Synthesis of new C-sulfosugars and C-sulfoalditols: Amadori rearrangement of 6-C-sulfo-D-fucose

Article abstract of DOI:10.1016/S0957-4166(03)00160-5

The novel 6-deoxy-6-C-sulfo-D-galactose (6-sulfofucose) potassium salt was prepared by oxidation of 1,2,3-tri-O-acetyl-6-S-acetyl-4-O-benzoyl-6-deoxy-α-D-galactopyranose with hydrogen peroxide and potassium acetate in acetic acid. Its cyclohexylammonium s

Full text of DOI:10.1016/S0957-4166(03)00160-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1009–1018
Synthesis of new C-sulfosugars and C-sulfoalditols: Amadori
rearrangement of 6-C-sulfo- -fucose
D
Jose´ G. Ferna´ndez-Bolan˜os,a,* Victor Ulgar,a Ine´s Maya,a Jose´ Fuentes,a Ma6 Jesu´s Dia´nez,b
Ma6 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 553, E-41071, Sevilla, Spain
bInstituto de Ciencias de Materiales de Sevilla and Departamento de F´ısica de la Materia Condensada,
CSIC-Universidad de Sevilla, Apartado 1065, E-41071 Sevilla, Spain
Received 25 November 2002; accepted 22 January 2003
Abstract—The novel 6-deoxy-6-C-sulfo-
6-S-acetyl-4-O-benzoyl-6-deoxy-a- -galactopyranose with hydrogen peroxide and potassium acetate in acetic acid. Its cyclohexyl-
ammonium salt underwent a spontaneous conversion into 1-cyclohexylamino-1,6-dideoxy- -tagatofuranose-6-C-sulfonic acid 4
through an Amadori rearrangement. 6-Deoxy-6-C-sulfo- -glucose (sulfoquinovose) and 6-deoxy-6-C-sulfo- -galactose were
D-galactose (6-sulfofucose) potassium salt was prepared by oxidation of 1,2,3-tri-O-acetyl-
D
D
D
D
transformed into the corresponding 6-deoxy-6-C-sulfoalditols and 1-amino-1,6-dideoxy-6-C-sulfoalditols by reduction and
reductive amination, respectively. The a anomeric configuration of 4, crystallised as the monohydrate, was assigned by X-ray
4
crystallographic analysis. A conformation between E5 and T5 for the sugar ring, stabilised by a strong intramolecular hydrogen
bond between NH and O-4, was observed. © 2003 Elsevier Science Ltd. All rights reserved.
potent antitumor activities.12,13 These extensive biologi-
cal activities led to the synthesis of different SQDGs
1. Introduction
and SQMGs in order to study the structure–function
relationship as DNA polymerase inhibitors and as anti-
tumor agents.14–19 Anti-HIV activity of synthetic
SQDG has also been shown.20 The b-configuration
types of SQDG derivatives, not found in Nature, were
potent immunosuppressive agents without cytotoxic
side effects, indicating that they could be used clinically
for long periods.21,22
Sulfoquinovose is the carbohydrate constituent of the
sulfolipid sulfoquinovosyldiacylglycerol (SQDG, 1,2-di-
O-acyl-3-O-(a-D-sulfoquinovosyl)-glyceride), which is
present in photosynthetic plants, algae, protozoa, lichen
and bacteria,1 and which has also been isolated from
non-photosynthetic bacteria of the genus Rhizobium2
and from the eggs and sperm cells of the sea urchin
Pseudocentrotus depressus.3 Sulfoquinovose has been
recently identified in the asparagine-linked branched
hexasaccharide chains of a hemoprotein isolated from
the archaeon Sulfolobus acidocaldarius.4 A sulfofucose
derivative (glucosyl-3%,6%-disulfate)-6-sulfofucosyl diac-
ylglycerol was detected in Phaeophyta algae,5 although
the proposed structure was not confirmed by NMR.
Several syntheses of the parent sugar sulfoquinovose23–
25 and of sulfoquinovosyl glycerol24,26 have been
described. To our knowledge, no synthesis of 6-deoxy-
6-C-sulfo-D-galactose (6-sulfofucose) has been reported
hitherto; although a preparation of sulfofucosylac-
ylglycerol derivatives has been recently described and
proved to be active as DNA polymerase inhibitors.27
SQDG and SQMG (sulfoquinovosylmonoacylglycerol)
from natural products were reported to be potent mam-
malian DNA a- and b-polymerases, and terminal
deoxynucleotidyl transferase inhibitors.6–8 These sul-
folipids also showed P-selectine receptor inhibition,9
HIV-RT inhibition,7,10 AIDS antiviral activity11 and
Continuing our work in C-sulfosugar chemistry,28–32 we
present herein the first synthesis of sulfofucose 3 and
report the spontaneous conversion of its cyclohexylam-
monium salt into 6-deoxy-6-sulfo- -tagatosamine 4 via
D
an Amadori rearrangement. To our knowledge, this is
the second report on the synthesis of a C-sulfoamino-
hexulose; a crystalline 1-amino-1,3,4-trideoxy-4-sulfo-2-
* Corresponding author. Tel.: +34 95 4557151; fax: 34 95 4624960;
e-mail: bolanos@us.es
hexulose was obtained from D-glucosamine and sodium
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00160-5

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J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
bisulfite, via a sulfonated polyhydroxyalkylpyrazine
in the medium to give the imine B, which isomerises to
the ketose D via 1,2-enaminol C. Cyclization of D to
the furanose form E, followed by an acid–base equi-
librium between the cyclohexylammonium and the sec-
ondary amine affords the zwitterion 4. The
crystallisation of 4 acts as driving force displacing the
equilibrium totally towards the hexulose. Trying to
prepare the cyclohexylammonium salt of sulfo-
quinovose 5 we did not observe its transformation into
derivative.33
We also report the preparation of zwitterionic C-sul-
foaminopoliols 12 and 13 by reductive amination of
sulfofucose 3 and sulfoquinovose 5 with benzylamine,
followed by hydrogenolysis of the N-benzyl group.
These sulfoaminoalditols 12 and 13 can be considered
as polyhydroxylated homologues of the natural
aminoacid taurine, which has numerous physiological
functions,34,35 such as neurotransmitter,36 antioxidant,37
detoxificant,38 and it is involved in the process of cell
volume regulation.39 Pharmacologically, taurine can be
used in the treatment of cardiovascular diseases,40
hypercholesterolemia,41 atherosclerotic lesions,42 hyper-
tension,43 hepatic disorders,44 and alcoholism.45
the C-sulfo-D-fructosamine derivative.
13C NMR spectroscopy (Table 1) was used to confirm
the structure of 4, by comparison with the data
reported for
D D-tagato-
-tagatofuranose,48 and for the
furanose-related bicyclic Amadori compound 7.49 The
assignment of the signals was made by 2D spectroscopy
(H/H-COSY and H/C-COSY). According to integra-
1
tion of the H signals, 4 at equilibrium in D2O consists
of a- and b-furanose forms in a ratio of 8:5, whereas
2. Results and discussion
the a/b ratio is 2:5 for
D
-tagatofuranose,48 2:8 for
D
-tagatose 1,6-bisphosphate50 and ꢀ1:1 for 7.49 No
Sulfofucose 3 was prepared by oxidation with hydrogen
peroxide in glacial acetic acid29 of 1. This 6-thiogalac-
tose was obtained from peracetylated 4,6-benzylidene-
signals for the open-chain ketose or its hydrate were
detected. The marked increase of the content of the
a-anomer for 4 could be explained by favourable elec-
trostatic interactions between opposite charges of the
sulfo and the ammonium groups (Fig. 1).
a-D-galactopyranose following the procedure described
by Miljkovic46 via a 6-bromo derivative. Treatment of a
solution of 1 in glacial acetic acid with 34% (w/v)
hydrogen peroxide containing potassium acetate, pro-
duced
sulfo-a-
1,2,3-tri-O-acetyl-4-O-benzoyl-6-deoxy-6-C-
-galactose 2, which was deacylated with
2.1. Solid-state structure
D
NaOMe. Acidification with Amberlite IR-120(H+)
cation exchange resin and neutralisation with aqueous
KOH gave the potassium salt of sulfofucose 3 in 90%
The structure of 4 monohydrate, crystallised as a fura-
nose in the a anomeric configuration, was confirmed by
X-ray crystallographic analysis. An ORTEP51 view of
the molecule is shown in Fig. 2. The furanose ring is in
1
overall yield from 1 (Scheme 1). H NMR signals of 3
showed an a/b ratio of 34:66.
4
a conformation intermediate between E5 and T5. The
,
anomeric effect is observed [C(5)ꢀO(5)=1.447(4) A
,
Purification of 3 was attempted by crystallisation of the
cyclohexylammonium salt, as described for some sulfo-
quinovosides.26 Thus, the potassium salt was converted
into the free sulfonic acid using Amberlite IR-120(H+)
resin, and then cyclohexylamine was added until to pH
6. Solvent was removed and the residue slowly crys-
tallised (over a month) from H2O/EtOH at room tem-
perature to give a solid whose 1H and 13C NMR spectra
and O(5)ꢀC(2)=1.436(4) A]. The length of the three
,
SꢀO bonds are similar [from 1.436(4) to 1.454(3) A]
−
indicating that the negative charge on the SO3 is
delocalised over the three oxygen atoms.30 The bond
angles about the sulfonate group are similar to those
found in other sulfoaminosugars.29,30 The torsion
angles around the C-6ꢀS bond agree with the staggered
conformation, and the conformation around C-5ꢀC-6 is
trans-gauche (tg), whereas the found conformation for
6-sulfoquinovose derivatives in the pyranose form was
gauche-trans (gt).28,29
agree with the 6-C-sulfo- -tagatosamine derivative 4,
D
which was obtained in a 94% yield. We concluded that
the cyclohexylammonium salt of sulfofucose 3 under-
went an Amadori rearrangement.47
The a-anomeric configuration for 4, having the bulkier
group on C-2 on the crowded side of the ring, is
stabilised by a strong intramolecular hydrogen bond
NꢀH-1···O-4 (Table 2). The molecules form a compact
The formation of 4 is outlined in Scheme 2. The
open-chain aldehyde form of 6-C-sulfo- -fucose A
D
reacts with a minor amount of cyclohexylamine present
Scheme 1. Reagents and conditions: (i) (34% w/v) aq. H2O2, AcOH, KOAc (1 equiv.), 40°C, 16 h; (ii) NaOMe, MeOH, rt; (iii)
Amberlite IR-120(H+); (iv) aq. KOH (1 equiv.).

J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
1011
Scheme 2.
Table 1. 13C NMR data (l, ppm) for compounds 4 and 6 in D2O (75.5 MHz)
Compound
Anomer
C-1
C-2
C-3
C-4
C-5
C-6
4
a
b
58.07
58.16
103.17
100.15
78.56
73.18
72.25
71.92
75.56
75.86
50.71
51.76
648
a
b
62.64
62.86
105.10
102.71
76.92
70.90
71.43
71.27
79.41
80.24
60.29
61.20
Figure 1.
pates in a cooperative hydrogen bond system (O-
2ꢀH···O-3ꢀH···OWꢀH-1···O-62) involving three sugar
molecules and a water molecule. The third oxygen of
the sulfo group participates in a short contact interac-
tion with the water molecule (OWꢀH-2···O-61).
structure where a water-of-hydration molecule accepts
and donates H-bonds to symmetry related pairs of
molecules. The molecular packing is shown in Fig. 3.
The sulfoamino acid molecules are associated as dimers
with the oxygen of the sulfo group of one unit involved
as acceptor of the hydrogen bond to the ammonium
group of the other unit [NꢀH-2···O-63(i)], and vice
versa. The second oxygen of the sulfo group partici-
C-Sulfosugars 3 and 5 were used as starting materials
for the preparation of 6-C-sulfoalditols and 1-amino-6-

1012
J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
Figure 3. The packing for 4 viewed down the a axis. Hydro-
gen bonds are indicated by dashed lines.
Figure 2. ORTEP view of 4 showing the atomic numbering.
The ellipsoids enclose 50% probability.
C-sulfoalditols. Thus, treatment of an aqueous solution
of 3 with NaBH4 at 5°C, followed by acidification with
Amberlite IR-120(H+) resin and neutralisation with
with methanol was needed to cleave the boron com-
plexes formed during the reduction and to remove the
boric acid as its trimethylester. The second step was the
catalytic hydrogenolysis of the N-benzyl group to give
the N-deprotected compounds 12 and 13. Treatment of
an aqueous solution of 10 and 11 with atmospheric
hydrogen in the presence of 10% Pd/C at room temper-
ature for 12 h gave 12 and 13 in 96 and 90% yield,
respectively, after recrystallisation from MeOH–H2O.
aqueous KOH afforded 6-deoxy-C-sulfo-
potassium salt 8, in 93% yield after purification by
gel-filtration chromatography. Its isomer of -gluco
D-galactitol
D
configuration 9 (94%) was prepared from 5 using the
same procedure (Scheme 3).
A number of methods for the synthesis of 1-aminoaldi-
tols by reductive amination of reducing sugars has
previously been reported.52 We carried out the synthesis
of 1-amino-6-C-sulfoalditols 12 and 13 by the reductive
amination method with benzylamine previously used
for the synthesis of galactamine53 and of 1-aminoaldi-
tols derived from disaccharides.52 Reaction of 3 with an
excess of benzylamine at 60°C to form the imine inter-
mediate, followed by reduction with NaBH4 at 5°C and
finally treatment with Amberlite IR-120(H+) resin gave
the zwitterionic 1-benzylamino-1-deoxy derivative 10 in
50% overall yield after recrystallisation from MeOH–
H2O. Reaction of 5 under the same conditions gave the
The conformations of compounds 9–12 in D2O solu-
tions at room temperature were studied by H NMR
1
spectroscopy. Compound 8 was not included due to the
1
extensive signal overlapping observed in the H NMR
3
spectrum. In the
D
-galacto series, the JH,H values
(Table 3) for 12 indicate a zig-zag planar conformation
P54 in equilibrium with the conformations G+ and G−
1
5
(Fig. 4) associated with the chain-end flexibility;
whereas for compound 10 the chain end bearing the
N-benzyl group is mainly in the extended form (J1a,2 9.8
Hz, J1b,2 3.1 Hz). The symbolism G− denotes a sickle
n
conformation obtained by a 120° clockwise rotation of
the remote atom along the CnꢀCn+1 bond.
D
-gluco isomer 11 in 48% yield (Scheme 3). Acidifica-
tion to pH 1 with the resin followed by co-evaporation
Table 2. Geometry of the hydrogen-bonding system and short contacts for 4
Acceptor symmetry codea
D···A (A)
DꢀH (A)
H···A (A)
DꢀH···A (°)
,
,
,
Donor–H···acceptor
O-3···OW
(0)b
(0)b
(i)
(ii)
(iii)
(iv)
2.652(5)
2.773(4)
2.753(5)
2.700(4)
2.776(7)
3.048(8)
0.82
0.90
0.90
0.82
0.85
0.86
1.86
1.93
1.90
1.91
2.03
2.60
161
156
158
161
146
114
NꢀH-1···O-4
NꢀH-2···O-63
O-2···O-3
OWꢀH-1···O-62
OWꢀH-2···O-61
a Symmetry code: (0) x, y, z; (i) x−1/2, −y+1/2, −z+1; (ii) x−1, y, z; (iii) x+1/2, −y+3/2, −z+1; (iv) x−1/2, −y+3/2, −z+1.
b Intramolecular hydrogen bonds.

J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
1013
Scheme 3. Reagents and conditions: (i) NaBH4, H2O, 5°C, 12 h; (ii) Amberlite IR-120(H+), pH 1; (iii) aq. KOH (1 equiv.); (iv)
BnNH2/H2O, 60°C, 4 h; (v) H2, 10% Pd(C), H2O, rt, 12 h.
Table 3. Coupling constants (J, Hz) for compounds 8–13 in D2O (500 MHz)
J1a,2
J1b,2
J1a,1b
J2,3
J3,4
J4,5
J5,6a
J5,6b
J6a,6b
Glucitol54
9
10
11
12
13
4.3
3.5
9.8
3.4
7.7
3.3
6.6
5.8
3.1
9.6
5.0
9.4
5.4
5.7
1.5
4.8
1.6
4.8
2.5
2.4
9.5
2.9
9.5
2.9
7.7
7.5
1.3
7.2
1.4
7.2
3.3
1.9
5.1
2.1
5.1
2.1
6.2
9.4
7.2
9.2
7.2
9.1
11.8
13.0
12.9
–
14.6
14.4
14.6
–
13.1
14.6
In the
vicinal coupling constants indicate an increased confor-
mational mobility compared with -galacto isomers,
D
-gluco series (9, 11, 13, and
D
-glucitol55) the
3. Conclusion
D
Cyclohexylammonium salt of 6-C-sulfofucose 3, pre-
pared by oxidation of a peracylated 6-thiogalactose
derivative 1, undergoes a spontaneous Amadori rear-
rangement to yield the highly crystalline 6-deoxy-6-C-
sulfotagosamine 4. X-Ray analysis of 4 reveals its
a-furanose form in solid state, stabilised by an extensive
system of hydrogen bonds. Zwitterionic 1-amino-1,6-
dideoxy-6-C-sulfoalditols 12 and 13 can be prepared by
reductive amination with benzylamine of 6-C-sulfofu-
due to the unfavourable 1,3-parallel interaction
between OH-2 and OH-4 present in the P rotamer. The
rather large values observed for J2,3 (4.8–5.7 Hz) sup-
port the participation of the rotamer G−. Zwitterionic
compounds 11, 13 show the two chain2ends in extended
arrangements, whereas 9 presents the expected flexibil-
ity around C-1ꢀC-2 bond (1G+ rotamer, Fig. 5), and
D
-glucitol shows that flexibility for both ends.

1014
J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
Figure 5. Conformational equilibrium of
D-glucitol derivatives
Figure 4. Conformational equilibrium of
tives 10 (R=Bn) and 12 (R=H).
D-galactitol deriva-
9 (R=OH), 11 (R=NH2Bn+), and 13 (R=NH3+).
cose 3 and 6-C-sulfoquinovose 5, and subsequent cata-
lytic hydrogenation.
4.1. Potassium 6-deoxy-
nate 3
D
-galactopyranose-6-C-sulfo-
To a solution of 1,2,3-tri-O-acetyl-6-S-acetyl-4-O-ben-
zoyl-6-deoxy-a-
-galactopyranose 146 (1.38 g, 2.96
4. Experimental
D
mmol) in glacial acetic acid (15 mL) was added potassium
acetate (0.29 g, 2.96 mmol) and 34% hydrogen peroxide
(2.8 mL, 35.6 mmol). The mixture was heated at 40°C
for 16 h and the resulting solution was concentrated to
dryness, coevaporating several times with water to afford
crude 2. The residue was dried overnight in vacuum over
P2O5, then dissolved in dry methanol (20 mL) and 0.1 M
NaOMe was added up to pH 9–10. After 6 h at room
temperature, the solution was diluted with water and
taken to pH 0–1 using Amberlite IR-120(H+) cation
exchange resin. Resin was filtered off and washed, and
the combined filtrate and washings were taken to pH 7
using aqueous 0.1 M KOH. The solution was concen-
trated to dryness and the residue was lyophilised to
afford 3 as a yellowish foam (757 mg, 90%). An analytical
sample was obtained by gel-filtration chromatography.
Rf 0.30 (iPrOH/MeOH/H2O, 3:2:1); [h]D +43 (c 1.1,
H2O); 1H NMR (300 MHz, D2O): l 5.15 (d, 1H, J1,2=3.8
Hz, H-1a), 4.52 (d, 1H, J1,2=7.9 Hz, H-1b), 4.39 (dddd,
1H, J1,5=0.5 Hz, J4,5=1.2 Hz, J5,6a=4.7 Hz, J5,6b=7.3
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 disks) were obtained with an FT-IR
1
Bomem MB-120 spectrophotometer. H (300 and 500
MHz) and 13C (75.5 and 125.7 MHz) NMR spectra were
recorded on Bruker AMX-300 and AMX-500 spectrom-
eters for solutions in D2O (internal DOH at 4.75 ppm and
internal 1,4-dioxane at 67.4 ppm). The assignments of 1H
and 13C signals were confirmed by homonuclear COSY
and heteronuclear 2D correlated spectra, respectively.
Mass spectra were recorded on Kratos MS 80 RFA and
Micromass AutoSpeQ mass spectrometers. TLC was
performed on aluminium pre-coated sheets (E. Merck
silica gel 60 F254); spots were visualised by UV light and
by charring with 10% H2SO4 in EtOH. Gel-filtration
chromatography was performed on a 47×3.5 cm column,
using Biogel P2 as stationary phase and 1:1 MeOH–H2O
as eluent. Microanalyses were performed at ‘Instituto de
Investigaciones Qu´ımicas de la Cartuja’, Seville, Spain.

J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
1015
Hz, H-5a), 3.97 (ddd, 1H, J4,5=0.9 Hz, J5,6a=4.9 Hz,
5,6b=6.8 Hz, H-5b), 3.89 (dd, 1H, J3,4=3.3 Hz, H-4a),
3.86 (dd, 1H, J3,4=3.4 Hz, H-4b), 3.81 (dd, 1H, J2,3
l 4.38 (bt, 1H, H-5), 3.94 (bt, 1H, H-2), 3.66 (m, 4H,
H-1a, H-1b, H-3, H-4), 3.16 (d, 2H, 1/2(J5,6a+J5,6b)=6.2
Hz, H-6a, H-6b); 13C NMR (75.5 MHz, D2O): l 71.70
(C-4), 70.31 (C-2), 69.50 (C-3), 66.45 (C-5), 63.37 (C-1),
54.70 (C-6); IR: wmax 3355 (OH), 1219 and 1050 (SO2)
cm−1; FAB-MS: m/z 269 [100, (M−K+Na+H)+], 291
[50, (M−K+2Na)+], 307 [54, (M+Na)+]; HRFAB-MS
calcd for C6H13KNaO8S [M+Na]+ 306.9866, found
306.9867.
J
=
10.3 Hz, H-3a), 3.69 (dd, 1H, H-2a), 3.60 (dd, 1H,
J
J
2,3=10.0 Hz, H-3b), 3.38 (dd, 1H, H-2b), 3.17 (dd, 1H,
6a,6b=14.6 Hz, H-6ab), 3.12 (dd, 1H, J6a,6b=14.6 Hz,
H-6aa), 3.09 (dd, 1H, H-6bb), 3.05 (dd, 1H, H-6ba);
13C NMR (75.5 MHz, D2O): l 96.53 (C-1b), 92.40
(C-1a), 72.75 (C-3b), 71.60 (C-2b), 71.18 (C-5b), 71.12
(C-4a), 70.50 (C-4b), 69.20 (C-3a), 68.12 (C-2a), 66.66
(C-5a), 52.19 (C-6a), 52.04 (C-6b); IR: wmax 3370 (OH),
1187 and 1048 (SO2) cm−1; FAB-MS: m/z 305 [100,
(M+Na)+]; HRFAB-MS calcd for C6H11Na2O8S (M−
K+2Na)+ 288.9970, found 288.9982.
4.3.2. Potassium 6-deoxy- -glucitol-6-C-sulfonate 9.
D
Yield: 94 mg (94%); Rf 0.39 (iPrOH/MeOH/H2O,
1
3:1:1); [h]D +6 (c 1.0, H2O); H NMR (300 MHz, D2O):
l 4.15 (ddd, 1H, J4,5=7.5 Hz, J5,6a=1.9 Hz, J5,6b=9.4
Hz, H-5), 3.84 (dd, 1H, J2,3=5.7 Hz, J3,4=2.4 Hz,
H-3), 3.80 (m, 1H, J1a,2=3.5 Hz, J1b,2=5.8 Hz, H-2),
3.71 (dd, 1H, J1a,1b=11.8 Hz, H-1a), 3.60 (dd, 1H,
H-6b), 3.59 (dd, 1H, H-4), 3.33 (dd, 1H, J6a, 6b=14.6
Hz, H-6a), 3.00 (dd, 1H, H-6b); 13C NMR (75.5 MHz,
D2O): l 73.12 (C-4), 72.94 (C-2), 69.57 (C-3), 67.87
(C-5), 62.56 (C-1), 53.97 (C-6); IR: wmax 3317 (OH),
1204 and 1045 (SO2) cm−1; FAB-MS: m/z 269 [64,
(M−K+Na+H)+], 291 [100, (M−K+2Na)+], 307 [20,
(M+Na)+]; HRFAB-MS calcd for C6H13KNaO8S [M+
Na]+ 306.9866, found 306.9865.
4.2. 1-Cyclohexylamino-1,6-dideoxy-a-
D-tagatofuranose-
6-C-sulfonic acid 4
To a solution of 3 (262 mg, 0.93 mmol) in water (5 mL)
was added Amberlite IR-120(H+) cation exchange resin
up to pH 0–1. The resin was filtered off and washed,
and the combined filtrate and washings were taken to
pH 6 using cyclohexylamine (ca. 0.11 mL). The solution
was concentrated to dryness coevaporating several
times with absolute ethanol, and the resulting residue
was slowly crystallised from H2O/EtOH 1:1 (8 mL) to
afford a first crop of 4. Mother liquors were concen-
trated to dryness and the residue was crystallised from
H2O/EtOH 1:3 (4 mL) to give a second crop of 4. Total
yield: 300 mg (94%); Rf 0.50 (iPrOH/MeOH/H2O,
4.4. General procedure for the synthesis of 1-benzyl-
amino-1,6-dideoxy- -alditol-6-C-sulfonic acids 10, 11
D
1
To a solution of 6-deoxy-6-C-sulfo-D-aldopyranose
3:2:1); mp 224–226°C; [h]D +31 (c 0.6, H2O); H NMR
(300 mg, 1.06 mmol) in water (3 mL) was added
benzylamine (0.58 mL, 5.31 mmol), and the mixture
was stirred at 60°C for 4 h. The resulting solution was
cooled at 0°C and NaBH4 (80 mg, 2.11 mmol) was
added. The reaction was left at 5°C overnight and
Amberlite IR-120(H+) cation exchange resin was added
up to pH 0–1. The resin was filtered off and washed,
and the combined filtrate and washings were concen-
trated to dryness, coevaporating several times with
methanol. The residue was washed with hot methanol
(3 mL) to afford the crude products that were recrys-
tallised from H2O/MeOH. The following compounds
were prepared in this manner.
(300 MHz, D2O): l 4.57 (m, 1H, H-5a), 4.40–4.33 (m,
3 H, H-4a, H-3a, H-5b), 4.25 (dd, 1H, J3,4=4.6 Hz,
J4,5=3.6 Hz, H-4b), 4.12 (d, 1H, H-3b), 3.31–3.10 (m,
8H, H-1aa, H-1ab, H-1ba, H-1bb, H-6aa, H-6ab, H-
6ba, H-6bb), 2.04–1.11 (m, 22H, cyclohexyl); 13C NMR
(75.5 MHz, D2O): Table 1 and 28.84, 28.73, 28.68,
24.58, 24.17, 23.97 (cyclohexyl); IR: wmax 3468, 3333,
3079 (NH2 , OH), 1164 and 1053 (SO2) cm−1; FAB-MS:
+
m/z 326 [100, (M+H)+]. Anal. calcd for C12H23NO7S: C,
44.30; H, 7.12; N, 4.30. Found: C, 44.27; H, 6.82; N,
4.62.
4.3. General procedure for the synthesis of potassium
6-deoxy- -alditol-6-C-sulfonates 8 and 9
D
4.4.1. 1-Benzylamino-1,6-dideoxy- -galactitol-6-C-sul-
D
To a solution of 6-deoxy-6-C-sulfo-
D
-aldopyranose
fonic acid 10. Yield: 179 mg (50%); Rf 0.63 (iPrOH/
MeOH/H2O, 2:1:1); mp 216–218°C (from H2O/MeOH,
(100 mg, 0.35 mmol) in water (1 mL) cooled at 0°C was
added a solution of NaBH4 (15 mg, 0.40 mmol) in
water (0.5 mL). After 12 h at 5°C, Amberlite IR-120(H+)
cation exchange resin was added up to pH 0–1. The
resin was filtered off and washed, and the combined
filtrate and washings were concentrated to dryness,
coevaporating several times with methanol. The residue
was dissolved in water and the solution was neutralised
using aqueous 0.1 M KOH and lyophilised to give
crude products that were purified by gel-filtration chro-
matography. The following compounds were prepared
in this manner.
1
2:1); [h]D −19 (c 1.0, H2O); H NMR (500 MHz, D2O):
l 7.54 (s, 5H, Aromatic), 4.41 (ddd, 1H, J4,5=1.3 Hz,
J5,6a=5.1 Hz, J5,6b=7.2 Hz, H-5), 4.35 (s, 2H, CH2Ph),
4.28 (ddd, 1H, J1a,2=9.8 Hz, J1b,2=3.1 Hz, J2,3=1.5
Hz, H-2), 3.73 (dd, 1H, J3,4=9.5 Hz, H-4), 3.64 (dd,
1H, H-3), 3.32 (dd, 1H, J1a,1b=13.0 Hz, H-1a), 3.25
(dd, 1H, H-1b), 3.22 (dd, 1H, J6a,6b=14.4 Hz, H-6a),
3.19 (dd, 1H, H-6b); 13C NMR (125.5 MHz, D2O): l
131.81, 131.12, 130.95, 130.53 (aromatics), 72.63 (C-4),
71.66 (C-3), 67.36 (C-5), 66.94 (C-2), 55.63 (C-1), 52.37
(CH2Ph), 51.13 (C-1); wmax 3406, 3270 (OH), 2936, 2801
(NH2 ), 1201 and 1050 (SO2) cm−1; FAB-MS: m/z 336
+
4.3.1. Potassium 6-deoxy-
D
-galactitol-6-C-sulfonate 8.
[100, (M+H)+]. Anal. calcd for C13H21NO7S: C, 46.55;
H, 6.31; N, 4.18; S, 9.56. Found: C, 46.28; H, 6.35; N,
4.28; S, 9.99.
Yield: 93 mg (93%); Rf 0.48 (iPrOH/MeOH/H2O,
1
3:1:1); [h]D −3 (c 1.1, H2O); H NMR (300 MHz, D2O):

1016
J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
4.4.2. 1-Benzylamino-1,6-dideoxy-
D
-glucitol-6-C-sulfonic
4.6. Crystallographic analysis of compound 4
acid 11. Yield: 172 mg (48%); Rf 0.64 (iPrOH/MeOH/
H2O, 2:1:1); mp 266–268°C (from H2O/MeOH, 2:1);
4.6.1. Experimental conditions for the crystal structure
1
[h]D −10.3 (c 1.2, H2O); H NMR (500 MHz, D2O): l
determination
of
4.
Molecular
formula,
4.12 (ddd, 1H, J4,5=7.2, J5,6a=2.1, J5,6b=9.2 Hz, H-5),
4.06 (ddd, 1H, J1a,2=3.4, J1b,2=9.6, J2,3=4.8 Hz, H-2),
3.76 (dd, 1H, J3,4=2.9 Hz, H-3), 3.56 (dd, 1H, H-4),
3.28 (dd, 1H, J6a,6b=14.6 Hz, H-6a), 3.21 (dd, 1H,
C12H23NO7S.H2O; molecular weight, 343.391; crystal
system, orthorhombic; space group, P212121; unit-cell
,
dimensions, a=5.653(2), b=10.331(1), c=26.056(3) A;
3
,
unit-cell volume, V, 1521.5(5) A ; formula units per
J
1a,1b=12.9 Hz, H-1a), 3.15 (dd, 1H, H-1b), 2.97 (dd,
unit cell, Z 4; calculated density, Dcalcd, 1.50 g cm−3.
1H, H-6b); 13C NMR (125.5 MHz, D2O): l 131.74,
131.14, 130.98, 130.55 (aromatics), 73.81 (C-4), 71.64
(C-3), 69.13 (C-2), 69.03 (C-5), 54.92 (C-6), 52.34
(CH2Ph), 50.13 (C-1); wmax 3477, 3403 (OH), 3011,
Radiation, MoKa; wavelength, 0.71069 A; F(000)
,
value, 736; absorption coefficient, v, 0.254 mm−1; tem-
perature, 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; num-
ber of reflections used, 25; q range, 7–14°; intensity data
collection, w/2q scan mode; maximum q, 25°; range of
h, k, and l, −7 to 0, −1 to 14 and 0 to 36; standard
reflections; (−2 2 4), (−1 1 9) and (−1 −1 11); internal
agreement, Rint 0.006; number of measured reflections
2567; number of significant reflections, 2110; criterion
for significance, I>2|(I); number of refined parameters,
199; final R, 0.05; final ꢀR(F2), 0.18, goodness-of-fit S
1.058.
2790, 2634 (NH2 ), 1171 and 1048 (SO2) cm−1; FAB-
+
MS: m/z 336 [100, (M+H)+], 670 [16, (2M+H)+]. Anal.
calcd for C13H21NO7S: C, 46.55; H, 6.31; N, 4.18; S,
9.56. Found: C, 46.42; H, 6.12; N, 4.19; S, 9.45.
4.5. General procedure for the synthesis of 1-amino-1,6-
dideoxy- -alditol-6-C-sulfonic acids 12 and 13
D
A solution of 1-benzylamino-1,6-dideoxy-D-alditol-6-C-
sulfonic acid (100 mg, 0.29 mmol) in water (3 mL) was
hydrogenated at atmospheric pressure by stirring with
10% Pd(C) catalyst for 12 h at rt. After filtration of the
mixture through a thin Celite pad, the solution is
concentrated to dryness to afford the crude products
that were recrystallised from H2O/MeOH. The follow-
ing compounds were prepared in this manner.
Corrections were made for Lorentz polarisation 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 SIR56 to locate
all non-hydrogen atoms, and refinement based on F2
using SHELXL97.57 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.58
The geometrical analysis was performed using
PARST.59
4.5.1.
1-Amino-1,6-dideoxy-D-galactitol-6-C-sulfonic
acid 12. Yield: 68 mg (96%); Rf 0.13 (iPrOH/MeOH/
H2O, 2:1:1); mp 245–247°C (H2O/MeOH, 1:1); [h]D −13
1
(c 1.0, H2O); H NMR (500 MHz, D2O): l 4.38 (ddd,
1H, J4,5=1.4 Hz, J5,6a=5.1 Hz, J5,6b=7.2 Hz, H-5),
4.17 (dd, 1H, J1a,2=7.7 Hz, J1b,2=5.0 Hz, J2,3=1.6 Hz,
H-2), 3.70 (dd, 1H, J3,4=9.5 Hz, H-4), 3.64 (dd, 1H,
H-3), 3.17 (m, 4H, H-1a, H-1b, H-6a, H-6b); 13C NMR
(125.5 MHz, D2O): l 72.71 (C-4), 71.79 (C-3), 67.72
(C-2), 67.41 (C-5), 55.67 (C-6), 44.01 (C-1); wmax 3428,
Crystallographic data (excluding structure factors) for
this structure have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publi-
cation number CCDC 196071. 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].
3166, 3102 (NH2 , OH), 1172 and 1037 (SO2) cm−1;
+
FAB-MS: m/z 246 [100, (M+H)+)]. Anal. calcd for
C6H15NO7S·H2O: C, 27.38; H, 6.51; N, 5.32; S, 12.18.
Found: C, 27.80; H, 6.61; N, 5.19; S, 12.73.
Acknowledgements
4.5.2. 1-Amino-1,6-dideoxy- -glucitol-6-C-sulfonic acid
D
13. Yield: 64 mg (90%); Rf 0.13 (iPrOH/MeOH/H2O,
2:1:1); mp 216–218°C (H2O/MeOH, 1:1); [h]D −5 (c 1.0,
We thank the Direccio´n General de Ensen˜anza Supe-
rior e Investigacio´n Cient´ıfica (Grants No PB PB-98-
1126 and BQU 2001-3740) and the Junta de Andalucia
(FQM123 and FQM134) for financial support. V.U.
thanks the Ministerio de Educacio´n y Cultura for the
award of a fellowship. This work is part of the
European Programme COSTD13, action number D13/
0001/98.
1
H2O); H NMR (500 MHz, D2O): l 4.15 (ddd, 1H,
J4,5=7.2 Hz, J5,6a=2.1 Hz, J5,6b=9.1 Hz, H-5), 4.01
(ddd, 1H, J1a,2=3.3 Hz, J1b,2=9.4 Hz, J2,3=4.8 Hz,
H-2), 3.82 (dd, 1H, J3,4=2.9 Hz, H-3), 3.62 (dd, 1H,
H-4), 3.31 (dd, 1H, J6a,6b=14.6 Hz, H-6a), 3.20 (dd,
1H, J1a,1b=13.1 Hz, H-1a), 3.08 (dd, 1H, H-1b), 3.01
(dd, 1H, H-6b); 13C NMR (125.5 MHz, D2O): l 74.04
(C-4), 71.68 (C-3), 69.96 (C-2), 69.04 (C-5), 54.91 (C-6),
+
43.03 (C-1); wmax 3475, 3390, 3281, 3158 (NH2 , OH),
1172 and 1041 (SO2) cm−1; FAB-MS: m/z 246 [100,
(M+H)+], 491 [12, (2M+H)+]. Anal. calcd for
C6H15NO7S: C, 29.38; H, 6.16; N, 5.71; S, 13.07.
Found: C, 29.13; H, 6.11; N, 5.52; S, 13.34.
References
1. (a) Harwood, J. L. In The Biochemistry of Plants;
Stumpf, A., Ed.; Academic Press: New York, 1990; pp.

J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
1017
20. Gordon, D. M.; Danishefsky, S. J. J. Am. Chem. Soc.
1992, 114, 659–663.
301–320; (b) Okanenko, A. In Sulfur Nutrition and Sulfur
Assimilation in Higher Plants; Brunold, C.; Rennenberg,
H.; De Kok, L. J.; Stulen, I.; Davidian, J. C., Eds.; Paul
Haupt: Bern, Switzerland, 2000; pp. 203–216.
2. (a) Cedergren, R. A.; Hollingsworth, R. I. J. Lipid Res.
1994, 35, 1452–1461; (b) Wang, J.; Hollingsworth, R. I.
Carbohydr. Res. 1998, 307, 347–350.
21. Matsumoto, Y.; Sahara, H.; Fujita, T.; Hanashima, S.;
Yamazaki, T.; Takahashi, S.; Sugawara, F.; Mizushina,
Y.; Ohta, K.; Takahashi, N.; Jimbow, K.; Sakaguchi, K.;
Sato, N. Transplant. Proc. 2000, 32, 2051–2053.
22. Matsumoto, Y.; Sahara, H.; Fujita, T.; Shimazawa, K.;
Takenouchi, M.; Torigoe, T.; Hanashima, S.; Yamazaki,
T.; Takahashi, S.; Sugawara, F.; Mizushina, Y.; Ohta,
K.; Takahashi, N.; Gasa, S.; Jimbow, K.; Sakaguchi, K.;
Sato, N. Transplant 2002, 74, 261–267.
23. Ohle, H.; Mertens, W. Ber. Dtsch. Chem. Ges. 1935, 68,
2176–2187.
24. Miyano, M.; Benson, A. A. J. Am. Chem. Soc. 1962, 84,
59–62.
3. Isono, Y.; Mohri, H.; Nagai, Y. Nature 1967, 214, 1336–
1338.
4. Za¨hringer, U.; Moll, H.; Hettmann, T.; Knirel, Y. A.;
Scha¨fer, G. Eur. J. Biochem. 2000, 267, 4144–4149.
5. (a) Liem, P. Q.; Laur, M.-H. Biochim 1976, 58, 1367–
1380; (b) Kleppinger-Sparace, K. F.; Sparace, S. A.;
Mudd, J. B. In Sulfur Nutrition and Sulfur Assimilation in
Higher Plants; Rennenberg, H.; Brunold, C.; De Kok, L.
J.; Stulen, I., Eds.; SPB Academic Publishing: The
Hague, The Netherlands, 1990; pp. 77–88.
6. Mizushina, Y.; Watanabe, I.; Ohta, K.; Takemura, M.;
Sahara, H.; Takahashi, N.; Gasa, S.; Sugawara, F.; Mat-
sukage, A.; Yoshida, S.; Sakaguchi, K. Biochem. Pharma-
col. 1998, 55, 537–541.
7. Ohta, K.; Mizushina, Y.; Hirata, N.; Takemura, M.;
Sugawara, F.; Matsukage, A.; Yoshida, S.; Sakaguchi, K.
Chem. Pharm. Bull. 1998, 46, 684–686.
8. Ohta, K.; Mizushina, Y.; Hirata, N.; Takemura, M.;
Sugawara, F.; Matsukage, A.; Yoshida, S.; Sakaguchi, K.
Biol. Pharm. Bull. 1999, 22, 111–116.
9. Golik, J.; Dickey, J. K.; Todderud, G.; Lee, D.; Alford,
J.; Huang, S.; Klohr, S.; Eustice, D.; Aruffo, A.; Agler,
M. L. J. Nat. Prod. 1997, 60, 387–389.
10. Loya, S.; Reshef, V.; Mizrachi, E.; Silberstein, C.;
Rachamin, Y.; Carmeli, S.; Hizi, A. J. Nat. Prod. 1998,
61, 891–895.
11. Gustafson, K. R.; Cardellina, J. H., II; Fuller, R. W.;
Weislow, O. S.; Kiser, R. F.; Snader, K. M.; Patterson,
G. M. L.; Boyd, M. R. J. Natl. Cancer Inst. 1989, 81,
1254–1258.
12. Sahara, H.; Ishikawa, M.; Takahashi, N.; Ohtani, S.;
Sato, N.; Gasa, N.; Akino, T.; Kikuchi, K. British J.
Cancer 1997, 75, 324–332.
25. Roy, A. B.; Hewlins, M. J. E. Carbohydr. Res. 1997, 302,
113–117.
26. Roy, A. B.; Hewlins, M. J. E. Carbohydr. Res. 1998, 310,
173–176.
27. Yamazaki, T.; Sugawara, F.; Ohta, K.; Masaki, K.;
Nakayama, K.; Sakaguchi, K. Jpn Pat. WO 2000,052,021
A1; Chem. Abstr. 2000, 133, 208123.
28. (a) Ferna´ndez-Bolan˜os, J.; Maya Castilla, I.; Ferna´ndez-
Bolan˜os Guzma´n, J. Carbohydr. Res. 1986, 147, 325–329;
(b) Ferna´ndez-Bolan˜os, J.; Maya Castilla, I.; Ferna´ndez-
Bolan˜os Guzma´n, J. Carbohydr. Res. 1988, 173, 33–40.
29. Ferna´ndez-Bolan˜os, J. G.; Morales, J.; Garc´ıa, S.;
Dia´nez, M. J.; Estrada, M. D.; Lo´pez-Castro, A.; Pe´rez,
S. Carbohydr. Res. 1993, 248, 1–14.
30. Ferna´ndez-Bolan˜os, J. G.; Garc´ıa, S.; Ferna´ndez-
Bolan˜os, J.; Dia´nez, M. J.; Estrada, M. D.; Lo´pez-
Castro, A.; Pe´rez, S. Carbohydr. Res. 1996, 282, 137–147.
31. Robina, I.; Go´mez-Bujedo, S.; Ferna´ndez-Bolan˜os, J. G.;
Fuentes, J. Synth. Commun. 1998, 28, 2379–2397.
32. Ulgar, V.; Maya, I.; Fuentes, J.; Ferna´ndez-Bolan˜os, J.
G. Tetrahedron 2002, 58, 7967–7973.
33. Fujii, S.; Kosaka, Y. J. Org. Chem. 1982, 47, 4772–4774.
34. Kalir, A.; Kalir, H. H. In The Chemistry of Sulfonic
Acids, Esters and their Derivatives; Patai, S.; Rappoport,
Z., Eds.; John Wiley: Chichester, 1991; pp. 767–787.
35. Huxtable, R. J. Physiol. Rev. 1992, 72, 101–163.
36. Vitarella, D.; DiRisio, D. J.; Kimelberg, H. K.; Aschner,
M. J. Neurochem. 1994, 63, 1143–1149.
13. Quasney, M. E.; Carter, L. C.; Oxford, C.; Watkins, S.
M.; Gershwin, M. E.; German, J. B. J. Nutr. Biochem.
2001, 12, 310–315.
14. Hanashima, S.; Mizushina, Y.; Yamazaki, T.; Ohta, K.;
Takahashi, S.; Koshino, H.; Sahara, H.; Sakaguchi, K.;
Sugawara, F. Tetrahedron Lett. 2000, 41, 4403–4407.
15. Hanashima, S.; Mizushina, Y.; Ohta, K.; Yamazaki, T.;
Sugawara, F.; Sakaguchi, K. Jpn. J. Cancer Res. 2000,
91, 1073–1083.
37. (a) Ogasawara, M.; Nakamura, T.; Koyama, I.; Nemoto,
M.; Yoshida, T. In Taurine in Health and Disease;
Huxtable, R. J.; Michalk, D. V., Eds.; Plenum Press:
New York, 1994; pp. 71–78; (b) Eppler, B.; Dawson, R.,
Jr. Biochem. Pharmacol. 2002, 63, 1051–1060.
38. Hwang, D. F.; Wang, L. C. Toxicology 2001, 167, 173–
180.
16. Ohta, K.; Hanashima, S.; Mizushima, Y.; Yamazaki, T.;
Saneyoshi, M.; Sugawara, F.; Sakaguchi, K. Mutat. Res.
2000, 467, 139–152.
17. Ohta, K.; Mizushima, Y.; Yamazaki, T.; Hanashima, S.;
Sugawara, F.; Sakaguchi, K. Biochem. Biophys. Res.
Commun. 2001, 288, 893–900.
39. Pasantes-Morales, H.; Quesada, O.; Moran, J. Adv. Exp.
Med. Biol. 1998, 442, 209–217.
40. Yamori, Y.; Liu, L.; Ikeda, K.; Miura, A.; Mizushima,
S.; Miki, T.; Nara, Y. Hypertens. Res. 2001, 24, 453–457.
41. Mochizuki, H.; Oda, H.; Yokogoshi, H. J. Nutr.
Biochem. 2001, 12, 109–115.
18. Hanashima, S.; Mizushina, Y.; Yamazaki, T.; Ohta, K.;
Takahashi, S.; Sahara, H.; Sakaguchi; Sugawara, F.
Bioorg. Med Chem. 2001, 9, 367–376.
42. Kondo, Y.; Toda, Y.; Kitajima, H.; Oda, H.; Nagate, T.;
Kameo, K.; Murakami, S. Clin. Exp. Pharmacol. Physiol.
2001, 28, 809–815.
19. Murakami, C.; Yamazaki, T.; Hanashima, S.; Takahashi,
S.; Ohta, K.; Yoshida, H.; Sugawara, F.; Sakaguchi, K.;
Mizushina, Y. Arch. Biochem. Biophys. 2002, 403, 229–
236.
43. Meldrum, M. J.; Tu, R.; Patterson, T. A.; Dawson, R.,
Jr.; Petty, T. In Taurine in Health and Disease; Huxtable,
R. J.; Michalk, D. V., Eds.; Plenum Press: New York,
1994; pp. 207–215.

1018
J. G. Ferna´ndez-Bolan˜os et al. / Tetrahedron: Asymmetry 14 (2003) 1009–1018
44. Birdsall, T. C. Alt. Med. Rev. 1998, 3, 128–136.
45. Quertemont, E.; Goffaux, V.; Vlaminck, A. M.; Wolf, C.;
De Witte, P. Alcohol 1998, 16, 201–206.
52. Christiansen-Brams, I.; Meldal, M.; Bock, K. J. Carbo-
hydr. Chem. 1992, 11, 813–835 and references cited therein.
53. Kagan, F.; Robenstorf, M. A.; Heinzelman, R. V. J. Am.
Chem. Soc. 1957, 79, 3541–3544.
46. Yeagley, D. A.; Benesi, A. J.; Miljkovic´, M. Carbohydr.
54. Blanc-Muesser, M.; Defaye, J.; Horton, D. Carbohydr.
Res. 1996, 289, 189–191.
Res. 1980, 87, 71–86.
55. Hoffman, R. E.; Rutherford, T. J.; Mulloy, B.; Davies, D.
B. Magn. Reson. Chem. 1990, 28, 458–464.
56. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.
L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.;
Polidori, G.; Spagna, R. SIR97. J. Appl. Crystallogr. 1999,
32, 115–119.
57. Sheldrick, G. M., SHELXL97-Program for Crystal Struc-
ture Refinement (Release 97-2); University of Go¨ttingen:
Germany, 1997.
47. (a) Hodge, J. E. Adv. Carbohydr. Chem. 1955, 10, 169–205;
(b) Verstraeten, L. M. J. Adv. Carbohydr. Chem. 1967, 22,
229–305; (c) Lederer, M. O.; Dreisbusch, C. M.; Bund-
schuh, C. R. Carbohydr. Res. 1997, 301, 111–121; (d)
Aze´ma, L.; Bringaud, F.; Blonski, C.; Pe´rie´, J. Bioorg. Med.
Chem. 2000, 8, 717–722.
48. (a) Bock, K.; Pedersen, C. Adv. Carbohydr. Chem. Biochem.
1983, 41, 27–66; (b) Freimund, S.; Huwig, A.; Giffhorn, F.;
Ko¨pper, S. J. Carbohydr. Chem. 1996, 15, 115–120.
&
49. Horvat, S.; Rosˇcˇic´, M.; Varga-Defterdarovicˇ, L.; Horvat,
58. International Tables for X-Ray Crystallography; Hahn, T.,
Ed.; Kluwer Academic Publishers: Dordrecht, The Nether-
lands, 1995; Vol. A.
J. J. Chem. Soc., Perkin Trans. 1 1998, 909–914.
50. Eyrisch, O.; Sinerius, G.; Fessner, W.-D. Carbohydr. Res.
1993, 238, 287–306.
59. (a) Nardelli, M. PARST. J. Comput. Chem. 1983, 7, 95–98;
(b) Nardelli, M. J. Appl. Crystallogr. 1995, 28, 659.
51. Farrugia, L. J. ORTEP3 for Windows. J. Appl. Crystallogr.
1997, 30, 565.