5.06 (m, 1H, J1,2=3.6
Hz, H-2), 5.01 (d, 1H, H-1), 4.68 (dd, 1H, J5,6a=6.4
Hz, J6a,6b=11.1 Hz, H-6a), 4.50 (t, 1H, J5,6b=7.1 Hz,
H-5), 4.35 (dd, 1H, H-6b), 3.47 (s, 3H, OMe); 13C
NMR (75.5 MHz, CDCl3): l 167.19 (CON), 166.43 and
165.71 (COO), 133.68, 133.51, 133.38, 131.67, 130.05,
129.52, 128.91, 128.43, 128.37, 128.12, 126.78 (18C Ar),
118.25 (1JC,F 319, CF3), 98.56 (C-1), 81.86 (C-4), 68.30
(C-3), 66.12 (C-5), 61.44 (C-6), 55.77 (OMe), 47.96
(C-2); wmax 3328 (NH), 1726 (CꢁO, benzoate), 1659
(Amide I), 1530 (Amide II), 1602, 1580, 1450, 688 cm−1
(phenyl); FABMS: m/z 660 ([M+Na]+, 64%), 638 ([M+
H]+, 77), 534 ([M−Bz+2H]+, 80), 606 ([M−OMe]+, 64),
488 ([M−TfO]+, 31), 366 ([M−TfO−BzOH]+, 24); HR–
FABMS calcd for C29H26F3NO10RbS [M+Rb]+
722.0346, found 722.0376.
3.3. Methyl 4-S-acetyl-2-benzamido-3,6-di-O-benzoyl-2-
deoxy-4-thio-a- -glucopyranoside 7
D
To a solution of crude 6 (2.29 g, 3.6 mmol) in acetone
(12 mL) was added potassium thioacetate (680 mg, 6
mmol) and the mixture was stirred at room tempera-
ture. After 1 h, TLC (40:1 CH2Cl2–MeOH) showed
complete conversion of 6 (Rf 0.79) into a major product
(7, Rf 0.43). Insoluble material was collected and
washed with acetone, the combined filtrate and wash-
ings were concentrated to dryness. A solution of the
residue in CH2Cl2 was washed with water, dried
(MgSO4) and evaporated. The residue, recrystallized
from MeOH after treatment with activated charcoal,
gave 7 (1.02 g). The mother liquor was purified by flash
column chromatography (ether–hexane, 5:1) to give an
extra amount of 7, 280 mg (total yield 64% from 5); mp
1
122–124°C; [h]2D0=+156 (c 1.0, CH2Cl2); H NMR (500
MHz, CDCl3): l 8.13–7.35 (m, 15H, Ar-H), 6.51 (d,
1H, J2,NH 9.2 Hz, NH), 5.58 (t, 1H, J2,3=10.6 Hz,
J
3,4=10.7 Hz, H-3), 5.00 (d, 1H, J1,2=3.5 Hz, H-1),
4.71 (ddd, 1H, H-2), 4.64 (dd, 1H, J5,6a=1.6 Hz,
6a,6b=12.1 Hz, H-6a), 4.56 (dd, 1H, H-6b), 4.21 (m,
2H, J5,6b=4.4 Hz, H-4, H-5), 3.42 (s, 3H, OMe), 2.22
J

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J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 3761–3768
(s, 3H, SAc); 13C NMR (75.5 MHz, CDCl3): l 192.22
(COS), 167.03 (CON), 167.03 and 166.21 (COO), 133.78,
133.33, 133.08, 131.53, 129.81, 129.68, 128.84, 128.44,
128.36, 128.33, 126.89 (18C Ar), 98.52 (C-1), 70.80 (C-3),
68.71 (C-5), 63.81 (C-6), 55.44 (OMe), 53.76 (C-2), 43.90
(C-4), 30.58 (SAc); wmax 3430, 3381, 3323 (NH), 2840
(MeO), 1722 (CꢁO, benzoate), 1700 (CꢁO, thioacetate),
1665, 1660 (Amide I), 1535 (Amide II), 1600, 1580, 1450,
710 cm−1 (phenyl); FABMS: m/z 586 ([M+Na]+, 4%), 564
([M+H]+, 100), 532 ([M−OMe]+, 29); Anal. calcd for
C30H29NO8S: C, 63.93; H, 5.19; N, 2.48; S, 5.69. Found:
C, 63.64; H, 5.03; N, 2.46; S, 5.87.
167.85 (COO), 135.71, 134.32, 134.06, 132.64, 131.54,
131.43, 131.08, 130.51, 129.64, 129.44, 129.26, 128.37
(18C Ar), 99.94 (C-1), 71.62 (C-3), 69.10 (C-5), 68.03
(C-6), 59.89 (C-4), 55.61 (OMe), 49.45 (C-2); wmax 3437,
3433 (NH), 2839 (MeO), 1718, 1712 (CꢁO, benzoate),
−
1655, 1643 (Amide I), 1527 (Amide II), 1178, 1035 (SO3 ),
1600, 1580, 1450 cm−1 (phenyl); FABMS: m/z 1796
([3M+Na]+, 3%), 1204 ([2M+Na−H]+, 6), 614 ([M+Na]+,
100), 592 ([M+H)]+, 3), 510 ([M−SO3H]+, 16). Anal. calcd
for C28H26NO10SNa·2H2O: C, 53.58; H, 4.82; N, 2.23; S,
5.11. Found: C, 53.47; H, 4.64; N, 2.25; S, 4.57.
3.6. Methyl 2-amino-2,4-dideoxy-a-
D-glucopyranoside-4-
3.4. Methyl 2-benzamido-3,6-di-O-benzoyl-2,4-dideoxy-
C-sulfonic acid 11
a- -glucopyranoside-4-C-sulfonate sodium salt 9
D
(a) Starting from methyl 2-benzamido-3,6-di-O-benzoyl-
2,4-dideoxy-a- -glucopyranoside-4-sulfonate sodium
To a solution of 7 (430 mg, 0.76 mmol) and sodium
acetate (62.6 mg, 0.76 mmol) in acetic acid (5 mL) was
added aqueous 33% w/v hydrogen peroxide (0.63 mL, 6.8
mmol). After 5 h at 80°C the solution was concentrated
to dryness and the residue (437 mg) was purified by
column chromatography on Biogel P2 (1:1 MeOH–H2O)
to give 9 (234 mg, 52%); mp 216–218°C (dec.) from
EtOH; [h]2D0=+94 (c 1.0, MeOH); Rf 0.56 (5:1 CH2Cl2–
D
salt 9. A solution of 9 (290 mg, 0.49 mmol) in 2 M
aqueous sodium hydroxide (3 mL) was heated under
reflux for 24 h, and then deionised with Amberlite
IR-120(H+) resin. The resin was filtered, the filtrate was
concentrated and the residue (174 mg) was purified by
column chromatography on Biogel P2 (1:1 MeOH–H2O)
to yield 11 (113 mg, 90%), which crystallized from
water–propan-2-ol; mp 250°C (dec.); [h]2D0=+99 (c 1.0,
1
MeOH); H NMR (300 MHz, CD3OD): 7.99–7.23 (m,
1
15H, Ar-H), 6.10 (t, 1H, J2,3=10.3 Hz, J3,4=10.3 Hz,
H-3), 5.03 (dd, 1H, J5,6a=1.8 Hz, J6a,6b=11.7 Hz, H-6a),
4.93 (d, 1H, J1,2=3.6 Hz, H-1), 4.92 (dd, 1H, J5,6b=5.7
Hz, H-6b), 4.62 (dd, 1H H-2), 4.58 (m, 1H, J4,5=10.4 Hz,
H-5), 3.64 (t, 1H, H-4), 3.52 (s, 3H, OMe); 13C NMR
(75.5 MHz, CD3OD): l 168.11 (CON), 167.89 (2 COO),
135.30, 134.29, 133.92, 132.78, 131.77, 131.50, 130.89,
130.60, 129.64, 129.46, 129.23, 128.43 (18C Ar), 99.55
(C-1), 70.25 (C-3), 68.30 (C-5), 66.96 (C-6), 61.36 (C-4),
55.87 (OMe), 54.83 (C-2); wmax 3500, 3437 (NH), 2840
(MeO), 1712 (CꢁO, benzoate), 1649 (Amide I), 1528
H2O); Rf 0.40 (6:2:1:1 EtOAc–MeOH–AcOH–H2O); H
NMR (500 MHz, D2O): l 4.99 (d, 1H, J1,2=3.5 Hz, H-1),
4.26 (t, 1H, J2,3=10.1 Hz, J3,4=10.0 Hz, H-3), 3.97 (m,
2H, H-5, H-6a), 3.89 (dd, 1H, J5,6b=5.7 Hz, J6a,6b=12.8
Hz, H-6b), 3.35 (dd, 1H, H-2), 3.10 (t, 1H, J4,5=10.0 Hz,
H-4), 3.40 (s, 3H, OMe); 13C NMR (125.5 MHz, D2O):
l 96.46 (C-1), 69.25 (C-5), 65.99 (C-3), 62.63 (C-6), 62.20
+
(C-4), 56.17 (OMe), 54.96 (C-2); wmax 3450, 3217 (NH3 ,
OH), 2850 (MeO), 1604, 1512 (NH3 ), 1195, 1053 cm−1
+
(SO3 ). FABMS: m/z 302 ([M+2Na−H]+, 21%), 280
−
([M+Na]+, 49), 258 ([M+H]+, 47); HR–FABMS calcd for
C7H15NO7RbS [M+Rb]+ 341.9686, found 341.9714.
(Amide II), 1180, 1040 (SO3 ), 1600, 1580, 1450 cm−1
−
(phenyl); FABMS: m/z 1205 ([2M+Na]+, 16%), 614
([M+Na]+, 100), 592 ([M+H]+, 15), 528 ([M+H−SO2]+,
26), 510 ([M−SO3H]+, 14); Anal. calcd for
C28H26NO10SNa: C, 56.85; H, 4.43; N, 2.37; S, 5.42.
Found: C, 56.75; H, 4.04; N, 2.51; S, 5.24.
(b) Starting from methyl 2-benzamido-3,6-di-O-benzoyl-
2,4-dideoxy-a-D-galactopyranoside-4-sulfonate sodium
salt 10. A solution of 10 (415 mg, 0.7 mmol) in 2 M
aqueous sodium hydroxide (4 mL) was treated and
purified in the same way as described above to give 11
(113 mg, 63%).
3.5. Methyl 2-benzamido-3,6-di-O-benzoyl-2,4-dideoxy-
a- -galactopyranoside-4-C-sulfonate sodium salt 10
D
3.7. Crystallographic analysis of compound 11
To a solution of methyl 4-S-acetyl-2-benzamido-3,6-di-
O-benzoyl-2-deoxy-4-thio-a-
-galactopyranoside 825 (1
D
3.7.1. Experimental conditions for the crystal structure
determination of 11. Molecular formula, 2(C7H15NO7S·
H2O); molecular weight, 550.55; crystal system, mono-
clinic; space group, C2; unit-cell dimensions, a=
g, 1.8 mmol) and NaOAc (145 mg, 1.8 mmol) in AcOH
(10 mL) was added aqueous 33% w/v hydrogen peroxide
(1.48 mL, 16 mmol). After 8 h at 80°C, the solution was
concentrated to dryness and the residue (1.1 g) was
purified by column chromatography on Biogel P2 (1:1
MeOH–H2O) to give 10 (620 mg, 59%). The analytical
sample was recrystallized from EtOH; mp 196–198°C
(dec.); [h]2D0=+103 (c 1.0, MeOH); Rf 0.55 (5:1 CH2Cl2–
MeOH); 1H NMR (500 MHz, CD3OD): l 8.08–7.35 (m,
15H, Ar-H), 5.71 (m, 1H, J1,2=3.4 Hz, J2,3=11.1 Hz,
H-2), 5.65 (dd, 1H, J3,4=5.0 Hz, H-3), 5.03 (d, 1H, H-1),
5.03 (td, 1H, J6a,6b=12.2 Hz, J5,6a=8.5 Hz, H-6a), 4.75
(dd, 1H, J5,6b=1.7 Hz, H-6b), 4.62 (m, 1H, J4,5=2.4 Hz,
H-5), 4.09 (m, 1H, H-4), 3.40 (s, 3H, OMe); 13C NMR
(125.5 MHz, CD3OD): l 170.63 (CON), 168.05 and
,
21.452(4), b=7.506(1), c=13.931(2) A, i=90.6(1)°;
3
,
unit-cell volume, V, 2243.0(6) A ; formula units per unit
cell, Z=2; calculated density, Dcalcd, 1.63 g cm−3. Radi-
,
ation, MoKa; wavelength, 0.71069 A; F(000) value,
1168; absorption coefficient, v, 0.32 mm−1; temperature,
T, 293 K; crystal shape, prismatic; crystal size, 0.20×
0.40×0.40 mm; diffractometer, Enraf–Nonius CAD-4;
determination of unit cell, least squares; number of
reflections used, 25; q range, 2–15°; intensity data collec-
tion, w/2q scan mode; maximum q, 30°; range of h, k,
and l, −28 to 28, −8 to 8 and −16 to 4; standard
reflections; (−3 −1 −7), (−4 −2 −6) and (−4

J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 3761–3768
3767
−2 4); internal agreement, Rint 0.009; number of mea-
sured reflections 5748; number of significant reflections,
5351; criterion for significance, I>2|(I); number of
refined parameters, 307; final R, 0.04; final ꢀR(F2);
0.12, goodness-of-fit, S, 1.07.
9. Za¨hringer, U.; Moll, H.; Hettmann, T.; Knirel, Y. A.;
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Corrections were made for Lorentz polarization effects,
but not for extinction and absorption. This effect was
not taken into account because the crystal absorption
with Mo radiation was practically negligible. The struc-
ture was solved by direct methods using SIR42 to locate
all non-hydrogen atoms, and refinement based on F2
using SHELXL97.43 All H-atoms were included fixed in
the later refinement placed in geometrically calculated
positions. Atomic scattering factors were taken from
the International Tables for X-Ray Crystallography.44
The geometrical analysis was performed using
PARST.45
Crystallographic data (excluding structure factors) for
this structure have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publi-
cation number CCDC 199015. Copies of the data can
be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
11223-336033 or e-mail: deposit@ccdc.cam.ac.uk]
14. Matsumoto, Y.; Sahara, H.; Fujita, T.; Shimazawa, K.;
Takenouchi, M.; Torigoe, T.; Hanashima, S.; Yamazaki,
T.; Takahashi, S.; Sugawara, F.; Mizushina, Y.; Ohta,
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Acknowledgements
We thank the Direccio´n General de Ensen˜anza Supe-
rior e Investigacio´n Cient´ıfica (Grants No BQU 2001-
3740 and BFM 2002-3327), FEDER fundings and the
Junta de Andaluc´ıa (FQM123 and FQM134) for finan-
cial support. S.G. thanks El Monte for the award of a
fellowship.
16. Ferna´ndez-Bolan˜os, J. G.; Ulgar, V.; Maya, I.; Fuentes,
J.; Dia´nez, M. J.; Estrada, M. D.; Lo´pez-Castro, A.;
Pe´rez-Garrido, S. Tetrahedron: Asymmetry 2003, 14,
1009–1018.
17. Robina, I.; Go´mez-Bujedo, S.; Ferna´ndez-Bolan˜os, J. G.;
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18. Ulgar, V.; Maya, I.; Fuentes, J.; Ferna´ndez-Bolan˜os, J.
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