Anhydroazasugars as key intermediates in the stereocontrolled preparation of azasugars and their ethyl thioglycosides

Article abstract of DOI:10.1016/j.tetasy.2004.01.003

Bicyclic azasugar thioglycosides, a new type of azasugar and alkaloid derivative, are stereoselectively prepared from easily available glycosylenamines (D-gluco and L-rhamno configurations), via 1,4-anhydroazasugar derivatives. Polyhydroxylated pyrrolidines (nonreducing pyrrolidine azasugars) are also prepared by reduction with sodium cyanoborohydride of the same 1,4-anhydroazasugars. The stereochemical assignments of the new stereogenic centres are based on NMR experiments, including a study of the interproton distances from quantitative treatment of NOE data and molecular modeling.

Full text of DOI:10.1016/j.tetasy.2004.01.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 603–615
Anhydroazasugars as key intermediates in the stereocontrolled
preparation of azasugars and their ethyl thioglycosides
*
ꢀ
Jose Fuentes, Francisco J. Sayago, Jose M. Illangua, Consolacion Gasch,
ꢀ
ꢀ
ꢀ
Manuel Angulo and M. Angeles Pradera
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 12 September 2003; revised 19 December 2003; accepted 5 January 2004
Abstract—Bicyclic azasugar thioglycosides, a new type of azasugar and alkaloid derivative, are stereoselectively prepared from
easily available glycosylenamines (D-gluco and L-rhamno configurations), via 1,4-anhydroazasugar derivatives. Polyhydroxylated
pyrrolidines (nonreducing pyrrolidine azasugars) are also prepared by reduction with sodium cyanoborohydride of the same 1,4-
anhydroazasugars. The stereochemical assignments of the new stereogenic centres are based on NMR experiments, including a study
of the interproton distances from quantitative treatment of NOE data and molecular modeling.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
glycoside in which the anomeric oxygen atom has been
substituted by a sulfur atom.7 The thioglycosides have
also been used as chiral inductors in enzymatic synthe-
ses.8 As a consequence of their enzyme-inhibitory
activity, both types of compounds have been tested as
potential drugs to treat a variety of carbohydrate-med-
iated diseases.9;10
The stereocontrolled preparation of highly functional-
ized molecules, as natural and pharmaceutically impor-
tant products, is currently a challenge in organic
chemistry.1 In these syntheses, key compounds with
defined stereogenic properties are frequently generated,
to be later transformed into the desired target. Among
such intermediates are carbohydrate derivatives because
they have numerous stereogenic centres and, due to their
conformational properties, can be used in highly stereo-
selective reactions.2 During the last few years, we have
described 1,4-anhydroazasugars3 and 1,6-anhydro-
azasugars,4 which are easily prepared from inexpensive
glycosylamines, and have been used, as versatile inter-
mediates, in the stereocontrolled preparation of 4-ami-
nosugars,3 of seven-membered iminocyclitols4 and of
N-vinyl derivatives of O-protected hydroxypyrrolidines.3
The bibliographic data on iminocyclitol derivatives
having a thioalkoxy group on the pseudoanomeric car-
bon atom, that is azasugar thioglycosides, are very
scarce, and limited to thioanalogues of the indolizidine
alkaloid castanospermine having the sulfur atom taking
part in the five-membered ring.11
Continuing our work on the chemistry of anhydro-
azasugars,3;4 herein we present the preparation of the
D
-galacto 6 and L-talo 18 and 23 derivatives from
readily available glycosylenamines 1 and 13, and their
use, as key intermediates, in the stereoselective synthesis
of the dihydroxypyrrolidines 8 and 20, and of the aza-
sugar ethyl thioglycosides, or thioalkoxy alkaloid
At the same time, the wide range of physiological and
pathological processes controlled by glycosidases has
stimulated the isolation from natural sources and the
syntheses of specific inhibitors of such enzymes.5 Among
these inhibitors are azasugars (for instance polyhydr-
oxylated pyrrolidines and pyrrolizidines, which can be
considered as alkaloid derivatives mimicking the struc-
ture of monosaccharides6), and thioglycosides, a type of
derivatives, 11, 12, 24 and 25. The imino-D-galactitol 9
is an inhibitor of E. coli K12 UDP-Gal mutase and
micobacterial galactan biosynthesis,12 and several multi-
step and/or low overall yielding syntheses of this com-
pounds have been reported. One of these synthesis12
starts from an aldolactone, and uses a strategy involving
the formation of the pyrrolidine ring by reaction of
benzylamine with a 1,4-di-O-mesyl acyclic D-glucose
derivative. Other syntheses start from sugar acetals,13
* Corresponding author. Tel.: +34-954557150; fax: +34-954624960;
e-mail: jfuentes@us.es
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.003

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J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
a-glycosides,14 pyrrole-1-nitrones,15 and glucose dithio-
acetal.16 The hydroxypyrrolidine 22 has not been pre-
viously reported, although the hydrochloride of its
enantiomer has been prepared17 from a lactam. Our
previous results on azasugar thioglycosides have been
recently communicated.18
azasugar 6 in high yield. Treatment of 6 with sodium
cyanoborohydride in acetic acid caused N-deprotection,
reduction of the anomeric carbon and N-acetylation
with formation of the pyrrolidine derivative 7, which
was not purified and characterized only by FABMS.
In situ treatment of 7 with a catalytic amount of sodium
methoxide afforded 8 in 77% yield from 6. The NMR
data in methanol-d4 of 8 showed the presence of the 2-
oxapyrrolizidine 8a (minor product), coming from the
internal addition of the OH on the carbonyl group.
Compound 8a was not isolated and is in equilibrium, in
the NMR tube, with 8. Its 13C NMR data are included
in the Experimental section. Simultaneous N- and O-
deprotection of 8 with 1 M HCl in methanol yielded
(95%) the target iminocyclitol 10, whose NMR data as
ammonium hydrochloride 9 and as the free base were
consistent with those previously reported.12 The overall
yield of the sequence 1–10 is 23.1%.
2. Results and discussion
2.1. Synthesis and structure
The preparation of the anhydroazasugars was based on
the capacity of the diethoxycarbonylvinyl group to sta-
bilize an amide ion3;4 and to produce internal SN2
reactions in suitably substituted sugar derivatives. The
starting material for 6 (Scheme 1) was the b-D-gluco-
pyranosylenamine 1,19 which by reaction with
anisaldehyde dimethyl acetal produced the 4,6-O-p-
methoxybenzylidene acetal 2. Di-O-benzoylation of 2
(fi3), followed by reduction with sodium cyanoboro-
hydride gave the partially O-protected glucosylenamine
4, which by successive reactions with mesyl chloride
(fi5) and sodium methoxide produced the anhydro-
The structures of compounds 2–6 and 8 were based on
analytical and spectroscopic data (see Tables 1 and 2,
and experimental). For stereochemical assignments see
Section 2.2. The benzoylation of the HO-2 and HO-3 in
3, and the mesylation of HO-4 in 5 were evident from
the deshielding in the resonances of H-2, H-3 and H-4,
O
O
HO
PMBOCH2
MP
O
MP
O
O
O
i
ii
iii
O
NHP
O
NHP
OBz
HO
NHP
HO
BzO
NHP
OBz
HO
OH
BzO
HO
OH
3
1
2
4
O
O
PMBOCH2
BzO
PMBOCH2
MsO
OH
OH
O
N
O
N
v
vi
PMBO
N
vii
iv
PMBO
NHP
P
OBz
BzO
OBz
BzO
OBz
OH
HO
6
7
5
8
OH
H
N
O
H
N
OH
HO
OH
HO
H
Cl —
viii
+
ix
N
PMBO
HO
HO
OH
O
OH
HO
OH
10
9
8a
CO2Et
P = -CH=C(CO2Et)2
SEt
OR
EtO2C
x
6
N
H
OR
MP =
OMe
PMBOCH2
OMe
PMB =
CH2
),
11R = Bz (5S 11aR = Bz (5R)
12R = H (5 )
S
Scheme 1. Reagents and conditions: (i) anisaldehyde dimethyl acetal, DMF/PTSA, 50 ꢁC/20 mmHg, 1 h; (ii) ClBz/Py, rt, 24 h; (iii) NaBH3CN/AcOH,
rt, 2.5 h; (iv) ClMs/Py, rt, 24 h; (v) NaOMe/DMF, 45 ꢁC/20 mmHg, 15 min; (vi) NaBH3CN/AcOH, rt, 24 h; (vii) NaOMe (catalytic)/MeOH, rt, 6 h;
(viii) MeOH/HCl, 65 ꢁC, 1 h; (ix) Dowex 50w8x; (x) EtSH/Cl2CH2/PTSA, rt, 15 min; (xi) NaOMe (catalytic)/MeOH, rt, 4 h.

J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
605
Table 1. Selected NMR spectroscopic data (d, ppm; J, Hz) for compounds 2–6, 14–18 and 23 at 500 MHz
Sugar ring
Enamino moiety
dH-1
dJ1;2
dH-2
dH-3
dH-4
dC-1
dC-4
dNH
d ¼ CH
d ¼ CH
d ¼ C
2a
4.68t
4.84t
8.6
8.9
3.29m
5.52t
5.41t
3.46m
5.89t
5.68t
3.40t
3.93t
88.6
87.8
87.3
87.4
88.1
84.7
84.6
85.8
84.8
89.6
89.1
80.2
78.4
69.4
74.2
65.1
71.3
79.9
82.0
77.9
65.6
66.3
9.13dd
9.37dd
9.30dd
9.28dd
––
8.04d
7.98d
8.15d
7.96d
7.69s
8.04d
8.02d
8.04d
8.07d
7.69s
7.79s
158.1
157.4
158.5
157.1
145.9
158.0
157.7
158.0
156.9
146.3
146.5
91.3
94.9
94.7
95.1
100.1
93.8
94.5
93.7
94.6
98.9
99.5
3b
4c
5.23t
4.74t
5.83d
9.1
9.3
4.05m
5.17t
5b
5.44t
5.84t
6b
2.2
2.0
5.14m
4.27dd
4.37dd
4.11br s
5.90dd
5.37dd
5.11d
4.39dd
4.60dd
3.78dd
5.51dd
5.31d
4.44m
4.76s
3.54t
14b
15b
16b
17b
18b
23b
4.76dd
4.79dd
4.61dd
5.01dd
5.58br s
5.36br s
9.42dd
9.42dd
9.52dd
9.45dd
––
1.5
4.51dd
4.47t
4.90t
<0.5
1.2
<0.5
<0.5
4.67br s
––
a In DMSO-d6.
b In CDCl3.
c In (CD3)2CO.
Table 2. Selected NMR d values (ppm) for pyrrolidines 8, 20, and pyrrolizidines 11, 11a, 12, 24, 24a, 25 and 25a at 500 MHz
R
4
N
N
5
R
1
3
6
2
5
2
7a
O
7
4
3
1
R
8, 20
11, 11a, 12, 24, 24a, 25, 25a
Heterocyclic moiety
Aglycone
H-1
––
H-2
H-3
4.15
H-5
3.87
H-7a
––
C-1
––
C-2
C-3
C-5
C-7a
––
NC@O CH2
CH2
8a
4.13–
4.10
67.5
79.0
55.5
172.8
––
––
3.42
3.61
3.38
4.35
20b
11a
––
3.90
––
3.96
5.61
5.82
5.41
––
––
69.4
––
74.7
95.2
91.5
95.8
56.4
72.4
72.1
72.0
––
173.8
––
––
––
4.33
4.17
4.35
3.80
3.62
4.10
80.8
82.6
79.8
69.0
65.8
70.9
2.74
2.67
2.65
2.54
2.65
22.3
28.1
22.0
11aa
12b
––
4.92
––
––
––
4.20–
4.15
––
––
2.55
2.67
2.58
2.57
2.78
2.63
24b
3.67
3.65
––
––
5.56
5.26
4.29
4.43
3.09
3.27
79.1
77.4
––
––
90.3
96.4
74.9
76.2
74.4
75.0
––
––
27.7
25.1
24ab
25a
25aa
4.51
3.97
––
––
5.68
5.35
4.51
4.72
3.48
3.53
79.6
78.2
––
––
90.5
96.2
72.6
72.5
72.6
72.8
––
––
27.5
25.2
a In CDCl3.
b In CD3OD.
when they were compared with the same signals in the
parent compounds 2, and 4. The 1H NMR spectrum of 6
had no signal for NH, and showed a singlet (7.69 ppm)
for the HC@ of the enamino moiety (@CHNR2) instead
of the doublet (@CHNHR) of the parent compounds 2–
5. The signal for H-1 was downfield shifted, whereas the
resonances for H-4 and C-4 were 0.41 and 9.1 ppm,
respectively, upfield shifted as corresponds to the sub-
stitution of an ester group by an enamino group.3 The
formation of 6 involves a strong change in the confor-
mation of the sugar ring, which produces important
changes in the values of all the ring coupling constants,
these values being in agreement with that expected for
the B1;4 conformation. The monocyclic structure of 8 is
supported on its 13C NMR signals at d 22.7 (N–COCH3)
and 172.8 (N–COCH3) ppm, which are in agreement
with the presence of an N-acetyl group.20 The 13C NMR
signal for C-3 of 8a appeared at 114.7 ppm as
CO2Et
CO2Et
OH
N
BPMO
SEt
OBz
11
Et
H
+
6
S
BzO
26
Scheme 2. Formation of 11.

606
J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
corresponds to a carbon atom simultaneously bonded to
two oxygens and one nitrogen.21
for 11 and 4.92 ppm for 11a). For stereochemical
assigments see NOE study in Section 2.2.
Reaction of 6 with ethanethiol in dichloromethane in the
presence of p-toluensulphonic acid (PTSA) at rt for
15 min produced a diastereoisomeric mixture of the
ethyl thioglycosides of azasugars 11 (3S,5S) and 11a
(3S,5R) in virtually quantitative yield, the 11/11a ratio
being 4:1. In the formation of 11 and 11a (similarly for
the formation of 24 and 25) the attack of ethanethiol
takes place preferably on the opposite side of the bulky
OBz group producing the 5S ethylthiopyrrolidine 26 as
major intermediate compound (Scheme 2). The stere-
oselectivity of the addition step in 26 is 100%, the
bicyclic compound 11 being produced only with the 3S
configuration.
Conventional deacylation4 of 11 with NaOMe/MeOH
afforded 12 in 70% yield.
Reaction of b-L
-rhamnopyranosylenamine 1319 with
anisaldehyde dimethyl acetal gave the di-O-protected
derivative 14, which was O-mesylated to have 15
(Scheme 3). The acetal group was removed with etha-
nethiol, under transacetalation conditions,22 giving 16.
The treatment of 16 with benzoyl chloride (fi17) fol-
lowed by reaction with sodium methoxide in DMF
produced the anhydroazasugar derivative 18, which by
reduction with sodium cyanoborohydride in acetic acid
gave the N-acetyl pyrrolidine 18, which was no isolated,
and in situ de-O-benzoylated to have 20. As in the case
of 8, the NMR data of 20 showed that this compound in
methanol-d4 is in equilibrium with the oxapyrrolizidine
20a. N-Deprotection of 20 with 1 M HCl in methanol
gave the pyrrolidine hydrochloride 21, not previously
reported. Its 1H NMR data coincided with that reported
for its enantiomer.17 Treatment of 21 with resin Dowex
50W 8x produces the free base 22. The overall yield for
the transformations 13–22 is 31.4%.
The chemical shift (72.4 ppm) for the resonance of C-5
in 11 was in agreement with the presence of the sulfur
atom. This resonance undergoes an upfield shift of
16 ppm with respect to that for the same atom (C-1) in 6.
The ethylthio group was also evident from the MS data
and from the resonances of H-1, and S–CH2 (Table 2).
The NMR spectra of 11 showed no signals for the vinyl
group, and the chemical shift values for the resonances
of H-3 (5.61 ppm) and C-3 (95.2 ppm) were in the range
expected for a CH group simultaneously joined to
oxygen and nitrogen atoms. The structural data for 11a
were similar, the main difference between 11 and 11a
being the value for the chemical shift of H-5 (4.35 ppm
The structural data for compounds 14–17 (Table 1) were
similar to those discussed above for 2–5. The NMR
spectra of the 1,4-anhydroazasugars 18 and 23 showed
the same strong changes with respect to the data for 17
O
O
N
O
O
v
i
ii
HO
NHP
HO
HO
NHP
MsO
NHP
P
OH
O
O
O
O
O
O
13
14
15
23
MP
MP
MP
viii
iii
O
O
CO2Et
N
O
v
SEt
EtO2C
N
iv
MsO
BzO
NHP
MsO
NHP
P
OH
BzO
OBz
OBz
HO
OH
O
17
18
16
vi
H
OH
24 5S
24a 5R
O
O
OH
OH
OH
OH
viii
N
N
N
vii
OH
OH
O
BzO
H
OBz
OH
CO2Et
SEt
EtO2C
20a
20
19
N
OBz
OBz
O
ix
H
H
OH
HO
H
H
N
Cl
N
25 5S
25a 5R
x
HO
HO
OH
OH
22
21
Scheme 3. Reagents and conditions: (i) anisaldehyde dimethyl acetal, DMF/PTSA, rt/20 mmHg, 1 h; (ii) ClMs/Py, rt, 24 h; (iii) EtSH/Cl2CH2/PTSA,
rt, 4 h; (iv) ClBz/Py, rt, 24 h; (v) NaOMe/DMF, 45 ꢁC/20 mmHg, 15 min; (vi) NaBH3CN/AcOH, rt, 2.5 h; (vii) NaOMe/MeOH, rt, 4 h; (viii) EtSH/
Cl2CH2/PTSA, rt, 15 min; (ix) MeOH/HCl, 65 ꢁC, 1 h; (x) Dowex 50w8x.

J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
607
and 15, respectively, as in the case of 6, and also the
vicinal coupling constants were indicative of the B1;4
conformation.
ments of a contact between H-6 and the methylene
group of the SEt linked to C-5 supports an S configu-
ration for this stereogenic centre.
The pyrrolidine structure of 20 was evident from the 13
C
On the other hand, this enhancement is absent in the 1D
NOESY spectrum of 25a, indicating a possible change
in the configuration of C-5 (R configuration) with
respect to the former. The observation of the weak NOE
interactions H-5/H-7a for 25 or H-5/H-1 and H-5/H-7
for 25a also agreed with these assignments. Analo-
gously, similar NOE contacts observed for the SEt
group in the NOESY spectra of compounds 11 and 11a
suggest that these compounds also differ in the config-
uration of C-5 (5S for 11 and 5R for 11a).
NMR resonances at 22.4 (CH3) and 173.8 (CO) ppm for
the N-acetyl group. In this case, the NMR data showed
that the bicyclic compound 20a exists in the equilibrium
in a 9:1 (20/20a) ratio. The resonance for C-3 in 20a
appears at 114.7 ppm.
Treatment of 23 with ethanethiol in the aforementioned
conditions gave, after column chromatography, the O-
unprotected ethyl thioglycosides 24 (5S, 49% yield) and
24a (5R, 21% yield).
With the configuration of C-5 already assigned, the
analysis of the NOE contact between H-5 and H-3 seems
to be a good indication of the configuration at C-3.
Nevertheless, a simple determination of the NOE
intensities showed no great differences between these
compounds for this interaction, probably due to differ-
ences in their conformations. For 25 and 25a, the evi-
dence for the assignment of the configuration at C-3
came from the weak interactions observed for H-3.
Thus, a medium-intensity NOE contact with H-1 in
both compounds clearly indicates a R configuration for
C-3. Furthermore, a weak contact between H-3 and the
methylene of the SEt group in 25 (not observed for 25a)
confirms the proposed configurations. In agreement
with this assignment is the presence of a weak contact
between the CH(COOEt)2 and the methyl group linked
to C-1, which can be considered as exclusive of the R
configuration. For 11 and 11a, no such a clear indica-
tions for the configuration at C-3 could be detected in
the NOESY spectra. Only the trivial NOE contacts with
H-5 and CH(COOEt)2 were observed. Furthermore, the
high overlapping in the spectral region where
CH(COOEt)2 is located made it very difficult to
extract reliable information for this pair of diastereo-
isomers.
The best way to prepare the di-O-benzoyl derivatives 25
and 25a, useful for the NMR study discussed in Section
2.2, was the reaction of 18 with ethanethiol. This reac-
tion was virtually quantitative, 25 and 25a were isolated
products, and the 25/25a ratio was 7:3. The attack of the
EtSH on 18 and 23, to give 25, 25a, and 24, 24a,
respectively, also occurs mainly in trans relationship
with respect to the substituent on C-2 of the sugar ring,
with formation of the 5S thioglycoside as major com-
pound. The internal addition was 100% stereoselective
as in the case of 11. Benzoylation of 24 with benzoyl-
chloride and pyridine gave 25. The structural data of 24,
24a, 25 and 25a are included in Table 2 and Experi-
mental section. For stereochemical assignments, see
Section 2.2.
2.2. Stereochemical study
Assignment of proton and carbon resonances of 8, 11,
11a, 25 and 25a was helped by COSY, 1D TOCSY and
HMQC experiments. Proton–proton coupling constants
1
were directly measured from the H NMR spectra. For
the determination of the configuration of the two new
stereogenic carbon atoms C-3 and C-5, one- and two-
dimensional NOESY experiments were carried out.
NMR analysis of 11 and 11a was performed on a sample
To address the problem of the stereochemistry at the C-
3 centre in 11 and 11a we decided to go further into the
spectroscopic analysis and obtain interproton distances
from a quantitative treatment of the NOE data, and
compare them with those obtained for the energy opti-
mized conformations resulting from the study by
molecular modeling of the four possible diastereoiso-
mers (3R,5R; 3S,5S; 3R,5S and 3S,5R). The same study
was also applied to 25, in order to check this approach
in a similar compound whose asymmetric centres have
been previously assigned.
containing
a mixture (4:1) of both compounds.
Although these spectra were complex on account of the
presence of two different set of signals, the assignment of
all resonances, as well as the NOESY study, were pos-
sible for both diastereoisomers.
The values of the coupling constants 3J1;7a and 3J3;CH for
the pairs of compounds 25/25a and 11/11a showed that
the corresponding torsion angles are very similar for the
members of each pair, and therefore it could be expected
that the main structural differences between these com-
pounds are located in another part of the molecule. For
The longitudinal cross-relaxation rate constants (rNOE
)
were obtained from the NOE build-up curves (1D
NOESY for 25 and 2D NOESY for 11 and 11a) as
described in the Experimental part. Providing that the
interaction between two protons with a known distance
(rref ) can be clearly identified in the NOESY spectra, and
assuming a rigid isotropic hydrodynamic behaviour
of the molecule in solution, it is possible to extract
unknown distances (rij) by comparing the longitudinal
cross-relaxation rate constants (rij and rref ) according to
3
25 the small value of J5;6 (less than 1 Hz) indicates a
dihedral angle close to 90ꢁ between this pair of nuclei.
This could be interpreted as an indication of a trans
relative disposition of H-5 and H-6, since it is difficult to
consider a stable conformation of the pyrrolidine ring
compatible with such a small J value for a cis geometry.
Furthermore, the observation in the NOESY experi-

608
J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
1=6
match for the diastereoisomers with the proposed
configurations for C-5 (5S for 11 and 25 and 5R for
11a).
rij ¼ rref ðrref =rijÞ
Thus, for the evaluation of all the interproton distances,
:
the ortho–meta interaction in the aromatic moiety was
ꢁ
used as a reference with a value of 2.48 A.
For compound 8, a series of 1D NOESY spectra (mixing
time of 400 ms), with selective excitation of the well-
resolved signals, together with a 2D NOESY spectrum
(mixing time of 300 ms) were performed. All these
spectra showed the presence of EXSY peaks coming
from the hydroxyl groups and from a minor compound
present in the sample, which could be attributed to the
bicyclic compound 8a, although no further spectro-
scopic information could be obtained for this com-
pound. The concomitant presence of NOE and exchange
peaks made difficult in some cases the extraction of the
desired information for this compound. In this case, the
use of a longer mixing time (1 s) clearly improved
the situation. Under these conditions, the NOESY
spectra showed clear NOE contacts between the methyl
group of the N-acetyl moiety and the protons H-5a and
H-5b indicating a major participation of a Z confor-
mation of the N–CO bond. Taking into account this
geometry and the high stereoselectivity observed in the
case of the enamino group (compounds 11 and 11a), we
would expect the cycloaddition of the OH to the car-
bonyl group to give exclusively the R configuration for
C-3 in 8a.
For those peaks of compound 25 in which the overlap-
ping of signals prevented the use of selective experi-
ments, a modified equation was used to calculate
distances using the values of the normalized integral
volumes Vref and Vij:
1=6
rij ¼ rref ðVref =VijÞ
;
where the normalized integral volumes were measured in
a 2D NOESY experiment with a mixing time of 300 ms
(appropriate mixing time for this approximation in the
light of the NOE build-up curves). For the well-resolved
signals, it was also possible to estimate distances using
the initial slope in the build-up curves (1D NOESY
experiments), and compare them with those obtained
from the analysis of the 2D NOESY spectrum, and a
ꢁ
good match was found (differences lower than 0.08 A).
For compounds 11 and 11a, the interproton distances
were deduced from the 2D NOESY spectra.
Since no stereospecific assignment was available for the
two protons of the methylene group of the SEt moiety
and no correction23 was applied, the estimated distances
between these protons and H-6 or H-3 (data not shown)
were considered from a qualitative point of view as a
mere indication of the proximity between these parts of
the molecule. These distances showed that the SEt group
lies closer to H-3 in compound 11a than in 11,
suggesting an S configuration for C-3 in both com-
pounds.
3. Conclusion
1,4-Anhydroazasugars, which can be easily obtained
from inexpensive glycosylenamines, are suitable inter-
mediates to prepare stereoselectively two types of aza-
sugar derivatives. (a) The reduction with sodium
cyanoborohydride leads to N-acetyl polyhydroxypyr-
rolidines, with one methylene group adjacent to the
nitrogen atom. (b) Reaction with ethanethiol gives aza-
sugar thioglycosides with structure of 3-oxapyrroliz-
idines with a thioalkoxy group in the pseudoanomeric
position. In both cases, the overall yields are high. For
azasugars the method is an alternative to other described
methods, and azasugar thioglycosides constitute a new
class of glycoside. The only limitation is the necessary
trans relationship between the enamino and the mesyloxy
groups in the formation of the 1,4-anhydroazasugar.
Theoretical distances were measured from the energeti-
cally favourable conformations obtained by molecular
mechanics calculations with MM2 force field. Experi-
mental and theoretical values are shown in Table 3. The
listed values for the H3/H5 distance clearly indicate that
only one configuration for C-3 is in fair agreement
between experimental and theoretical data, supporting
the proposed configurations (3S for 11 and 11a and 3R
for 25). In addition, the H5/H6 distance shows a better
ꢁ
Table 3. Experimental and theoretical interproton distances (A) for 11, 11a and 25
Proton pair
Experimental
Theoretical
3S,5R
11
11a
3S,5S
3R,5S
3R,5R
H1–H7
H3–H5
H5–H6
H6–H7
2.17
2.25
3.01
2.55
2.24
2.61
2.11
2.89
2.35
2.17
2.76
2.79
2.44
3.64
2.79
2.79
2.20
2.77
2.37
3.09
2.19
3.76
2.39
3.10
25
3R,5S
3S,5S
3R,5R
3S,5R
H1–H7
H3–H5
H5–H6
H6–H7
2.22
2.78
2.64
2.40
2.38
2.98
2.72
2.50
2.21
3.75
2.70
2.46
2.32
2.41
2.49
2.43
2.31
3.50
2.41
2.48

J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
609
4. Experimental
4.1. General methods
For all the studied compounds, the NOESY cross peaks
were positive. 1D and 2D NOESY peak intensities were
evaluated with the XWINNMR program (Bruker).
Normalized integrals were obtained by division of the
measured integrals by the auto-peak value. The same
integration regions were used for all mixing times. If the
two peaks in the NOESY spectra for any pair of protons
were well isolated, the average normalized integral was
used; otherwise only one peak was considered. NOE
build-up curves were obtained from the normalized
integrals at different mixing times, and the cross-relax-
ation rates were calculated as the initial slope by linear
least-squares fitting of the measured points, assuming
the isolated spin-pair approximation (ISPA).27 The good
linearity observed in the build-up curves (R >0:99 in all
cases), within the range of mixing-time values used,
warranted the applicability of such approximation.
Melting points were determined with a Gallenkamp
apparatus and are uncorrected. A Perkin–Elmer Model
141 MC polarimeter, 1-cm tubes, and solutions in
CH2Cl2, at 589 nm, were used for measurement of
specific rotations. IR spectra were recorded for KBr
discs on a Bomen Michelson MB-120 FTIR spectro-
photometer. Mass spectra (EI, CI and FAB) were
recorded with a Kratos MS-80RFA or a Micromass
AutoSpecQ instrument with a resolution of 1000 or
60,000 (10% valley definition). For the FAB spectra,
ions were produced by a beam of xenon atoms (6–
7 keV), using 3-nitrobenzyl alcohol or thioglycerol as
matrix and NaI as salt. TLC was performed on
silica gel HF254, with detection by UV light or char-
ring with H2SO4. Silica gel 60 (Merck, 70–230 and
230–400 mesh) was used for preparative chromato-
graphy.
All the stereoisomers were modeled using the MM2
force field as implemented in CS Chem3D Ultraꢂ soft-
ware (CambridgeSoft).
NMR experiments were recorded on a Bruker AMX 500
(500.13 MHz for 1H and 125.75 MHz for 13C) or a
Bruker AMX 300 spectrometer (300.15 MHz for 1H and
75.50 MHz for 13C). Sample concentrations were typi-
cally in the range 10–15 mg per 0.5 mL of CDCl3.
Chemical shifts are given in ppm, using the TMS as
4.2. Preparation of compounds 2 and 14
A solution of the corresponding compounds19 1 and 13
(51.5 mmol), 4-methoxybenzaldehyde dimethyl acetal
(14.0 g, 76.8 mmol) and PTSA (97 mg, 0.48 mmol) in
DMF (50 mL) was rotated under aspirator pressure
(20 mmHg) at 50 ꢁC for 25 h. The solution was poured
onto a stirred mixture of ice (50 g), and satd aq NaHCO3
(100 mL). The solid residue was filtered off, washed
successively with light petroleum and water, and dried.
The residue was crystallized from ethanol.
1
reference. H and 13C assignments were confirmed by
2D conventional experiments. For the stereochemical
study, a 5 mm inverse detection probe operating at
303 K was used. Selective inversion 1D experiments were
performed by using the DANTE-Z module24 (n ¼ 300,
s ¼ 125 ls, h ¼ 0:3ꢁ). In 1D TOCSY experiments,
WALTZ16 was used for the 150 ms isotropic mixing
time (p=2 pulse width of 49 ls).25 For the 1D NOESY
experiments, mixing times of 100, 200, 300 and 600 ms
were used for 25, and 400 ms for 8, 11 and 25a. Typi-
cally, for all the 2D experiments, a spectral width of
4.2.1. N-(2,2-Diethoxycarbonylvinyl)-4,6-O-(4-methoxy-
benzylidene)-b-D-glucopyranosylamine, 2. Yield 91%;
21
mp 134–136 ꢁC (ethanol); ½aꢀ ¼ +20 (c 0.7, CH2Cl2);
D
1
5300 Hz in the H dimension and 27,000 Hz in the 13C
FABMS m=z 490 [(M+Na)þ]; IR 3484, 3260, 2978, 2930,
2878, 1701, 1649, 1607, 1383, 1248, 1101, 1013,
dimension were used. The 2D homonuclear COSY was
performed using a standard pulse sequence. The data
matrix of 1024 · 256 used in this experiment was zero-
filled to 512 data points in the indirect dimension and
multiplied by sine-bell functions in both dimensions.
The 2D heteronuclear one bond proton–carbon corre-
lation experiment was collected using the HMQC
sequence with BIRD filter (null time for this filter of
400 ms). A total of 256 increments were collected with 16
transients per increment (data matrix of 256 · 1024
points), using a 1 s relaxation delay and a delay corre-
sponding to a J value of 145 Hz. 13C decoupling was
achieved using the GARP scheme. The 2D NOESY
experiments were obtained with mixing times of 300 ms
and 1 s for 8, 200, 300, 400, and 600 ms for 11 and 11a,
and 300 ms for 25. Sixty-four scans of 1024 points were
accumulated for 256 t1-increments, using a recycle delay
of 2 s. The TPPI-States procedure was used for fre-
quency discrimination in the indirect dimension.26 Prior
to Fourier transformation, an expansion of the data by
zero-filling to 2048 · 1024 was performed, and shifted
sine-bell window functions were applied in both
dimensions.
1
797 cmꢁ1; H NMR (500 MHz, DMSO-d6) d 9.13 (dd,
1H, JNH;1 ¼ 8:6, JNH;HC@ ¼ 13:8, NH), 8.04 (d, 1H,
HC@), 7.35–6.91 (m, 4H, Ar), 5.67 (d, 1H, J2;OH ¼ 5:8,
OH–H-2), 5.52 (s, 1H, OCHO), 5.46 (d, 1H, J3;OH ¼ 5:0,
OH–H-3), 4.68 (t, 1H, J1;2 ¼ 8:6, H-1), 4.17 (m, 1H,
H-5), 4.13 (q, 2H, JH;H ¼ 7:1, CH2CH3), 4.07 (q,
2H, CH2CH3), 3.74 (s, 3H, CH3O), 3.65 (t, 1H,
J5;6a ¼ J6a;6b ¼ 10:1, H-6a), 3.49 (m, 1H, H-6b), 3.46 (m,
1H, H-3), 3.40 (t, 1H, J3;4 ¼ J4;5 ¼ 9:3, H-4), 3.29 (m,
1H, H-2), 1.20, (m, 6H, 2CH2CH3); 13C NMR
(125.7 MHz, DMSO-d6) d 167.4 (CO chelated), 164.8
(CO free), 159.5–113.3 (Ar), 158.1 (HC@), 100.6
(OCHO), 91.3 (@C), 88.6 (C-1), 80.2 (C-4), 73.6 (C-2),
73.1 (C-3), 67.9 (C-6), 67.6 (C-5), 59.3, 59.1 (2CH2CH3),
55.1 (OCH3), 14.3, 14.2 (2CH2CH3); Anal. Calcd for
C22H29NO10: C, 56.52; H, 6.25; N, 3.00. Found: C,
56.26; H, 6.27; N, 2.84.
4.2.2. N-(2,2-Diethoxycarbonylvinyl)-2,3-O-(4-methoxy-
benzylidene)-b-L-rhamnopyranosylamine, 14. Yield 98%;
25
mp 174–176 ꢁC (ethanol); ½aꢀ ¼ +27 (c 0.9, CH2Cl2);
D

610
J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
FABMS m=z 474 [(M+Na)þ]; IR 3476, 2976, 2915, 1707,
1H, H-5), 2.85 (s, 3H, CH3SO2), 1.56 (d, 3H, J5;6 ¼ 6.2,
H-6), 1.28, and 1.17, (each t, each 3H, JH;H ¼ 7:1,
2CH2CH3); 13C NMR (125.7 MHz, CDCl3) d 167.7 (CO
chelated), 165.6 (CO free), 165.5, 165.2 (2CO), 156.9
(HC@), 134.0–128.6 (Ar), 94.6 (@C), 84.8 (C-1), 77.9
(C-4), 71.5 (C-3), 72.6 (C-5), 70.4 (C-2), 60.2, 60.1
(2CH2CH3), 39.1 (SO2CH3), 18.0 (C-6), 14.4, 14.2
(2CH2CH3); HRCIMS m=z obsd 620.1778, calcd for
C29H34NO12S 620.1802. Anal. Calcd for C29H33NO12S: C,
56.21; H, 5.37; N, 2.26. Found: C, 56.19; H, 5.41; N, 2.28.
1
1601, 1379, 1250, 1094, 804 cmꢁ1; H NMR (500 MHz,
CDCl3) d 9.42 (dd, 1H, JNH;1 ¼ 9:0, JNH;HC@ ¼ 14:0,
NH), 8.04 (d, 1H, HC ¼ ), 7.36–6.87 (m, 4H, Ar), 6.10 (s,
1H, OCHO), 4.76 (dd, 1H, J1;2 ¼ 2:0, H-1), 4.39 (dd, 1H,
J3;4 ¼ 7:0, H-3), 4.27 (dd, 1 H, J2;3 ¼ 5:5, H-2), 4.18 (m,
4H, 2CH2CH3), 3.79 (s, 3H, CH3O), 3.54 (t, 1H,
J4;5 ¼ 7:0, H-4), 3.41 (m, 1H, H-5), 1.35 (d, 3H, J5;6 ¼ 6:5,
H-6), 1.26 (m, 6H, 2CH2CH3); 13C NMR (125.7 MHz,
CDCl3) d 167.5 (CO chelated), 165.9 (CO free), 158.0
(HC@), 160.5–114.0 (Ar), 103.7 (OCHO), 93.8 (@C),
84.7 (C-1), 80.7 (C-3), 73.9 (C-2), 72.4 (C-5), 71.3 (C-4),
60.1, 60.0 (2CH2CH3), 55.3 (OCH3), 17.6 (C-6), 14.3,
14.2 (2CH2CH3); Anal. Calcd for C22H29NO9: C, 58.53;
H, 6.47; N, 3.10. Found: C, 58.35; H, 6.41; N, 3.17.
4.4. 2,3-Di-O-benzoyl-N-(2,2-diethoxycarbonylvinyl)-
6-O-(4-methoxybenzyl)-b-D-glucopyranosylamine, 4
A solution of 3 (434 mg, 0.64 mmol) in acetic acid
(8.68 mL), was treated with NaBH3CN (135 mg,
2.04 mmol), stirred for 2.5 h at rt and controlled by TLC
(CH2Cl2/MeOH, 100:1). The mixture was added to ice–
water and extracted with CH2Cl2. The organic layer was
separated, washed with satd aq NaHCO3, and water,
dried (MgSO4), filtered and evaporated to dryness. The
4.3. Preparation of compounds 3 and 17
Into a stirred solution of the corresponding compound
2, 16 (5.6 mmol) in dry pyridine (13.8 mL), at 0 ꢁC,
benzoyl chloride (22.4 mmol) was dropped. The solution
was stirred at rt for 24 h, then poured into ice–water and
extracted with CH2Cl2. The combined extracts were
washed with 1 M H2SO4, satd aq NaHCO3, and water,
dried (MgSO4) and evaporated to dryness. The residue
was purified by column chromatography.
residue was purified by column chromatography
22
D
(CH2Cl2). Yield 68% as amorphous solid; ½aꢀ ¼ )10 (c
0.5, CH2Cl2); FABMS m=z 700 [(M+Na)þ]; IR 3464,
3072, 2905, 1724, 1669, 1607, 1382, 1265, 1101,
712 cmꢁ1 1H NMR (500 MHz, [(CD3)2CO]) d 9.30
;
(dd, 1H, JNH;1 ¼ 9:1, JNH;HC@ ¼ 13:4, NH), 8.15 (d,
1H, HC@), 7.95–6.87 (m, 14H, Ar), 5.68 (t, 1H,
J2;3 ¼ J3;4 ¼ 9:1, H-3), 5.41 (t, 1H, J1;2 ¼ 9:1, H-2), 5.23
(t, 1H, H-1), 5.09 (d, 1H, J4;OH ¼ 5:6, OH–H-4), 4.52 (m,
2H, CH2OPMB), 4.15, 4.13 (each m, each 2H,
CH2CH3), 4.05 (m, 1H, H-4), 3.92 (ddd, 1H, J4;5 ¼ 9.8,
J5;6a ¼ 1:9, J5;6b ¼ 5:3, H-5), 3.89 (dd, 1H, J6a;6b ¼ 11:0,
H-6a), 3.79 (m, 1H, H-6b), 3.78 (s, 3H, CH3O), 1.22,
1.17 (each t, each 3H, JH;H ¼ 8:6, 2CH2CH3); 13C NMR
(125.7 MHz, [(CD3)2CO]) d 168.4 (CO chelated), 166.3,
166.2, 165.3 (3CO), 158.5 (HC@), 134.4–114.4 (Ar),
94.7(@C), 87.3 (C-1), 78.7 (C-5), 77.0 (C-3), 73.6
(CH2OPMB), 72.9 (C-2), 69.4 (C-4), 64.4 (C-6), 60.3,
60.1 (2CH2CH3), 55.5 (OCH3), 14.3 (2CH2CH3); Anal.
Calcd for C36H39NO12: C, 63.80; H, 5.80; N, 2.07.
Found: C, 63.52; H, 5.73; N, 1.98.
4.3.1. 2,3-Di-O-benzoyl-N-(2,2-diethoxycarbonylvinyl)-
4,6-O-(4-methoxybenzylidene)-b-D-glucopyranosylamine,
3. Column chromatography CH2Cl2. Yield 91%; amor-
23
D
phous solid; ½aꢀ ¼ )36 (c 0.9, CH2Cl2); CIMS m=z 676
[(M+H)þ]; IR 3069, 2982, 2944, 2903, 1730, 1663, 1613,
1
1267, 1101, 712 cmꢁ1; H NMR (500 MHz, CDCl3) d
9.37 (dd, 1H, JNH;1 ¼ 8:9, JNH;HC@ ¼ 13:2, NH), 7.98 (d,
1H, HC@), 7.95–6.83 (m, 14H, Ar), 5.89 (t, 1H,
J2;3 ¼ J3;4 ¼ 9:6, H-3), 5.53 (s, 1H, OCHO), 5.52 (t, 1H,
J1;2 ¼ 8:9, H-2), 4.84 (t, 1H, H-1), 4.40 (dd, 1H,
J5;6a ¼ 4:1, J6a;6b ¼ 9:9, H-6a), 4.26 (m, 2H, CH2CH3),
4.14 (m, 2H, CH2CH3), 3.93 (t, 1H, J4;5 ¼ 9:3, H-4), 3.82
(t, 1H, J5;6b ¼ 9:9, H-6b), 3.79 (m, 1H, H-5), 3.77 (s, 3H,
CH3O), 1.33, and 1.25, (each t, each 3H, 2CH2CH3); 13
C
NMR (125.7 MHz, CDCl3) d 167.5 (CO chelated), 165.5
(CO free), 165.3 (2CO), 160.1–113.5 (Ar), 157.4 (HC@),
101.5 (OCHO), 94.9 (@C), 87.8 (C-1), 78.4 (C-4), 71.9
(C-3), 71.8 (C-2), 68.7 (C-6), 68.3 (C-5), 60.3, 60.2
(2CH2CH3), 55.2 (OCH3), 14.3, 14.2 (2CH2CH3); Anal.
Calcd for C36H37NO12: C, 63.99; H, 5.52; N, 2.07.
Found: C, 63.66; H, 5.40; N, 2.32.
4.5. Preparation of compounds 5 and 15
Into a cooled (0 ꢁC) stirred solution of the correspond-
ing compounds 4 and 14 (0.894 mmol) in pyridine
(3.1 mL) under argon, mesyl chloride (326 lL,
4.11 mmol) was dropped. The mixture was stirred at rt
for 24 h and the reaction was controlled by TLC
(CH2Cl2/MeOH, 100:1). The solution was poured into
ice–water and extracted with CH2Cl2; the organic layer
was separated, washed with 1 M sulfuric acid, satd aq
NaHCO3, and water, dried (MgSO4), filtered, and
evaporated to dryness. The residue was purified by
column chromatography (CH2Cl2).
4.3.2. 2,3-Di-O-benzoyl-N-(2,2-diethoxycarbonylvinyl)-4-
O-mesyl-b-L-rhamnopyranosylamine, 17. Column chro-
matography CH2Cl2, and CH2Cl2/MeOH, 60:1. Yield
26
D
88%; amorphous solid; ½aꢀ ¼ +14 (c 0.9, CH2Cl2);
FABMS m=z 642 [(M+Na)þ]; IR 3291, 2984, 2940, 1736,
1661, 1609, 1269, 1082, 843, 712 cmꢁ1; 1H NMR
(500 MHz, CDCl3) d 9.45 (dd, 1H, JNH;1 ¼ 8:8, JNH;HC@
¼
13:2, NH), 8.07 (d, 1H, HC@), 8.05–7.34 (m, 10H, Ar),
5.90 (dd, 1H, J1;2 ¼ 1:2, J2;3 ¼ 3:4, H-2), 5.51 (dd, 1H,
J3;4 ¼ 9:8, H-3), 5.01 (dd, 1H, H-1), 4.90 (t, 1H, J4;5 ¼ 9:8,
H-4), 4.17, 4.07 (each m, each 2H, 2CH2CH3), 3.85 (m,
4.5.1. 2,3-Di-O-benzoyl-N-(2,2-diethoxycarbonylvinyl)-4-
O-mesyl-6-O-(4-methoxybenzyl)-b-D-glucopyranosyl-
28
amine, 5. Amorphous solid. Yield 85%; ½aꢀ ¼ 0 (c 1.0,
D

J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
611
CH2Cl2); FABMS m=z 778 [(M+Na)þ]; IR 3285, 2978,
2907, 2872, 1726, 1663, 1611, 1362, 1265, 1098, 957, 829,
1H, J2;3 ¼ 1:0, J3;4 ¼ 0, H-3), 4.76 (s, 1H, J4;5 ¼ 0, H-4),
4.49, 4.44 (each d, each 1H, JH;H ¼ 11:6, CH2OPMB),
4.06 (dd, 1H, J5;6a ¼ 5:5, J5;6b ¼ 7:3, H-5), 4.19 (m, 4H,
CH2CH3), 3.79 (s, 3H, CH3O), 3.47 (dd, 1H,
J6a;6b ¼ 10:1, H-6a), 3.33 (dd, 1H, H-6b), 1.27, 1.20
(each t, each 3H, JH;H ¼ 7:2, 2CH2CH3); 13C NMR
(125.7 MHz, CDCl3) d 166.0, 165.9, 165.8, 165.6 (4CO),
159.3–113.8 (Ar), 145.9 (HC@), 100.1 (@C), 88.1 (C-1),
79.9 (C-2), 76.9 (C-3), 75.3 (C-5), 73.2 (CH2O), 68.9 (C-
6), 65.1 (C-4), 60.9, 60.5 (2CH2CH3), 55.2 (OCH3), 14.2,
and 14.0 (2CH2CH3); Anal. Calcd for C36H37NO11: C,
65.54; H, 5.65; N, 2.12. Found: C, 65.34; H, 5.56; N,
2.26.
1
712 cmꢁ1; H NMR (500 MHz, CDCl3) 9.28 (dd, 1H,
JNH;1 ¼ 9:3, JNH;HC@ ¼ 13:2, NH), 7.96 (d, 1H, HC@),
7.96–6.89 (m, 14H, Ar), 5.84 (t, 1H, J2;3 ¼ J3;4 ¼ 9:3,
H-3), 5.44 (t, 1H, J1;2 ¼ 9:3, H-2), 5.17 (t, 1H, J4;5 ¼ 9:3,
H-4), 4.74 (t, 1H, H-1), 4.57, 4.53 (each d, each 1H,
JH;H ¼ 11:3, CH2OPMB), 4.26 (m, 2H, CH2CH3), 4.15
3
(q, 2H, JH;H ¼ 7:1, CH2CH3), 3.89–3.85 (m, 2H, H-5,
H-6a), 3.81 (s, 3H, CH3O), 3.76 (dd, 1H, J5;6b ¼ 4:0,
J6a;6b ¼ 11:4, H-6b), 2.82 (s, 3H, Ms), 1.32, 1.25 (each t,
each 3H, JH;H ¼ 7:0, 2CH2CH3); 13C NMR (125.7 MHz,
CDCl3) d 167.2 (CO chelated), 165.6, 165.4, 165.3 (CO),
159.4–113.5 (Ar), 157.1 (HC@), 95.1 (@C), 87.4 (C-1),
75.4 (C-5), 74.2 (C-4), 73.5 (CH2OPMB), 72.4 (C-3),
71.1 (C-2), 67.4 (C-6), 60.3, 60.0 (2CH2CH3), 55.2
(OCH3), 38.8 (Ms), 14.3, 14.2 (2CH2CH3); Anal. Calcd
for C37H41NO14 S: C, 58.80; H, 5.47; N, 1.85. Found: C,
58.47; H, 5.50; N, 1.75.
4.6.2.
1,4-Anhydro-2,3-di-O-benzoyl-N-(2,2-diethoxy-
-rhamnopyranosylamine 18. Column
chromatography AcOEt/hexane 1:4. Amorphous solid.
carbonylvinyl)-b-
L
24
Yield 60%; ½aꢀ ¼ +22 (c 0.9, CH2Cl2); CIMS m=z 524
D
[(M+H)þ]; IR 3063, 2991, 1736, 1609, 1458, 1370, 1283,
1
1029, 714 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.88–
4.5.2. N-(2,2-Diethoxycarbonylvinyl)-4-O-mesyl-2,3-O-
(4-methoxybenzylidene)-b-L-rhamnopyranosylamine, 15.
7.22 (m, 10H, Ar), 7.69 (s, 1H, HC@), 5.58 (br s, 1H, H-
1), 5.37 (d, 1H, J2;3 ¼ 6:0, H-2), 5.31 (d, 1H, H-3), 4.67
(br s, 1H, J4;5 ¼ 0, H-4), 4.18 (m, 4H, 2CH2CH3), 4.05
(m, 1H, H-5), 1.26 (d, 1H, J5;6 ¼ 6:0, H-6), 1.25, 1.13
(each t, each 3H, JH;H ¼ 7:0, 2CH2CH3); 13C NMR
(125.7 MHz, CDCl3) 166.5 (2CO), 165.6, 165.2, (2CO),
146.3 (HC@), 133.9–128.3 (Ar), 98.9 (@C), 89.6 (C-1),
74.1 (C-2), 73.5 (C-5), 73.4 (C-3), 65.6 (C-4), 60.9, 60.6
(2CH2CH3), 19.6 (C-6), 14.4, 14.1 (2CH2CH3); HRC-
IMS m=z obsd 524.1917, calcd for C28H30NO9 524.1921.
24
Yield 93%; mp 150–152 ꢁC (ethanol); ½aꢀ ¼ +39 (c 0.9,
D
CH2Cl2); CIMS m=z 530 [(M+1)þ]; IR 3290, 2986, 2940,
1697, 1653, 1597, 1346, 1252, 1177, 847 cmꢁ1;1H NMR
(500 MHz, CDCl3)
d
9.42 (dd, 1H, JNH;1 ¼ 9:0,
JNH;HC@ ¼ 13:5, NH), 8.02 (d, 1H, HC@), 7.35–6.88 (m,
4H, Ar), 6.21 (s, 1H, OCHO), 4.79 (dd, 1H, J1;2 ¼ 1:5, H-
1), 4.60 (dd, 1H, J2;3 ¼ 5:5, J3;4 ¼ 7:0, H-3), 4.51 (dd, 1H,
J4;5 ¼ 9:0, H-4), 4.37 (dd, 1H, H-2), 4.19 (m, 4H,
2CH2CH3), 3.80 (s, 3H, CH3O), 3.59 (m, 1H, H-5), 3.16
(s, 3H, Ms), 1.42 (d, 3H, J5;6 ¼ 6:0, H-6), 1.27, 1.26 (each
t, each 3H, JH;H ¼ 7:0, 2CH2CH3); 13C NMR
(125.7 MHz, CDCl3) d 167.5, 165.7 (2CO), 160.7–113.9
(Ar), 157.7 (HC@), 104.0 (OCHO), 94.5 (@C), 84.6 (C-
1), 79.9 (C-4), 78.0 (C-3), 74.2 (C-2), 70.5 (C-5), 60.2, 60.1
(2CH2CH3), 55.3 (OCH3), 39.2 (Ms), 17.5 (C-6), 14.3,
14.2 (2CH2CH3); Anal. Calcd for C23H31NO11S: C,
52.17; H, 5.90; N, 2.65. Found: C, 51.94; H, 5.81; N, 3.00.
4.6.3. 1,4-Anhydro-N -(2,2-diethoxycarbonylvinyl)-2,3-O-
(4-methoxybenzylidene)-b-L-rhamnopyranosylamine, 23.
Column chromatography (AcOEt/hexane 1:4). Yield
28
93%; ½aꢀ ¼ )53 (c 1.0, CH2Cl2); EIMS m=z 433 [Mþ];
D
IR 3079, 2991, 2896, 1712, 1609, 1379, 1275, 1077,
838 cmꢁ1 1H NMR (500 MHz, CDCl3), 7.79 (s, 1H,
;
HC@), 7.29–6.82 (m, 4H, Ar), 6.10 (s, 1H, OCHO), 5.36
(s, 1H, H-1), 4.44 (m, 3H, H-2, H-3, H-4), 4.28, 4.20
(each m, each 2H, 2CH2CH3), 3.77 (s, 3H, CH3O), 3.67
(m, 1H, H-5), 1.30, 1.27 (each t, each 3H, JH;H ¼ 7:3,
2CH2CH3), 1.12 (d, 1H, J5;6 ¼ 6:0, H-6); 13C NMR
(125.7 MHz, CDCl3) d 166.6, 166.4 (2CO), 160.6–113.9
(Ar), 146.5 (HC@), 107.0 (OCHO), 99.5 (@C), 89.8 (C-
1), 80.4 (C-2), 79.9 (C-3), 71.7 (C-5), 66.3 (C-4), 61.1,
60.7 (2CH2CH3), 55.4 (OCH3), 19.3 (C-6), 14.4, 14.2
(2CH2CH3); HREIMS m=z obsd 433.1739, calcd for
C22H27NO8 433.1737.
4.6. Preparation of compounds 6, 18 and 23
To a stirred solution of the corresponding mesyl com-
pounds 5, 17 and 15 (0.24 mmol) in DMF (3.2 mL) at
40 ꢁC and 20 mmHg, sodium methoxide (14 mg,
0.24 mmol) was added. The reaction was stirred for
15 min, and controlled by TLC (CH2Cl2/MeOH 100:1).
The mixture was poured into ice–water and extracted
with CH2Cl2. The organic layer was separated, washed
with water, dried (MgSO4), filtered and evaporated to
dryness. The residue was purified as described.
4.7. Preparation of compounds 8 and 20
To a solution of the corresponding 1,4-anhydroglyco-
pyranosylamines 6 and 18 (0.083 mmol) in acetic acid
(0.9 mL), NaBH3CN (18.2 mg, 0.28 mmol) was added.
The solution was stirred for 24 h at rt and controlled by
TLC (CH2Cl2/MeOH, 70:1). The mixture was added to
ice-saturated aqueous sodium hydrogencarbonate and
extracted with CH2Cl2. The organic layer was separated,
dried (MgSO4), filtered, and evaporated to dryness. To a
solution of the residue (0.083 mmol) in anhydrous
4.6.1. 1,4-Anhydro-2,3-di-O-benzoyl-N-(2,2-diethoxy-car-
bonylvinyl)-6-O-(4-methoxybenzyl)-b-D-glucopyranosyl-
amine 6. Column chromatography (CH2Cl2). Amor-
23
D
phous solid. Yield 66%; ½aꢀ ¼ +49 (c 0.5, CH2Cl2);
FABMS m=z 682 [(M+Na)þ]; IR 3063, 2980, 2866, 1723,
1
1609, 1381, 1265, 1099, 714 cmꢁ1; H NMR (500 MHz,
CDCl3) d 8.08–6.86 (m, 14H, Ar), 7.69 (s, 1H, HC@),
5.83 (d, 1H, J1;2 ¼ 2:2, H-1), 5.14 (m, 1H, H-2), 5.11 (d,

612
J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
methanol (16 mL) at rt, 1 M NaOMe in methanol (53 lL)
was added. The process was controlled by TLC until
total deacylation of the starting material was achieved.
After 4 h the reaction mixture was neutralized with acid
resin Amberlite IR-120(Hþ), filtered, and the solvent was
evaporated under reduced pressure. The residue was
purified as described. When 8 and 20 were dissolved in
methanol-d4 to obtain the NMR spectra the equilibria 8,
8a and 20, 20a (see Discussion) were produced.
(catalytic amount) were added. The reaction mixture
was stirred for 4 h at rt and controlled by TLC (CH2Cl2/
MeOH 15:1), neutralized with basic resin Amberlite
IRA-400(OHꢁ), filtered, and the solvent was evaporated
to dryness. The residue was purified by column chro-
matography (CH2Cl2, CH2Cl2/MeOH, 30:1) and gave
24
16 as amorphous solid. Yield 96%; ½aꢀ ¼ )45 (c 1.0,
CH2Cl2); FABMS m=z 434 [(M+Na)þD];)þ]; IR 3488,
3298, 2984, 2876, 1723, 1649, 1597, 1344, 1252, 1071,
1
855, 801 cmꢁ1; H NMR (500 MHz, CDCl3) d 9.52 (dd,
1H, JNH;1 ¼ 9:0, JNH;HC@ ¼ 13:5, NH), 8.04 (d, 1H,
HC@), 4.61 (d, 1H, H-1), 4.47 (t, 1H, J4;5 ¼ J3;4 ¼ 9:5,
H-4), 4.18 (m, 4H, 2CH2CH3), 4.11 (br s, 1H, H-2), 3.78
(dd, 1H, J2;3 ¼ 2:5, H-3), 3.53 (dq, 1H, J5;6 ¼ 6:0, H-5),
3.17 (s, 3H, CH3SO2), 1.36 (d, 1H, H-6), 1.29, 1.26 (each
t, each 3H, JH;H ¼ 7:0, 2CH2CH3); 13C NMR
(125.7 MHz, CDCl3) d 168.3, 166.1 (2CO), 158.0
(HC@), 93.7 (@C), 85.8 (C-1), 82.0 (C-4), 72.0 (C-3),
71.5 (C-5), 70.9 (C-2), 60.5, 60.3 (2CH2CH3), 38.9
(SO2CH3), 17.6 (C-6), 14.4, 14.3 (2CH2CH3); HREIMS
m=z obsd 412.1281, calcd for C15H26NO10S 412.1277.
4.7.1. (2S,3S,4S,10R)-1-Acetyl-3,4-dihydroxy-2-(10-hydr-
oxy-20-p-methoxybenzyloxy)ethylpyrrolidine, 8. Column
chromatography CH2Cl2/MeOH 15:1. Yield 77%;
30
½aꢀ ¼ +47 (c 1.0, CH2cc Cl2); EIMS m=z 325 [Mþ]; IR
D
3309, 2936, 2856, 1625, 1521, 1371, 1251, 1124, 850 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 7.25–6.86 (m, 4H, Ar),
4.50, 4.46 (each d, each 1H, JH;H ¼ 11:5, CH2Ph), 4.15 (br
s, 1H, H-3), 4.13–4.10 (m, 2H, H-2, 4), 4.03 (m, 1H, H-10),
3.87 (dd, 1H, J4;5a ¼ 6:0, J5a;5b ¼11:5, H-5a), 3.79 (s, 3H,
OCH3), 3.67 (dd, 1H, J1 ;2 a ¼ 4:5, J2 a;2 b ¼ 10:5, H-20a),
0
0
0
0
3.50 (dd, 1H, J1;2 b ¼ 7:0, H-20b), 3.42 (dd, 1H, J4;5b ¼ 2:5,
0
H-5b), 2.07 (s, 3H, CH3). 13C NMR (125.7 MHz, CDCl3)
d 172.8 (N–CO), 159.6–114.0 (Ar), 79.0 (C-3), 75.4 (C-4),
73.4 (H2COMP), 73.3 (C-10), 72.5 (C-20), 67.5 (C-2), 55.5
(C-5), 55.4 (OCH3), 22.7 (CH3). HREIMS m=z obsd
325.1523, calcd for C16H23NO6 325.1525.
4.9. Preparation of compounds 9 and 21
To a solution of the corresponding compounds 8 and 20
(0.283 mmol) in methanol (7.5 mL), HCl 12 N (600 lL)
was added. The mixture was stirred at 65 ꢁC for 1 h, and
then the solvent was evaporated under reduced pressure.
Compound 9 had the same spectroscopic data previ-
4.7.2. (1R,3R,S,6R,7S,7aS)-3,6,7-trihydroxy-1-p-meth-
oxybenzyloxymethyl-2-oxapyrrolizidine 8a. 13C NMR
(125.7 MHz, MeOD) d 160.9–114.7 (6C, Ar), 114.6 (C-
3), 79.7 (C-7), 76.0 (C-6), 74.1 (CH2PhOMe), 72.9
(CH2O), 70.6 (C-1), 70.2 (C-7a), 55.7 (OMe), 54.0 (C-5),
22.4 (CH3–C).
1
ously reported.12 The H NMR data of compound 21
coincided with those reported17 for its enantiomer.
4.10. Preparation of compounds 10 and 22
A solution of the corresponding compounds 9 and 21
(0.283) was treated in a chromatographic column with
ion-exchange Dowexꢂ 50W-XS resin NHþ4 form (4 g).
The column was eluted first with methanol, after with
water, and then with a NH4OH solution. The fractions
containing the product were concentrated to dryness.
The NMR data of compound 10 coincided with those
reported.12
4.7.3. (2R,3S,4R,10S)-1-Acetyl-3,4-dihydroxy-2-(10-hydr-
oxy)ethylpyrrolidine, 20. Column chromatography
CH2Cl2/MeOH 15:1. Yield 75%; CIMS m=z 190
[(M+H)þ]; IR 3309, 2964, 2933, 1722, 1645, 1479, 1261,
1
1093 cmꢁ1; H NMR (300 MHz, MeOD) d 4.22 (ddd,
1H, J3;4 ¼ 2:4, J4;5a ¼ 6:3, J4;5b ¼ 4:8, H-4), 4.12 (m, 1H,
H-10), 3.96 (dd, 1H, J2;3 ¼ 4:5, H-3), 3.90 (dd, 1H,
0
J2;1 ¼ 8:2, H-2), 3.61 (dd, 1H, J5a;5b ¼ 10:8, H-5a), 3.38
(dd, 1H, H-5b), 2.07 (s, 3H, COCH3), 1.14 (d, 3H, CH3–
CHOH) 13C NMR (125.7 MHz, CDCl3) d 173.8
(COCH3), 74.7 (C-3), 71.4 (C-4), 73.3 (C-1), 70.2 (C-10),
69.4 (C-2), 56.4 (C-5), 22.4 (COCH3), 20.4 (20). HRC-
IMS m=z obsd 190.1089, calcd for C8H16NO4 190.1079.
4.10.1. (2R,3R,4S,10S)-3,4-dihydroxy-2-(10-hydroxy)-eth-
ylpyrrolidine, 22. Amorphous solid. Yield 72% from
23
D
18; ½aꢀ ¼ +27 (c 1.5, EtOH); CIMS m=z 148 [(M+H)þ];
IR 3352, 2930, 2933, 1623, 1548 cmꢁ1
;
1H NMR
(500 MHz, MeOD) d 4.02 (m, 1 H, H-4), 3.81 (m, 2H,
H-10, H-3), 3.14 (dd, 1H, J4;5a ¼ 5:5, J5a;5b ¼ 11:5, H-5a),
2.81 (dd, 1H, J4;5b ¼ 4:0, H-5b), 2.80 (m, 1H, H-2), 1.24
MeOD) d 74.9 (C-3), 72.8 (C-4), 69.0 (C-2), 66.8 (C-10),
52.1 (C-5), 21.3 (CH). HRCIMS m=z obsd 148.0972,
calcd for C6H14NO3 148.0974.
4.7.4. (1R,3R,S,6R,7R,7aR)-3,6,7-trihydroxy-1-methyl-
2-oxapyrrolizidine 20a. 13C NMR (125.7 MHz, MeOD)
d 114.7 (C-3), 74.8 (C-7), 73.1 (C-6), 70.8 (C-1), 69.1 (C-
7a), 51.4 (C-5), 22.4 (CH3–CO2N), 20.4 (CH3–CO).
(d, 3H, J1 ;CH3, CH3–CHOH). 13C NMR (125.7 MHz,
0
4.8. N-(2,2-Diethoxycarbonylvinyl)-4-O-mesyl-b-L-
rhamnopyranosylamine 16
4.11. Preparation of compounds 11, 11a, 24, 24a, and 25
To a solution of 15 (400 mg, 0.756 mmol) in dry CH2Cl2
(9.6 mL), ethanethiol (560 lL, 7.56 mmol), and PTSA
To a stirred solution of the corresponding 1,4-anhydro-
compounds 6,23 and 18 (0.527 mmol) in dry CH2Cl2

J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
613
ꢁ
(10.0 mL) over 3 A molecular sieves at rt, ethanethiol
(500 MHz, CDCl3) d 5.56 (d, 1H, J3;CH ¼ 7:5, H-3), 4.31
(21.6 mmol), and PTSA (catalytic amount) were added.
The reaction was stirred for 15 min, controlled by TLC
(CH2Cl2/MeOH), and then neutralized with satd aq
NaHCO3, washed with water, and dried (MgSO4) for 25
and 11. The mixture was treated with basic resin Am-
berlite IRA-400(OHꢁ) for 24. In all cases, the mixture
was filtered and evaporated to dryness. Column chro-
matography (CH2Cl2, CH2Cl2/MeOH 100:1) of the
residue gave in the case of 6 a mixture of 5R and 5S
diastereoisomers 11 and 11a (98%, 11/11a ratio 4:1),
whereas in the cases of 23 and 18 gave the corresponding
thioglycosides 24 and 24a, or 25 and 25a as isolated
products.
(br s, 1H, H-6), 4.29 (s, 1H, H-5), 4.42–4.13 (m, 5H, H-7,
2CH2CH3), 3.67 (dq, 1H, J1;7a ¼ 8:5, J1;CH ¼ 6:0, H-1),
3
3.52 (d, 1H, CH(CO2Et)2), 3.09 (dd, 1H, J7;7a ¼ 4:5,
H-7a), 2.90 (br s, 2H, OH-6, OH-7), 2.67 (m, 2H,
SCH2CH3), 1.27 (m, 12H, 1 CH3, 2OCH2CH3, 1
SCH2CH3). 13C NMR (125.7 MHz, CDCl3) d 167.2,
166.8 (2CO), 90.3 (C-3), 81.6 (C-6), 79.1 (C-1), 74.9 (C-
5), 74.4 (C-7a), 72.6 (C-7), 61.6, 61.5 (2OCH2CH3), 58.6
[CH(CO2Et)2], 27.7 (SCH2CH3), 18.7 (CH3), 15.5
(SCH2CH3), 14.2, 14.1 (2OCH2CH3). HREIMS m=z
obsd 377.1510, calcd for C16H27NO7S 377.1508.
4.11.3. (1R,3R,5R,6R,7R,7aR)-3-diethoxycarbonylmeth-
yl-5-ethylthio-6,7-dihydroxy-1-methyl-2-oxapyrrolizidine,
24a. 1H NMR (500 MHz, CDCl3) d 5.26 (d, 1H,
J3;CH ¼ 8:5, H-3), 4.43 (d, 1H, J5;6 ¼ 6:0, H-5), 4.29–4.18
(m, 5H, H-6, 2CH2CH3), 3.98 (br s, 1H, H-7), 3.65 (dq,
4.11.1. (1S,3S,5S,6R,7S,7aS)-6,7-Dibenzoyloxy-3-dieth-
oxycarbonylmethyl-5-ethylthio-1-p-methoxybenzyloxy-
methyl-2-oxapyrrolizidine, 11 and (1S,3S,5R,6R,7S,7aS)-
6,7-dibenzoyloxy-3-diethoxycarbonylmethyl-5-ethylthio-
1H, J1;7a ¼ 8:5, J1;CH ¼ 6:0, H-1), 3.47 [d, 1H,
3
1-p-methoxybenzyloxymethyl-2-oxapyrrolizidine,
11a.
CH(CO2Et)2], 3.33 (d, 1H, J6;OH-6 ¼ 5:5, OH-6), 3.27
(dd, 1H, J7a;7 ¼ 2:5, H-7a), 2.81 (d, 1H, J7;OH-7 ¼ 7:5,
OH-7), 2.58, 2.57 (each q, each, 1H, JH;H ¼ 7:5,
SCH2CH3), 1.33 (d, 3H, CH3), 1.30–1.23 (m, 6 H,
2CH2CH3). 13C NMR (125.7 MHz, CDCl3) d 166.4,
166.2 (2CO), 96.4 (C-3), 77.4 (C-1), 76.2 (C-5), 75.0 (C-
7a), 73.7 (C-7), 70.4 (C-6), 61.7, 61.6 (2OCH2CH3), 58.7
[CH(CO2Et)2], 25.1 (SCH2CH3), 19.5 (SCH2CH3), 15.0
(CH3), 14.1 (2OCH2CH3).
Compound 11 was an amorphous solid. FABMS m/z
744 [(M+Na)þ]; IR, 2980, 2932, 2870, 1734, 1609, 1514,
1370, 1252, 831, 719 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 8.09–6.77 (m, 14H, Ar), 5.82 (dd, 1H, J5;6 ¼ 6:3,
J6;7¼ ¼ 3:7, H-6), 5.61 (d, 1H, J3;CH ¼ 8:8, H-3), 5.34 (dd,
1H, J7;7a ¼ 1:8, H-7), 4.53, 4.48 (each d, each, 2H,
JH;H ¼ 11:7, H2COPMB), 4.35 (d, 1H, H-5), 4.33 (m,
1H, H-1), 4.25–4.14 (m, 4H, OCH2CH3), 3.80 (dd, 1H,
J1;7a ¼ 8:0, H-7a), 3.78 [(d, 1H, HC(CO2Et)2], 3.77–3.70
(m, 2H, H-8a, H-8b), 3.75 (s, 3H, OCH3), 2.74, 2.68
(each dq, each 1H, 2JH;H ¼ 11:5, 3JH;H ¼ 7:5,
SCH2CH3), 1.28–1.24 (m, 9 H, 2OCH2CH3, SCH2CH3).
13C NMR (125.7 MHz, CDCl3) d 166.7 (CO), 166.0
(2CO), 165.2 (CO), 159.2–113.7 (Ar), 95.2 (C-3), 80.8
(C-1), 80.4 (C-6), 79.0 (C-7), 73.2 (OCH2MP), 72.4 (C-
5), 69.6 (H2COPMB), 69.0 (C-7a), 61.5 (2OCH2CH3),
58.5 [CH(CO2Et)2], 55.3 (OCH3), 22.3 (SCH2CH3),
14.2, 14.1 (each OCH2CH3), 14.2 (SCH2CH3). HRC-
IMS m=z obsd 722.2608, calcd for C38H44NO11S
722.2635.
4.11.4. (1S,3R,5S,6R,7R,7aR)-6,7-dibenzoyloxy-3-dieth-
oxycarbonylmethyl-5-ethylthio-1-methyl-2-oxapyrrolizi-
26
D
dine, 25. Amorphous solid. ½aꢀ ¼ +37 (c 0.9, CH2Cl2);
CIMS m=z 586 [(M+H)þ]; IR, 3071, 2991, 2928, 1736,
1
1649, 1545, 1371, 1116, 719 cmꢁ1; H NMR (500 MHz,
CDCl3) d 8.04–7.31 (m, 10 H, Ar), 5.92 (d, 1H,
J6;7 ¼ 4:5, H-6), 5.68 (d, 1H, J3;CH ¼ 8:0, H-3), 5.63 (dd,
1H, J7;7a ¼ 5:0, H-7), 4.51 (s, 1H, H-5), 4.20, 4.08 (each
m, each 2H, OCH2CH3), 3.98 (dq, 1H, J1;7a ¼ 8:0,
J1;CH ¼ 6:0, H-1), 3.54 [(d, 1H, HC(CO2Et)2], 3.48 (dd,
3
1H, H-7a), 2.78, (q, 2H, 3JH;H ¼ 7:5, SCH2CH3), 1.37 (t,
3H, SCH2CH3). 1.33 (d, 3H, CH3), 1.25, 1.13 (each t,
each 3H, JH;H@ ¼ 7:5, OCH2CH3). 13C NMR
(125.7 MHz, CDCl3) d 166.7 (2CO), 165.9 (CO), 165.7
(CO), 133.5–128.5 (Ar), 90.5 (C-3), 82.0 (C-6), 79.6
(C-1), 73.4 (C-7), 72.6 (2C, C-5, C-7a), 61.6, 61.4
(2OCH2CH3), 59.1 [CH(CO2Et)2], 27.5 (SCH2CH3),
19.3 (CH3), 15.5 (SCH2CH3), 14.2 (2OCH2CH3).
HRCIMS m=z obsd 586.2093, calcd for C30H36NO9S
586.2111. Conventional benzoylation of 24 (see Section
4.3) gave 25.
Compound 11a had, 1H NMR (500 MHz, CDCl3) d
8.09–6.71 (m, 14H, Ar), 5.86 (dd, 1H, J5;6 ¼ 5:5,
J6;7¼ ¼ 8:2, H-6), 5.82 (d, 1H, J3;CH ¼ 8:8, H-3), 5.51 (dd,
1H, J7;7a ¼ 4:3, H-7), 4.92 (d, 1H, H-5), 4.49, 4.38 (each
d, each 1H, JH;H ¼ 11:7, H2COMBn), 4.25–4.14 (m, 4 H,
OCH2CH3), 4.17 (m, 1H, H-1), 3.74 (s, 3H, OCH3), 3.73
[(d, 1H, HC(CO2Et)2], 3.69 (m, 2H, H-8a, H-8b), 3.62
(dd, 1H, J1;7a ¼ 8:4, H-7a), 2.63–2.56 (m, 2H,
SCH2CH3), 1.31–1.24 (m, 6H, 2OCH2CH3), 1.19 (t, 3H,
3JH;H ¼ 7:4, SCH2CH3). 13C NMR (125.7 MHz, CDCl3)
d 166.8–165.2 (4CO), 159.2–113.6 (Ar), 91.5 (C-3), 82.6
(C-1), 78.4 (C-6), 76.7 (C-7), 73.1 (OCH2MP), 72.1 (C-
5), 69.2 (H2COPMB), 65.8 (C-7a), 61.5 (2OCH2CH3),
58.1 [CH(CO2Et)2], 55.3 (OCH3), 28.1 (SCH2CH3), 15.7
(SCH2CH3), 14.5, 14.4 (each OCH2CH3).
4.11.5. (1S,3R,5R,6R,7R,7aR)-6,7-dibenzoyloxy-3-dieth-
oxycarbonylmethyl-5-ethylthio-1-methyl-2-oxapyrrolizi-
dine, 25a. Amorphous solid. FABMS m/z 744
[(M+Na)þ]; IR, 2980, 2932, 2870, 1734, 1609, 1514,
1370, 1252, 831, 719 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 8.04–7.33 (m, 10 H, Ar), 5.75 (dd, 1H, J5;6 ¼ 6:1,
J6;7 ¼ 5:4, H-6), 5.48 (dd, 1H, J7;7a ¼ 2:4, H-7), 5.35 (d,
1H, J3;CH ¼ 7:71, H-3), 4.72 (d, 1H, H-5), 4.24-4.18 (m,
4.11.2. (1R,3R,5S,6R,7R,7aR)-3-diethoxycarbonylmeth-
yl-5-ethylthio-6,7-dihydroxy-1-methyl-2-oxapyrrolizidine,
24. Amorphous solid; IR, 3444, 2983, 2935, 1720, 1593,
1386, 1243 cmꢁ1; CIMS m/z 378 [Mþ]; 1H NMR

614
J. Fuentes et al. / Tetrahedron: Asymmetry 15 (2004) 603–615
4. Fuentes, J.; Gasch, C.; Olano, D.; Pradera, M. A.;
Repetto, G.; Sayago, F. J. Tetrahedron: Asymmetry
2002, 13, 1743–1753.
5. For a recent review see Lillelund, V. H.; Jensen, H.
H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515–
553.
6. Hartmann, T.; Witte, L. Chemistry, Biology, and
Chemoecology of the pyrrolizidine Alkaloids. In Alka-
loids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Pergamon: Oxford, 1995; Vol. 9, pp 155–
233.
7. See as examples: (a) Driguez, H. In Thiooligosaccharides in
Glycobiology; Driguez, H.; Thiem, J. Eds.; Top. Curr.
Chem.; 1997; Vol. 187, p 85; (b) Bertozzi, C.; Bednasski,
M. In Modern Methods in Carbohydrate Synthesis; Khan,
S. H., OÕNeil, R. A., Eds.; Harwood Academic: Amster-
dam, 1996; pp 316–351.
8. Defaye, J.; Gelas, J. In Studies in Natural Products
Chemistry; Attaur-Rahman Ed.; Elsevier Science: Amster-
dam; 1991; Vol. 8.
9. For thioglycosides see as examples (a) Witczak, Z. J.;
Boryczewski, D. Bioorg. Med. Chem. Lett. 1998, 8, 3265–
3268; (b) Fitz, W.; Rosenthal, P.; Wong, C. H. Bioorg.
Med. Chem. Lett. 1996, 4, 1349–1353.
10. For iminocyclitols see as examples (a) Asano, N.; Nash, R.
J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asym-
metry 2000, 11, 1645–1680; (b) Deshpande, P. P.; Dani-
shefsky, S. J. Nature 1997, 387, 164; (c) Winchester, B.;
Fleet, G. W. J. Glycobiology 1992, 2, 199–215; (d)
Papandreou, G.; Tong, M. K.; Ganem, B. J. Am. Chem.
Soc. 1993, 115, 11682–11690; (e) Stutz, A. E. Iminosugars
as Glycosidase Inhibitors. Nojirimycin and Beyond; Wiley
VCH: Weinheim, 1999.
11. (a) Berges, D. A.; Fan, J.; Devinck, S.; Liu, N.; Dalley, N.
K. Tetrahedron 1999, 55, 6759–6770; (b) Marek, D.;
Wadouachi, A.; Uzau, R.; Beaupere, D.; Nowogrocki, G.;
Laplace, G. Tetrahedron Lett. 1996, 37, 49–52; (c)
Siriwardena, A. H.; Chiaroni, A.; Riche, C.; Grierson,
D. S. J. Org. Chem. 1992, 57, 5661–5666.
4H, OCH2CH3), 3.97 (m, 1H, H-1), 3.58 [(d, 1H,
HC(CO2Et)2], 3.53 (dd, 1H, J1;7a ¼ 7:7, H-7a), 2.61, (q,
3
2H, JH;H ¼ 7:5, SCH2CH3), 1.37 (t, 3H, SCH2CH3).
1.33 (d, 3H, J1;CH ¼ 6:1, CH3), 1.27 (m, 6H,
3
2OCH2CH3). 13C NMR (125.7 MHz, CDCl3) d 166.3
(2CO), 165.9 (CO), 165.6 (CO), 133.4–128.4 (Ar), 96.2
(C-3), 78.2 (C-1), 74.0 (C-7), 73.5 (C-6), 72.8 (C-7a), 72.5
(C-5), 61.7, 61.6 (2OCH2CH3), 59.5 [CH(CO2Et)2], 25.2
(SCH2CH3), 19.8 (CH3), 14.8 (SCH2CH3), 14.2, 14.1
(2OCH2CH3). HRCIMS m=z obsd 586.2120, calcd for
C30H36NO9S 586.2111.
4.12. (S,3S,5S,6R,7S,7aS)-3-Diethoxycarbonylmethyl-
5-ethylthio-6,7-dihydroxy-1-p-methoxybenzyloxymethyl-
2-oxapyrrolizidine, 12
To a solution of 11 (0.036 mmol) in anhydrous methanol
(6.8 mL) at rt, 1 M NaOMe in methanol (17.2 lL) was
added. The process was controlled by TLC (CH2Cl2/
MeOH, 15:1) until total deacylation of the starting
material was achieved. After 4 h, the reaction mixture
was neutralized with CO2, filtered, and the solvent was
evaporated under reduced pressure. The residue was
purified by column chromatography (CH2Cl2, CH2Cl2/
MeOH, 15:1). Compound 12 (70%) was an amorphous
1
solid. CIMS m=z 514 [(M+H)þ]; H NMR (500 MHz,
MeOD) d 5.41 (d, 1H, J3;CH ¼ 8:5, H-3), 4.35 (m, 1H, H-
1), 4.20–4.15 (m, 3H, H-5, 6, 7), 4.10 (m, 1H, H-7a), 3.78
(s, 3H, OCH3), 3.73 [d, 1H, CH(CO2Et)2], 2.65–2.55 (m,
2H, SCH2CH3). 13C NMR (125.7 MHz, MeOD) d 169.5
(CO), 169.3 (CO), 160.8–114.7 (Ar), 95.8 (C-3), 79.8 (C-
1), 77.5 (C-6), 74.1 (C-7), 74.0 (OCH2MP), 72.0 (C-5),
71.0 (C-7a), 70.9 (CH2OPMB), 61.3 (2C, OCH2CH3),
59.5 [CH(CO2Et)2], 55.7 (OCH3), 22.0 (SCH2CH3), 19.3
(CH3), 14.8, 14.5 (2OCH2CH3), 14.4 (SCH2CH3).
HRCIMS m=z obsd 514.2112, calcd for C24H36NO9S
514.2111.
12. Lee, R. E.; Smith, M. D.; Nash, R. J.; Griffiths, R. C.;
McNeil, M.; Grewal, R. K.; Yan, W.; Besra, G. S.;
Brenan, P. J.; Fleet, G. W. G. Tetrahedron Lett. 1997, 38,
6733–6736.
13. Paulsen, H.; Steinert, K.; Heyns, K. Chem. Ber. 1970, 103,
1599–1620.
14. Bernotas, C. R. Tetrahedron Lett. 1990, 31, 469–
473.
Acknowledgements
15. Lombardo, M.; Fabbroni, S.; Trombini, C. J. Org. Chem.
2001, 66, 1264–1268.
16. Pham-Huu, D.-Ph.; Gizaw, Y.; Be-Miller, J. N.; Petrus, L.
Tetrahedron Lett. 2002, 43, 383–385.
17. Dudot, B.; Micouin, L.; Bausanne, I.; Royer, J. Synthesis
1999, 688–694.
18. (a) Pradera, M. A.; Sayago, F. J.; Illangua, J. M.; Gasch,
C.; Fuentes, J. Tetrahedron Lett. 2003, 44, 6605–6608; (b)
Sayago, F. J.; Fuentes, J.; Illangua, J. M.; Gasch, C.;
Pradera, M. A. Book of Abstracts, Presented at the 12th
European Carbohydrate Symposium Grenoble, France,
July 6–11, 2003; p 229.
ꢀ
~
We thank the Direccion General de Ensenanza Superior
ꢀ
ꢀ
e Investigacion Cientıfica of Spain and the Junta de
Andalucia for financial support (grant numbers
BQU2001-3740 and FQM-134), and the Ministerio de
ꢀ
ꢀ
Educacion, Cultura y Deporte, and the Fundacion
Camara of the University of Seville, for the award of
fellowships to F.J.S., and J.M.I., respectively. This work
is part of the European Programme COST D13, action
number D13/0001/98.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
19. Gomez Sanchez, A.; Gomez Guillen, M.; Cert Ventula,
A.; Scheiddeger, V. An. Real Soc. Espan. Fis. Quim. 1968,
~
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