cis-Fused bicyclic sugar thiocarbamates. Reactivity towards amines

Article abstract of DOI:10.1016/j.tet.2008.09.093

1,2-cis-Fused bicyclic sugar thiocarbamates of gluco and manno configurations have been prepared by treatment of the corresponding O-unprotected amino sugars and glycopyranosyl amines with thiophosgene. The reactivity of these compounds towards amines has been studied in order to determine whether these compounds could act as latent isothiocyanates; it is shown that 1,2-cis-fused bicyclic sugar thiocarbamates are more stable than their trans analogues, and are not transformed into thioureas upon treatment with amines. An unprecedented isomerization of a peracetylated glucopyranoso[2,1-d]oxazolidine-2-thione into a glucopyranoso[2,1-d]thiazolidin-2-one in DMF is also reported. The structure of this thiazolidin-2-one was confirmed by X-ray crystallography.

Full text of DOI:10.1016/j.tet.2008.09.093

Tetrahedron 64 (2008) 11789–11796
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
cis-Fused bicyclic sugar thiocarbamates. Reactivity towards amines
a
a
a
a
a
b
a
b
´
´
´
´
´
´
´
´
Oscar Lopez , Encarnacion Zafra , Ines Maya , Jose Fuentes , M Jesus Dianez , M Dolores Estrada ,
b
a,
*
´
´
´
˜
Simeon Perez-Garrido , Jose G. Fernandez-Bolanos
a
´
´
´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Sevilla, P.O. Box 1203, E-41071 Sevilla, Spain
b Instituto de Ciencias de Materiales de Sevilla and Departamento de F´ısica de la Materia Condensada, CSIC-Universidad de Sevilla, P.O. Box 1065, E-41071 Sevilla, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2-cis-Fused bicyclic sugar thiocarbamates of gluco and manno configurations have been prepared by
treatment of the corresponding O-unprotected amino sugars and glycopyranosyl amines with thio-
phosgene. The reactivity of these compounds towards amines has been studied in order to determine
whether these compounds could act as latent isothiocyanates; it is shown that 1,2-cis-fused bicyclic
sugar thiocarbamates are more stable than their trans analogues, and are not transformed into thioureas
upon treatment with amines. An unprecedented isomerization of a peracetylated glucopyranoso[2,1-d]
oxazolidine-2-thione into a glucopyranoso[2,1-d]thiazolidin-2-one in DMF is also reported. The structure
of this thiazolidin-2-one was confirmed by X-ray crystallography.
Received 7 August 2008
Received in revised form
19 September 2008
Accepted 22 September 2008
Available online 8 October 2008
Keywords:
Thiophosgene
Thiocarbamates
Carbamates
Annelation
Ó 2008 Elsevier Ltd. All rights reserved.
Amino sugars
1. Introduction
2-N-3-O-Carbamate protected glucosamine donors have been used
in glycosylation procedures,15 and some bicyclic 5/5-cis-fused sugar
Five- and six-membered cyclic thiocarbamates and carbamates
(1,3-oxazolidine- and oxazinane-2-ones and 2-thiones) are im-
portant structural motifs in organic chemistry.1 Some compounds
bearing these structures have been reported to exhibit interes-
ting biological effects,2 including fructose transport inhibition,3
antitumour,4 and clinically useful antibacterial activity.5 Oxazoli-
dine-2-thiones obtained by enzyme-mediated hydrolysis of glu-
cosinolates present in crucifer plants are known to cause goitre.6
Furthermore, bicyclic trans-fused sugar carbamates have been de-
scribed as detoxificant products upon interaction of plants with
phytotoxic allelochemicals.7
thiocarbamates have been used in the preparation of nucleoside
derivatives.16 Bicyclic 5/5 and 5/6-fused thiocarbamates and car-
bamates are also interesting from a conformational point of view,
and some theoretical calculations have been made,17 together with
X-ray diffraction studies.18
A classical procedure for the preparation of fused glycofurano
and glycopyrano oxazolidin-2-one and -2-thione scaffolds consists
of treatment of O-unprotected reducing sugars with KNCO19 or
KNCS,20 respectively, in acidic medium. Kovacs et al. have also
´
reported the preparation of fused bicyclic sugar carbamates by
Staudinger reaction of the corresponding glycopyranosyl azides
with triphenylphosphane, followed by treatment with carbon
dioxide.21 Rollin’s group has extensively studied the synthesis of
spiranic and fused 1,3-oxazolidine-2-thiones by treatment of
From a synthetic point of view, the use of chiral 1,3-oxazolidine-
2-thiones has emerged as
a promising area in asymmetric
synthesis, as these heterocycles are structurally related to Evans
oxazolidinones.8 In this context, chiral cyclic carbamates and
thiocarbamates have been synthesized and used in Diels–Alder9
and inverse hetero-Diels–Alder10 reactions, in the preparation of
a
-hydroxyketones,22 ulosides23 or ketohexose backbones24 with
thiocyanic acid. Carbohydrate-derived 1,3-oxazolidine- and 1,3-
oxazinane-2-thiones can also be accessed when an isothiocyanate
and a hydroxyl group are simultaneously present in the molecule,25
depending on the relative arrangement of both functional groups,
and thus, on the inherent strain of the cyclic moiety.1,26
b
-lactam derivatives,11 and in aldol condensations,12 an important
tool for the total synthesis of biologically active compounds.13
Sugar-derived oxazolidine-2-thiones have been recently used in
desulfurative Sonogashira cross-coupling reactions with alkynes.14
We have previously reported27 the preparation of fully un-
protected
b-D-glycopyranosyl isothiocyanates 3,4 of gluco and
galacto configurations in equilibrium with the corresponding thio-
carbamates 5,6 by isothiocyanation reaction of glycopyranosyl
amines 1 and 2 with thiophosgene. These isothiocyanates were
* Corresponding author. Tel.: þ34 95 4550996; fax: þ34 95 4624960.
´
˜
E-mail address: bolanos@us.es (J.G. Fernandez-Bolanos).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.093

´
11790
O. Lo´pez et al. / Tetrahedron 64 (2008) 11789–11796
R2
OH
R2
R2
OH
OH
CSCl2
O
O
O
R1
R1
R1
NH
S
NH2
NCS
HO
HO
HO
OH
OH
O
R1= OH,R2= H
R1= H, R2= OH
3
R1= OH,R2= H
R1= H, R2= OH
5 R1= OH,R2= H
1
4
1= H, R2= OH
2
6 R
R3R4NH
R2
OH
O
H
N
R1
NR3R4
HO
OH
S
7
8
R1= OH,R2= H
R1= H, R2= OH
Scheme 1.
one-pot transformed into thioureas 7 and 8 upon treatment with
aliphatic and aromatic amines (Scheme 1). Furthermore, 1,2-trans-
fused glycopyranosyl carbamates, isosters of 5 and 6, have been
used in the preparation of urea-tethered neoglycoconjugates and
pseudooligosaccharides upon reaction with different amines.28,29
fused five-membered–six-membered hydrindane-type systems.31
This suggests that these cis-fused thiocarbamates are more stable
that their trans-fused analogues, so the former do not undergo ring
opening.
If annelation had taken place through hydroxyl group on C-3 or
through equatorial hydroxyl group of the
b-anomer, less stable
trans-fused thiocarbamates 12 or 13 would have been obtained,
respectively. Their equilibrium with isothiocyanate 10 would lead
to the irreversible formation of 11, as deduced by its NMR spectra.
Vicinal coupling constants of thiocarbamate 11, J1,2 6.8 Hz, J2,3
5.2 Hz, J3,4 5.3 Hz and J4,5 9.1 Hz, show a distorted pyranose ring for
this compound, suggesting the preferential participation of a boat
2. Results and discussion
We now report the synthesis of sugar-derived 1,2-cis-fused
bicyclic thiocarbamates by treatment of O-unprotected amino
sugars (2-amino-2-deoxy-D-glucose and -D-mannose) and b-D-
mannopyranosylamine with thiophosgene in an aqueous buffered
medium; the regioselectivity in the formation of these bicyclic
sugar-containing structures has been studied.
conformation32 0,3B) rather than the 0S2 pyranose conformation
(
(Fig. 1) previously reported for structurally related bicyclic glyco-
pyrano structures in solution.18,21b,32,33
cis-Fused bicyclic thiocarbamate 11 was prepared starting from
Thiocarbamate 11 was conventionally acetylated (Ac2O–Py)34
to afford tetra-acetylated derivative 14, which was crystallized
from EtOH (Scheme 2). In order to study the behaviour of thio-
carbamate 14 towards amines, compound 14 was treated with
p-toluidine (2.0 equiv) in EtOH at 65 ꢀC (Scheme 3). After 13 h at
this temperature, N-deacetylated derivate 15 was isolated as the
sole product in a 78% yield after chromatographic purification.
NMR spectrum of the crude reaction also showed the formation
of N-p-tolylacetamide. This transamidation could be explained
considering that the conjugation of the lone pair electrons on the
nitrogen atom with the C]S and C]O groups makes the car-
bonyl more electrophile, so the NAc group can react even with
poor nucleophilic amines such as p-toluidine in contrast with the
OAc groups.
2-amino-2-deoxy-D-glucose hydrochloride 9 and thiophosgene in
buffered aqueous dioxane (Scheme 2), in similar conditions as
those previously described by us for the preparation of glycopyr-
anosyl isothiocyanates 3 and 4.27 Thiocarbamate 11 was obtained in
a 77% yield after column chromatography purification and un-
derwent appreciable decomposition after storage at 0 ꢀC for several
days. The formation of this compound must take place through
non-detected isothiocyanate 10, followed by nucleophilic attack of
the axial hydroxyl group of the a-anomer on the isothiocyanate
group. 1H and 13C NMR spectra showed no equilibrium between cis-
fused thiocarbamate 11 and isothiocyanate 10, in contrast with our
reported data27,30 on trans-fused bicyclic thiocarbamates, which
are in a solvent-dependent equilibrium with the corresponding
isothiocyanate, as a result of the strain in the ring fusion of these
CSCl2
OH
OH
OH
O
NaHCO3/CO2
O
O
HO
HO
HO
HO
HO
HO
OH
OH
1:1 H2O/Dioxane
−10 °C, 40 min
NCS
NH2·HCl
HN O
9
10
S
11(77%)
OH
OH
O
O
Ac
2O-Py
HO
HO
HO
O
O
OH
S
NH
N
H
OAc
O
S
12
13
AcO
AcO
AcN
O
S
14 (45% from 9)
Scheme 2.

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O. Lo´pez et al. / Tetrahedron 64 (2008) 11789–11796
11791
OR
OR
carbonyl group the deshielding of H-3, observed in the 1H NMR
spectrum of 14 and in agreement with the behaviour of sugar-
derived N-acetylated imidazolidine-2-thiones and oxazolidin-2-
ones.33,36
OR
RO
O
O
RO
O
RO
O
RN
S
We attempted the opening of the thiocarbamate moiety of
compound 14 with several nucleophiles: with sodium azide in DMF
at 100 ꢀC 14 readily decomposed; however, with KSCN in DMF at
125 ꢀC an unexpected isomerization into glucopyranoso[2,1-
d]thiazolidin-2-one 16 took place (Scheme 3). Chromatographic
purification afforded 16 with a 52% yield. It is remarkable that, to
our knowledge, the only similar isomerization described in the
literature implies an isomerization of a cytidine 20,30-thionocar-
bonate into a 20-thiocytidine 20,30-carbonate at elevated tempera-
ture.37 The only examples of bicyclic glyco-thiazolidin-2-ones
previously reported are glycopyranoso[1,2-d]thiazolidin-2-ones
prepared by Santoyo et al.38 from 2-deoxy-2-iodoglycosyl iso-
thiocyanates. Recently, bicyclic glycopyrano-thiazolines have been
reported as potent and selective O-GlcNAcase inhibitors.32,39 The
isomerization must involve the opening of the thiocarbamate
moiety with the formation of a transient oxocarbenium ion and
cyclization through the more nucleophile sulfur atom on the
anomeric carbon. In the absence of KSCN under the same time and
temperature conditions, only a small amount of thiazolidin-2-one
16 was detected together with starting material and several de-
composition products. Participation of nucleophilic thiocyanate
anion in the opening of the thiocarbamate and the formation of the
non-detected glycopyranosyl isothiocyanate or thiocyanate cannot
be disregarded.40
S
0
0,3
S2
B
11 R= H
14 R= Ac
Figure 1.
OAc
O
OAc
OH
O
O
KSCN
NH3
AcO
AcO
AcO
AcO
HO
HO
DMF
MeOH
S
O
AcN
S
HN
AcN
125 °C
O
S
O
p-toluidine
16 (52%)
17 (79%)
14
EtOH, 65 °C
78%
OAc
O
Silica gel 60
KSCN
DMF
AcO
No reaction
AcO
EtOH, reflux
48%
O
HN
125 °C
S
15
Scheme 3.
It is remarkable that the extra equivalent of p-toluidine did not
react with the N-deacetylated derivative 15 to give the corre-
sponding thiourea; this result shows that cis-fused bicyclic thio-
carbamates do not act as latent isothiocyanates in reactions with
amines, in contrast with our results with their analogues trans-
fused counterparts.27,30 Derivative 15 was also obtained, although
in a lower yield (48%), by ethanolysis of 14 at reflux under mild
acidic conditions in the presence of silica gel (Scheme 3).
Both thiocarbamates 14 and 15 show the same conformational
preference as compound 11; the long-range coupling constant
found for thiocarbamate 14 (4J2,4¼0.8 Hz) indicates a W pathway
between protons H-2 and H-4, what agrees with the major 0,3B
conformation in solution. A strong deshielding of the NAc group (ca.
0.7 ppm) compared to acetate signals (2.09–2.00 ppm), and
a strong deshielding of H-3 (ca. 0.5 ppm) in 14 compared with 15,
can be explained considering the two possible rotamers of the
acetamido group (Fig. 2). s-cis Rotamer is unfavoured as a result of
the repulsion between the dipoles of the carbonyl and thiocarbonyl
groups.35 This repulsion is reduced in s-trans rotamer; the thio-
carbonyl provokes the deshielding of the methyl group and the
When this reaction was carried out on N-deacetylated oxazoli-
dine-2-thione 15 under the same reaction conditions, no isomeri-
zation took place; the reason might be that the higher electron
density on the nitrogen atom, as compared with 14, provokes
a lower electron-withdrawing effect of the thiocarbonyl group by
cross conjugation, and higher electron density on the anomeric
oxygen atom, thus becoming a worse leaving group.
The slightly distorted 4C1 conformation of thiazolidin-2-one 16
was deduced by the coupling constants found in the 1H NMR
spectrum (J1,2 6.7 Hz, J2,3 8.2 Hz, J3,4 9.4 Hz and J4,5 9.5 Hz). The
conformational behaviour of 16 differs from that of oxazolidine-2-
thiones 11, 14 and 15, which exhibit the 0,3B conformation as the
major one in solution. This boat conformation is also found for an
unprotected bicyclic cis-fused GlcNAc-thiazoline, a potent transi-
tion-state-mimicking inhibitor of b
-N-acetylglycosaminidases.32 In
contrast, GalNAc-thiazoline adopts the pseudo-chair 4C1 in solution
and in solid state;39a furthermore, GlcNAc-thiazoline binds in
BtGH84 enzyme active site in a slightly distorted chair 4C1 confor-
mation.41 The longer bonds of the sulfur atom compared to oxygen
might explain the stability of the chair conformation for the pyra-
nose ring in these bicyclic systems.
As observed for compound 14, 1H NMR and 13C NMR spectra of
16 showed a deshielding (ca. 0.35 and 4.8 ppm, respectively) of the
NAc group with respect to the acetate groups, in accordance with
the s-trans conformation (Fig. 2). Bicyclic thiazolidin-2-one 16 was
deacetylated with ammonia in methanol to give derivative 17 in
a 79% yield after chromatographic purification (Scheme 3).
Me
N
O
N
O
O
O
S
Me
S
s-trans
s-cis
14
2.1. X-ray structural analysis
An ORTEP42 view of 16 showing the atomic labelling scheme is
shown in Figure 3. The typical asymmetry of the endocyclic bonds
for the pyranose ring [O-5–C-5¼1.442(4) and O-5–C-1¼1.388(4) Å],
caused by the anomeric effect, is observed.43 The geometry of
the pyranose ring agrees with an almost undistorted 4C1 chair
conformation, in accordance with 1H NMR data in solution, with
the C-4 atom on one side [0.209(3) Å] and the C-1 atom on the
other side [0.107(2) Å] of the least-squares best plane. In terms of
Me
N
O
N
S
S
O
O
Me O
16
s-trans
s-cis
Figure 2.

´
O. Lo´pez et al. / Tetrahedron 64 (2008) 11789–11796
11792
form, precludes its formation. Vicinal coupling constants of the
-anomer of 20 (J1,2 0.0 Hz, J2,3 7.6 Hz, J3,4 3.7 Hz and J4,5 9.1 Hz)
a
agree with ring conformations that differ significantly from the
chair and which approach the 0H5 half-chair, as found for 2,3-O
carbonate protected manno- and rhamnopyranose derivatives.49
1H NMR spectrum showed compound 20 (see Section 3) to be in
an anomeric equilibrium, being the
a-anomer the major isomer
(5:1 in D2O and 15:1 in DMSO-d6); this is due to the anomeric effect
and to the cancelation of the dipoles associated with the anomeric
hydroxyl group and the thiocarbamate moiety. Furthermore, 1H
NMR showed a strong deshielding of H-3 (d 5.60 ppm), indicating
that hydroxyl group on C-3 is the one, which takes part in the
annelation to form the thiocarbamate moiety.
Acetylation of the crude reaction of 20, followed by selective
N-deacetylation with p-toluidine in EtOH at 65 ꢀC afforded the bi-
cyclic derivative 23, in a 31% overall yield for the three steps, after
chromatographic purification. If the N-deacetylation step with
ethanol is suppressed, a mixture of 23 and its N-acetylated de-
rivative is detected. 1H NMR spectrum showed compound 23 to be
the
reaction mixture.
The same isothiocyanation reaction conditions as described for
-glucosamine and -mannosamine were used when starting from
-mannopyranosylamine 24 (Scheme 5), obtained by saturating
a suspension of
-mannose in methanol with ammonia.50 In this
case, treatment with thiophosgene affords cis-fused bicyclic
thiocarbamate 25 as the major product (42% yield after column
chromatography). This compound is obtained as a result of
a spontaneous annelation of the non-detected isothiocyanate de-
rivative with the axial hydroxyl group on C-2. Together with thio-
carbamate 25, carbamate 2619b was unexpectedly obtained in a 10%
yield; the formation of this compound might be explained con-
sidering thiophosgene-mediated oxidation of thiocarbamate 25
under the reaction conditions, although these carbamates were not
detected together with thiocarbamates 11 and 20, prepared from
glucosamine and mannosamine, respectively. The oxidation of
thioureas and thioamides into the corresponding oxo derivatives by
using thiosphosgene has been reported.51
a-anomer, whereas the b-anomer was not isolated from the
Figure 3. An ORTEP view of 16.
D
D
ring-puckering coordinates,44 amplitude and phase magnitudes
b-D
D
are Q¼0.506(3) Å,
f
¼4(1)ꢀ and
q
¼168.5(3)ꢀ for the sequence C-1–
C-2–C-3–C-4–O-5. Nardelli45 asymmetry parameters are
DC2(C-
1)¼0.225(1) and
for the thiazole ring is intermediate between envelope and twist
and the ring-puckering coordinates are Q¼0.400(3) Å and ¼134
(4) for the sequence S-1–C-11–N–C-2–C-1. The asymmetry pa-
rameter is
D
Cs(O-5–C-1)¼0.283(1). The geometry observed
f
D
C2(C1)¼0.212(1). The dihedral angle between the py-
ranose and the thiazolidine rings is 66.9(1)ꢀ. The chain C-6–O-6–C-
61(O-61)–C-62 is planar (max. dev. 0.02 Å) and the conformation
through the C-5–C-6 bond is gauche–gauche (gg), the major con-
formation found for glucopyranosyl derivatives in solid state.46,47
The N-acetyl group is in the s-trans conformation (Fig. 2), in ac-
cordance with the conformation deduced in solution by NMR for
14 and 16.
1H and 13C NMR spectra of 25 and 26 showed that in solution
these compounds are not in equilibrium with the corresponding
glycosyl isothiocyanates or isocyanates. Reaction of compound 25
with p-toluidine did not afford the corresponding mannopyranosyl
thiourea, which again confirms that cis-fused bicyclic thio-
carbamates do not act as latent isothiocyanates in the reaction with
nucleophiles.
Conventional acetylation of the crude reaction mixture of 25
and 26, followed by heating in EtOH in the presence of p-toluidine
afforded the N-deacetylated derivatives 27 and 28,19b with an
overall yield for the three steps (isothiocyanation, acetylation and
Isothiocyanation reaction was also carried out on D-mannos-
amine hydrochloride 18 (Scheme 4), using the same reaction con-
ditions as described previously, to give cis-fused bicyclic
thiocarbamate 20 in a 41% yield after column chromatography. This
compound is the result of a spontaneous annelation through the
non-detected isothiocyanate 19 and the hydroxyl group on C-3. It is
remarkable that the cis-fused regioisomer 22 was not detected,
probably due to the fact that for 19 the major isomer is expected to
be the a
-anomer,48 together with the less nucleophilicity exhibited
by anomeric hydroxyl groups. The instability of the trans-fused
bicyclic thiocarbamate 21, with the pyranose ring in the inverted
S
CSCl2, NaHCO3/CO2
NH2·HCl
NCS
O
NH
OH
HO
HO
HO
1:1 H2O/dioxane, −10 °C
O
O
HO
HO
HO
O
OH
OH
HO
OH
20 (41%)
19
18
1. Ac2O/Py, 5 °C
2. p-Toluidine, EtOH, 65 °C
S
HO
OH
S
OH
HN
OH
O
NH
OAc
O
O
O
HO
HO
AcO
O
H
N
O
S
OAc
23 (31% from 18)
21
22
Scheme 4.

´
O. Lo´pez et al. / Tetrahedron 64 (2008) 11789–11796
11793
O
S
OH
OH
O
OH
OH
O
O
NH
NH
CSCl2, NaHCO3/CO2
O
O
NH2
HO
HO
HO
HO
HO
HO
+
1:1 H2O/dioxane, −10 °C
26 (10%)
25 (42%)
24
S
O
1. CSCl2, NaHCO3/CO2
1:1 H2O/dioxane, −10 °C
2. 1:1 Ac2O/Py, 5 °C
OAc
OAc
O
O
NH
O
O
NH
AcO
AcO
AcO
+
AcO
°C
3. p-Toluidine, EtOH, 65
27 (25%)
28 (27%)
Scheme 5.
N-deacetylation) of 25 and 27%, respectively, after preparative TLC
purification. The coupling constants J1,2 for 25–28 exhibit an un-
usual large value (3.2–4.0 Hz) for a b-anomer derived from man-
1H, J2,1¼6.8 Hz, J2,3¼5.2 Hz, H-2), 3.79 (dd, 1H, J6a,5¼2.1 Hz,
J6a,6b¼12.2 Hz, H-6a), 3.67 (dd, 1H, J6b,5¼4.7 Hz, J6b,6a¼12.2 Hz, H-
6b), 3.64 (t, 1H, J3,2¼5.2 Hz, J3,4¼5.3 Hz, H-3), 3.51 (ddd, 1H,
J5,4¼9.1 Hz, J5,6a¼2.1 Hz, J5,6b¼4.7 Hz, H-5), 3.50 (t, 1H, J4,3¼5.3 Hz,
nosamine 24 in the 4C1 conformation. The full set of vicinal
coupling constants suggests that the sugar ring of 25–28 should
adopt a preferential 1S5 conformation in solution, a conformation
found for mannosyl residues during enzymatic hydrolysis.52
In conclusion, the isothiocyanation reactions of 1,2-cis-config-
ured glycosylamines and amino sugars with thiophosgene afforded
cis-fused bicyclic thiocarbamates (glycopyrano-1,3-oxazolidine-2-
thiones). Treatment of these compounds with aromatic amines did
not afford thioureas unlike their isomeric trans-counterparts,
showing that the cis-fused hydrindane-type bicycles are more
stable due to a lower ring strain. An unprecedented isomerization
of a N-acetyl glucopyrano-1,3-oxazolidine-2-thione into a gluco-
pyrano-1,3-thiazolidin-2-one was also reported, and its structure
confirmed with X-ray crystallography.
J4,5¼9.1 Hz, H-4); 13C NMR (75.5 MHz, CD3OD)
d 190.0 (CS), 104.3
(C-1), 76.3 (C-5), 74.8 (C-3), 69.2 (C-4), 62.6 (C-6), 59.9 (C-2); FABMS
m/z 222 ([MþH]þ, 100%), 443 ([2MþH]þ, 12%). HRCI-MS m/z calcd
for C7H12NO5S [MþH]þ: 222.0436, found: 222.0432.
3.3. N-Acetyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-
a-D-
glucopyranoso)[2,1-d]oxazolidine-2-thione (14)
To a suspension of 2-amino-2-deoxy-D-glucosamine hydro-
chloride (1.0 g, 4.64 mmol) and NaHCO3 (1.29 g, 15.32 mmol) in 1:1
water–dioxane (20 mL) saturated with CO2 (pH 8) was added thi-
ophosgene (0.42 mL, 5.48 mmol). The mixture was stirred at ꢁ10 ꢀC
for 30 min and then it was concentrated to dryness. The residue
was conventionally acetylated with an 1:1 Ac2O–Py mixture
3. Experimental
(16 mL) and crystallized from EtOH to give 14: 0.81 g, 45%; mp 109–
25
111 ꢀC; Rf 0.68 (Et2O); [
a]
ꢁ34 (c 1.0, CH2Cl2); IR: nmax 1750 (C]O),
D
3.1. General procedures
1231 (AcO) cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 6.10 (d, 1H,
J1,2¼7.0 Hz, H-1), 5.37 (dd, 1H, J3,2¼4.5 Hz, J3,4¼6.0 Hz, H-3), 5.08
(m, 1H, J4,2¼0.8 Hz, J4,5¼7.5 Hz, H-4), 4.79 (m, 1H, H-2), 4.35 (dd, 1H,
J6a,5¼5.5 Hz, J6a,6b¼12.3 Hz, H-6a), 4.25 (dd, 1H, J6b,5¼3.0 Hz,
J6b,6a¼12.3 Hz, H-6b), 4.10 (ddd, 1H, J5,4¼7.5 Hz, J5,6a¼5.5 Hz,
J5,6b¼3.0 Hz, H-5), 2.79 (s, 3H, NAc), 2.11, 2.10, 2.06 (3s, 3H each,
Melting points were recorded on an Electrothermal apparatus
and are uncorrected, optical rotations were measured with a Per-
kin–Elmer 241 polarimeter, and IR spectra (KBr disks) were
obtained with an FTIR Bomem MB-120 spectrophotometer. 1H (300
and 500 MHz) and 13C (75.5 and 125.7 MHz) NMR spectra were
recorded on Bruker AMX-300 and AMX-500 spectrometers. 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 F254); spots were visualized
by UV light, by charring with 10% H2SO4 in EtOH. Column chro-
matography was performed using E. Merck Silica Gel 60 (40–
63 mm). Microanalysis was performed at the ‘Instituto de Inves-
3ꢂOAc); 13C NMR (75.5 MHz, CDCl3)
d 183.2 (CS), 170.7, 170.3, 169.2,
168.9 (4COCH3), 99.4 (C-1), 70.4 (C-5), 68.1 (C-3), 65.4 (C-4), 62.3
(C-6), 56.9 (C-2), 26.3 (NCOCH3), 20.6, 20.5, 20.4 (3C, 3ꢂCOCH3);
FABMS m/z 390 ([MþH]þ, 100%). Anal. Calcd for C15H19NO9S: C,
46.27; H, 4.92; N, 3.60. Found: C, 46.24; H, 4.81; N, 3.70.
3.4. (3,4,6-Tri-O-acetyl-1,2-dideoxy-a-D-glucopyranoso)[2,1-
d]oxazolidine-2-thione (15)
Method A: to a solution of 14 (50 mg, 0.13 mmol) in EtOH (7 mL)
was added p-toluidine (28 mg, 0.26 mmol). The solution was
heated at 65 ꢀC for 13 h and then it was concentrated to dryness
and the residue was purified by preparative TLC (80:1 CH2Cl2–
MeOH, two elutions) to give 15 as a syrup (35 mg, 78%). Method B:
to a solution of 14 (100 mg, 0.26 mmol) in EtOH (7 mL) was added
Silica Gel 60 (40–60 mesh, 400 mg) and the mixture was refluxed
for 48 h. Filtration and purification of the residue by preparative
´
tigaciones Quımicas’, Seville, Spain.
3.2. (1,2-Dideoxy-a-D-glucopyranoso)[2,1-d]oxazolidine-2-
thione (11)
To a suspension of 2-amino-2-deoxy-D-glucosamine hydro-
chloride (200 mg, 0.93 mmol) and NaHCO3 (312 mg, 3.71 mmol) in
1:1 water–dioxane (4 mL) saturated with CO2 (pH 8), was added
thiophosgene (0.08 mL, 1.14 mmol, 1.2 equiv). The mixture was
stirred at ꢁ10 ꢀC for 30 min and then it was concentrated to dry-
ness. The residue was purified by column chromatography (5:1
CH2Cl2–MeOH) to give 11 as a syrup: 159 mg, 77%. Rf 0.42 (5:1
TLC (80:1 CH2Cl2–MeOH) afforded 15 as a syrup: 43 mg, 48%; Rf 0.17
25
(80:1 CH2Cl2–MeOH); [
a
]
þ47 (c 0.6, CH2Cl2); IR: nmax 3302 (NH),
D
1746 (C]O), 1508 (NHC]S), 1229 (AcO) cmꢁ1; 1H NMR (300 MHz,
CDCl3)
d
7.28 (s, 1H, NH), 6.21 (d, 1H, J1,2¼7.3 Hz, H-1), 5.09 (dd, 1H,
J4,3¼5.9 Hz, J4,5¼9.1 Hz, H-4), 4.91 (dd, 1H, J3,2¼3.9 Hz, J3,4¼5.9 Hz,
H-3), 4.36 (dd, 1H, J6a,5¼5.0 Hz, J6a,6b¼12.4 Hz, H-6a), 4.21 (dd, 1H,
J6b,5¼2.6 Hz, J6b,6a¼12.4 Hz, H-6b), 4.07 (ddd, 1H, J5,4¼9.1 Hz,
CH2Cl2–MeOH); IR: nmax 3195 (OH, NH), 1636, 1526 (NHC]S) cmꢁ1
1H NMR (300 MHz, CD3OD)
6.11 (d, 1H, J1,2¼6.8 Hz, H-1), 3.87 (dd,
;
d

´
O. Lo´pez et al. / Tetrahedron 64 (2008) 11789–11796
11794
J5,6a¼5.0 Hz, J5,6b¼2.6 Hz, H-5), 4.02 (dd, 1H, J2,1¼7.3 Hz, J2,3¼3.9 Hz,
H-2), 2.13, 2.10, 2.10 (3s, 3H each, 3ꢂOAc); 13C NMR (75.5 MHz,
20
J2,3¼7.6 Hz, H-2, 20
20
), 4.27 (dd, 1H, J4,3¼3.7 Hz, J4,5¼9.1 Hz, H-4, 20
J5,4¼9.1 Hz, J5,6a¼2.8 Hz, J5,6b¼5.5 Hz, H-5, 20 ), 3.78 (dd, 1H,
J6a,5¼2.8 Hz, J6a,6b¼12.2 Hz, H-6a, 20 ), 3.63 (dd, 1H, J6b,5¼5.5 Hz,
J6b,6a¼12.2 Hz, H-6b, 20
); 13C NMR (75.5 MHz, D2O) for 20a d 191.0
a
), 5.27 (d, 1H, J1,2¼3.6 Hz, H-1, 20
), 4.50 (d, 1H, J2,1z0.0 Hz, J2,3¼7.4 Hz, H-2,
), 3.88 (ddd, 1H,
b
), 4.54 (dd, 1H, J2,1¼3.6 Hz,
b
CDCl3)
d
187.7 (CS), 170.5, 170.4,170.0 (3COCH3), 101.4 (C-1), 73.5 (C-
a
a
3), 69.1 (C-5), 65.5 (C-4), 61.8 (C-6), 56.8 (C-2), 20.6, 20.6, 20.5
(3COCH3); FABMS m/z 370 ([MþNa]þ, 100%), 348 ([MþH]þ, 24%).
Anal. Calcd for C13H17NO8S: C, 44.95; H, 4.93; N, 4.03. Found: C,
44.81; H, 4.84; N, 3.99.
a
a
a
(CS), 102.7 (C-1), 89.0 (C-3), 81.4 (C-4), 70.9 (C-5), 69.1 (C-2), 65.4
(C-6); CIMS m/z 204 ([MþHꢁH2O]þ, 48%), 222 ([MþH]þ, 100%);
HRCIMS m/z calcd for C7H12NO5S [MþH]þ: 222.0436, found:
222.0446.
3.5. N-Acetyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-
a-D-
glucopyranoso)[2,1-d]thiazolidin-2-one (16)
To a solution of 14 (151 mg, 0.39 mmol) in DMF (9 mL) was
added KSCN (76 mg, 0.78 mmol, 2.0 equiv) and the solution was
heated at 125 ꢀC for 5.5 h. Then it was concentrated to dryness,
diluted with CH2Cl2 (15 mL) and washed with water (2ꢂ10 mL). The
organic layer was dried over MgSO4, filtered and concentrated to
3.8. (1,4,6-Tri-O-acetyl-2,3-dideoxy-
d]oxazolidine-2-thione (23)
a-D-mannopyranoso)[2,3-
To a suspension of
D-mannosamine hydrochloride (150 mg,
0.70 mmol) and NaHCO3 (234 mg, 2.78 mmol) in 1:1 water–di-
oxane (2 mL) at ꢁ10 ꢀC was added thiophosgene (0.079 mL,
1.04 mmol). The mixture was stirred at that temperature for 35 min
and then it was concentrated to dryness and the residue was
acetylated with 1:1 Ac2O–Py (6 mL) at 5 ꢀC for 24 h. After conven-
tional work-up, the residue was dissolved in EtOH (3 mL) and to the
solution was added p-toluidine (150 mg, 1.40 mmol). The resulting
solution was heated at 65 ꢀC for 2 h and purified with preparative
dryness. The residue was purified by preparative TLC (80:1 CH2Cl2–
25
MeOH, two elutions) to afford 16: 78 mg, 52%. Rf 0.68 (Et2O); [a]
D
ꢁ117 (c 1.2, CH2Cl2); mp: 107–108 ꢀC (Et2O); IR nmax 1746 (C]O),
1713 (S–C]O), 1235 (AcO) cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 6.21
(d, 1H, J1,2¼6.7 Hz, H-1), 5.49 (m, 1H, J3,2¼8.2 Hz, J3,4¼9.4 Hz,
J3,5¼0.7 Hz, H-3), 5.19 (t, 1H, J4,3¼9.4 Hz, J4,5¼9.5 Hz, H-4), 5.04 (dd,
1H, J2,1¼6.7 Hz, J2,3¼8.2 Hz, H-2), 4.35 (dd, 1H, J6a,5¼4.6 Hz,
J6a,6b¼12.4 Hz, H-6a), 4.24 (m, 1H, H-5), 4.13 (dd, 1H, J6b,5¼2.1 Hz,
J6b,6a¼12.4 Hz, H-6b), 2.41 (s, 3H, NAc), 2.09, 2.05, 2.00 (3s, 3H each,
TLC (3:1 EtOAc–hexane and afterwards Et2O) to give 23 as a syrup:
24
74 mg, 31%. Rf 0.43 (80:1 CH2Cl2–MeOH); [
a]
ꢁ10 (c 1.9, CH2Cl2);
D
3ꢂOAc); 13C NMR (75.5 MHz, CDCl3)
d
170.4 (ꢂ2),169.3, 169.0, 168.3
IR nmax 3333 (NH), 1746 (C]O),1516 (NHC]S),1221 (AcO) cmꢁ1; 1H
NMR (300 MHz, CDCl3) 8.16 (br s, 1H, NH), 6.17 (s, 1H, J1,2z0.0 Hz,
(5CO), 80.4 (C-1), 72.1 (C-3), 70.4 (C-5), 66.0 (C-4), 61.3 (C-6), 59.4
(C-2), 25.3 (NAc), 20.6, 20.6, 20.4 (3ꢂOAc). EIMS m/z 389 ([M]þ, 6%).
Anal. Calcd for: C15H19NO9S; C, 46.27%; H, 4.92%; N, 3.60%; S, 8.24%.
Found: C, 46.53%; H, 5.03%; N, 3.60%; S, 8.37%.
d
H-1), 5.47 (dd, 1H, J3,2¼7.5 Hz, J3,4¼3.9 Hz, H-3), 5.27 (ddd, 1H,
J5,4¼8.1 Hz, J5,6a¼2.7 Hz, J5,6b¼4.8 Hz, H-5), 4.56 (dd, 1H,
J6a,5¼2.7 Hz, J6a,6b¼12.3 Hz, H-6a), 4.52 (d, 1H,
J2,1z0.0 Hz,
J2,3¼7.5 Hz, H-2), 4.43 (dd, J4,3¼3.9 Hz, J4,5¼8.1 Hz 1H, H-4), 4.17
3.6. (1,2-Dideoxy-a-D-glucopyranoso)[2,1-d]thiazolidin-
(dd, 1H, J6b,5¼4.8 Hz, J6b,6a¼12.3 Hz, H-6b), 2.09 (ꢂ2), 2.06 (3s, 3H
2-one (17)
each, 3ꢂOAc); 13C NMR (300 MHz, CDCl3)
d 188.8 (CS), 170.6, 169.5,
169.3 (3CO), 99.8 (C-1), 84.9 (C-3), 80.2 (C-4), 68.3 (C-5), 66.0 (C-2),
62.2 (C-6), 20.8, 20.7, 20.6 (3ꢂOAc); CIMS m/z 288 ([MþHꢁAcOH]þ,
100%), 306 ([MþHꢁCH2CO]þ, 47%), 348 ([MþH]þ, 48%); HRCI-MS
calcd for C13H18NO8S [MþH]þ 348.0753; found: 348.0746.
Through a solution of 16 (138 mg, 0.280 mmol) in dry methanol
(4 mL) at ꢁ10 ꢀC was bubbled ammonia for 15 min and then the
solution was kept at 5 ꢀC for 1.5 h. Then it was concentrated to
dryness and purified by preparative TLC (4:1 CH2Cl2–MeOH) to give
27
17 as a white solid: 62 mg, 79%. Rf 0.29 (5:1 CH2Cl2–MeOH); [
a]
3.9. (1,2-Dideoxy-b-D-mannopyranoso)[1,2-d]oxazolidine-2-
thione (25) and (1,2-dideoxy-b-D-mannopyranoso)[1,2-
d]oxazolidin-2-one (26)
D
þ31 (c 0.8, H2O); IR nmax 3281 (OH), 1667 (S–C]O) cmꢁ1; 1H NMR
(300 MHz, D2O)
d
6.37 (m, 1H, J1,2¼6.7 Hz, H-1), 3.89–3.81 (m, 3H,
H-2, H-3, H-4), 3.84 (dd, 1H, J6a,5¼2.3 Hz, J6a,6b¼12.7 Hz, H-6a), 3.73
(dd, 1H, J6b,5¼6.4 Hz, J6b,6a¼12.7 Hz, H-6b), 3.50 (ddd, 1H,
J4,5¼9.2 Hz, J5,6a¼2.3 Hz, J5,6b¼6.4 Hz, H-5); 13C NMR (75.5 MHz,
To a suspension of
b-D-mannopyranosylamine monohydrate
(200 mg, 1.01 mmol) and NaHCO3 (278 mg, 3.31 mmol) in 1:1 wa-
ter–dioxane (4 mL) at ꢁ10 ꢀC was added thiophosgene (0.12 mL,
1.66 mmol). The mixture was stirred at that temperature for 30 min
and then was concentrated to dryness. The residue was dissolved in
water (5 mL) and washed with CH2Cl2 (2ꢂ5 mL). The aqueous layer
was concentrated to dryness and treated with EtOH. After removal
of the salts, the filtrate was purified by column chromatography
D2O)
d 176.9 (CO), 85.2 (C-1), 75.9, 75.0 (C-3, C-4), 69.2 (C-5), 61.9
(C-6), 61.1 (C-2); CIMS m/z 222 ([MþH]þ, 100%); HRCI-MS calcd for
C7H12NO5S [MþH]þ: 222.0436. Found: 222.0435. Anal. Calcd for:
C7H11NO5S: C, 38.00; H, 5.01; N, 6.33. Found: C, 38.04; H, 5.08; N,
6.36.
3.7. (2,3-Dideoxy-
thione (20)
D
-mannopyranoso)[2,3-d]oxazolidine-2-
(CH2Cl2/5:1 CH2Cl2–MeOH). Eluted first was 25 (103 mg, 42%); Rf
26
0.40 (5:1 CH2Cl2–MeOH); [
a
]
ꢁ65 (c 0.8, H2O); IR nmax 3318 (OH,
D
NH), 1491 (NHC]S) cmꢁ1
;
1H NMR (300 MHz, D2O)
d 5.47 (d, 1H,
To a suspension of
D
-mannosamine hydrochloride (200 mg,
J1,2¼3.7 Hz, H-1), 4.98 (dd, 1H, J2,1¼3.7 Hz, J2,3¼4.6 Hz, H-2), 4.02
(dd, 1H, J3,2¼4.6 Hz, J3,4¼9.5 Hz, H-3), 3.84 (dd, 1H, J6a,5¼2.5 Hz,
J6a,6b¼12.3 Hz, H-6a), 3.66 (dd, 1H, J6b,5¼6.4 Hz, J6b,6a¼12.3 Hz, H-
6b), 3.58 (t, 1H, J4,3¼9.5 Hz, J4,5¼9.5 Hz, H-4), 3.44 (ddd, 1H,
J5,4¼9.5 Hz, J5,6a¼2.5 Hz, J5,6b¼6.4 Hz, H-5); 13C NMR (75.5 MHz,
0.93 mmol) and NaHCO3 (312 mg, 3.71 mmol) in 1:1 water–di-
oxane (4 mL) at ꢁ10 ꢀC was added thiophosgene (0.10 mL,
1.39 mmol). The mixture was stirred at that temperature for 35 min
and then it was concentrated to dryness. The residue was dissolved
in water (5 mL) and washed with CH2Cl2 (3ꢂ5 mL). The organic
layer was concentrated to dryness and treated with EtOH. After
removal of the salts the residue was purified by column chroma-
tography (CH2Cl2/5:1 CH2Cl2–MeOH) to give 20 as a syrup: 84 mg,
41%. Rf 0.58 (5:1 CH2Cl2–MeOH); [
3370 (OH, NH), 1551 (NHC]S) cmꢁ1D
D2O)
d 192.7 (CS), 85.8 (C-2), 84.0 (C-1), 76.8 (C-5), 71.0 (C-3), 68.1
(C-4), 62.0 (C-6); CIMS m/z 222 ([MþH]þ, 27%); HRCI-MS m/z calcd
for C7H12NO5S [MþH]þ 222.0436, found: 222.0425.
Eluted second was 26 (33 mg, 10%); Rf¼0.19 (5:1 CH2Cl2–
25
26
a
]
þ56 (c 0.6, H2O); IR nmax
MeOH); [
a
]
ꢁ31 (c 0.6, H2O); IR nmax 3401 (OH, NH), 1750, 1647
D
;
1H NMR (300 MHz, D2O)
(NHC]O) cmꢁ1; 1H NMR (300 MHz, D2O)
H-1), 4.82 (dd, 1H, J2,1¼3.2 Hz, J2,3¼4.6 Hz, H-2), 3.98 (dd, 1H,
J3,2¼4.6 Hz, J3,4¼9.6 Hz, H-3), 3.88 (dd, 1H, J6a,5¼2.4 Hz,
d
5.36 (d, 1H, J1,2¼3.2 Hz,
d
5.60 (dd, 1H, J3,2¼7.4 Hz, J3,4¼3.7 Hz, H-3, 20
a
), 5.46 (dd, 1H,
J3,2¼7.6 Hz, J3,4¼2.4 Hz, H-3, 20
b), 5.38 (s, 1H, J1,2z0.0 Hz, H-1,

´
O. Lo´pez et al. / Tetrahedron 64 (2008) 11789–11796
11795
J6a,6b¼12.2 Hz, H-6a), 3.70 (dd, 1H, J6b,5¼6.4 Hz, J6b,6a¼12.2 Hz, H-
6b), 3.62 (t, 1H, J4,3¼9.6 Hz, J4,5¼9.6 Hz, H-4), 3.44 (ddd, 1H,
J5,4¼9.6 Hz, J5,6a¼2.4 Hz, J5,6b¼6.4 Hz, H-5); 13C NMR (125.7 MHz,
h, k and l, ꢁ15<h<14, ꢁ11<k<11, 0<l<15. Three standard re-
flections were measured every hour to monitor crystal stability and
were re-centred after every hundred measured reflections to
monitor crystal orientation. No significant intensity changes were
observed. Number of measured reflections, 5451; number of sig-
D2O)
d 162.0 (CO), 82.3 (C-1), 80.6 (C-2), 76.4 (C-5), 71.6 (C-3), 68.2
(C-4), 62.0 (C-6); CIMS m/z 188 ([MþHꢁH2O]þ, 12%), 206 ([MþH]þ,
20%); HRCI-MS m/z calcd for C7H12NO6 [MþH]þ 206.0664, found:
206.0667.
nificant reflections, 3677; criterion for significance, I>2
s(Io); final R,
0.06; final
u
R(F2), 0.16; goodness-of-fit S, 0.99.
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 structure of 16 was solved by direct
methods using SIR200253 to locate all non-hydrogen atoms.
Refinement on F2 was performed using SHELX97.54 Atomic
scattering factors were taken from International Tables for X-ray
crystallography. The maximum and minimum residual densities in
the final difference map were 0.26 and ꢁ0.21 e Åꢁ3, respectively.
The geometrical analysis was performed using PARST.55
Crystallographic data for this structure have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 687037. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: þ44 01223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
3.10. (3,4,6-Tri-O-acetyl-1,2-dideoxy-
[1,2-d]oxazolidine-2-thione (27) and (3,4,6-tri-O-acetyl-1,2-
dideoxy- -mannopyranoso)[1,2-d]oxazolidin-2-one (28)
b-D-mannopyranoso)
b-D
To a suspension of
b-D-mannopyranosylamine monohydrate
(600 mg, 3.04 mmol) and NaHCO3 (847 mg, 10.08 mmol) in 1:1
water–dioxane (12 mL) at ꢁ10 ꢀC was added thiophosgene
(0.39 mL, 5.04 mmol). The mixture was stirred at that temperature
for 30 min and then it was concentrated to dryness and the residue
was acetylated with 1:1 Ac2O–Py (20 mL) at 5 ꢀC for 24 h. After
conventional work-up, the residue was dissolved in EtOH (20 mL)
and to the solution was added p-toluidine (652 mg, 6.08 mmol).
The resulting solution was heated at 65 ꢀC for 5 h and purified with
preparative TLC (40:1 CH2Cl2–MeOH). Eluted first was 27 (260 mg,
26
25%); Rf¼0.23 (80:1 CH2Cl2–MeOH); [
a
]
ꢁ106 (c 1.2, CH2Cl2); IR
D
nmax 3306 (NH), 1746 (C]O), 1487 (NHC]S), 1229 (AcO) cmꢁ1
;
1H
8.16 (s, 1H, NH), 5.39 (d, 1H, J1,2¼4.0 Hz, H-
NMR (300 MHz, CDCl3)
d
Acknowledgements
1), 5.33 (dd, 1H, J3,2¼4.0 Hz, J3,4¼9.5 Hz, H-3), 5.23 (dd, 1H,
J4,3¼9.5 Hz, J4,5¼8.2 Hz, H-4), 5.05 (t, 1H, J2,1¼4.0 Hz, J2,3¼4.0 Hz, H-
2), 4.24 (dd, 1H, J6a,5¼2.8 Hz, J6a,6b¼12.4 Hz, H-6a), 4.14 (dd, 1H,
J6b,5¼6.0 Hz, J6b,6a¼12.4 Hz, H-6b), 3.76 (ddd, 1H, J5,4¼8.2 Hz,
J5,6a¼2.8 Hz, J5,6b¼6.0 Hz, H-5), 2.13, 2.07, 2.06 (3s, 3H each,
´
´
We thank the Direccion General Investigacion of Spain (Grant
´
CTQ2005-01830/BQU) and the Junta de Andalucıa (FQM134) for
financial support.
3ꢂOAc); 13C NMR (75.5 MHz, CDCl3)
d 190.2 (CS), 170.7, 170.2, 169.1
References and notes
(3CO), 82.6 (C-1), 80.2 (C-2), 72.4 (C-5), 68.7 (C-3), 65.4 (C-4), 62.1
(C-6), 20.6, 20.5, 20.4 (3ꢂOAc); CIMS m/z 348 ([MþH]þ, 100%);
HRCI-MS calcd for C13H18NO8S [MþH]þ 348.0753; found: 348.0766.
´
1. (a) Ferna´ndez-Bolan˜os, J. G.; Lo´ pez, O. In Topics in Heterocyclic Chemistry;
Gupta, R. R., El Ashry, E. S. H., Eds.; Springer: Berlin, Heidelberg, 2007; Vol. 7,
pp 67–100; (b) Zappia, G.; Gacs-Baitz, E.; Delle Monache, G.; Misiti, D.; Nevola,
L.; Botta, B. Curr. Org. Synth. 2007, 4, 81–135; (c) Zappia, G.; Cancelliere, G.;
Gacs-Baitz, E.; Delle Monache, G.; Misiti, D.; Nevola, L.; Botta, B. Curr. Org.
Synth. 2007, 4, 238–307; (d) Ella-Menye, J.-R.; Wang, G. Tetrahedron 2007, 63,
10034–10041.
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Eluted second was 28 (269 mg, 27%); Rf 0.10 (80:1 CH2Cl2–
25
MeOH); [
a
]
ꢁ60 (c 0.9, CH2Cl2); IR nmax 3275 (NH), 1755, 1740
D
(C]O), 1246, 1223 (AcO) cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 6.18 (s,
1H, NH), 5.26 (t, 1H, J4,3¼9.6 Hz, J4,5¼9.6 Hz, H-4), 5.21 (d, 1H,
J1,2¼3.9 Hz, H-1), 5.20 (dd, 1H, J3,2¼4.5 Hz, J3,4¼9.6 Hz, H-3), 4.84 (t,
1H, J2,1¼3.9 Hz, J2,3¼4.5 Hz, H-2), 4.24 (dd, 1H, J6a,5¼5.4 Hz,
J6a,6b¼12.3 Hz, H-6a), 4.14 (dd, 1H, J6b,5¼2.7 Hz, J6b,6a¼12.3 Hz, H-
6b), 3.70 (ddd, 1H, J5,4¼9.6 Hz, J5,6a¼5.4 Hz, J5,6b¼2.7 Hz, H-5), 2.12,
3. Girniene, J.; Tatiboue¨t, A.; Sackus, A.; Yang, J.; Holman, G. D.; Rollin, P. Carbo-
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Rault, S. Bioorg. Med. Chem. 2003, 11, 1161–1167.
2.08, 2.06 (3s, 3H each, 3ꢂOAc); 13C NMR (300 MHz, CDCl3)
d 170.5,
170.1, 169.1, 157.3 (4CO), 80.8 (C-1), 74.9 (C-2), 71.9 (C-5), 69.4 (C-3),
65.4 (C-4), 62.1 (C-6), 20.6, 20.4 (3ꢂOAc); CIMS m/z 272
([MþHꢁAcOH]þ, 100%), 290 ([MþHꢁCH2CO]þ, 64%), 332 ([MþH]þ,
94%), 543 ([2MþHꢁ2AcOH]þ, 6%), 621 ([2MþHꢁCH2CO]þ, 10%),
663 ([2MþH]þ, 16%); HRCI-MS calcd for C13H18NO9 [MþH]þ
332.0982, found: 332.0977.
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3.11. Experimental conditions for the crystal structure
determination of 16
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Crystals of compound 16 with molecular formula C15H19NO9S
appear as colourless prisms with well shaped faces. Crystal size,
0.16ꢂ0.20ꢂ0.40 mm; crystal system, monoclinic; space group P21;
unit-cell dimensions, a¼10.797(2), b¼8.290(3), c¼11.116(2) Å,
b
¼109.433(9)ꢀ; unit-cell volume, V-¼938.3(4) Å3; formula units
per unit cell, Z¼2; calculated density, Dx¼1.378 g cmꢁ3; measured
density, Dm¼1.38 g cmꢁ3; F(000) value, 408; absorption coefficient,
m
¼0.219 mmꢁ1; temperature, T¼293 K. Unit-cell parameters and
crystal orientation matrix were determined on a CAD-4 Enraf–
Nonius automated four-circle diffractometer from the least-squares
treatment of the setting angles of 25 independent reflections. In-
tensity data were collected at room temperature in the
u/2q scan
mode, using Mo K
a
radiation, (
l
¼0.071069 Å), qmax¼30ꢀ; range of

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