Stereocontrolled synthesis of iminocyclitols with an ether bridge

Article abstract of DOI:10.1016/j.tet.2007.03.097

Nor-tropane related bicyclic (6+5) iminocyclitols with an ether bridge and different substituents (hydroxymethyl, aminomethyl, and aminoethyl) on C-1 are prepared starting from a β-d-psicofuranosyl cyanide. The method involves an internal nucleophilic attack of a stabilized amide ion on a 5-mesyloxy derivative. The intermediate N-acetyl O-protected iminocyclitols present atropoisomerism due to restricted rotation of the N-CO amido bond. Conformational aspects of the prepared compounds are discussed.

Full text of DOI:10.1016/j.tet.2007.03.097

Tetrahedron 63 (2007) 4695–4702
Stereocontrolled synthesis of iminocyclitols with an ether bridge
*
Francisco J. Sayago, Jose Fuentes, Manuel Angulo, Consolacion Gasch
ꢀ
and M. Angeles Pradera
ꢀ
ꢀ
Departamento de Quꢀımica Orgaꢀnica, Facultad de Quꢀımica, y Servicio de RMN, Universidad de Sevilla,
Apartado 1203, E-41071 Sevilla, Spain
Received 7 February 2007; revised 14 March 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—Nor-tropane related bicyclic (6+5) iminocyclitols with an ether bridge and different substituents (hydroxymethyl, aminomethyl,
and aminoethyl) on C-1 are prepared starting from a b-D-psicofuranosyl cyanide. The method involves an internal nucleophilic attack of a sta-
bilized amide ion on a 5-mesyloxy derivative. The intermediate N-acetyl O-protected iminocyclitols present atropoisomerism due to restricted
rotation of the N–CO amido bond. Conformational aspects of the prepared compounds are discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
structurally related with bicyclic alkaloids with nor-tropane
skeleton (2), which have biological activity as competitive
inhibitors of glycosidases.10,11 Related bicyclic alkaloids
having hydroxy(alkoxy)methyl groups instead of hydroxy
groups have also been described.12 Recently, we have de-
scribed13 the preparation of azasugar thioglycosides, using
a cyclization reaction through an amide ion.
The iminocyclitols are a type of sugar analog in which the en-
docyclic oxygen atom has been substituted by a nitrogen
atom. These compounds have biological and pharmaceutical
importance as they are inhibitors of glycosidases and glyco-
syltransferases,1 and consequently, they can be useful in
the treatment of metabolic disorders and inflammatory pro-
cesses.1–5 The first iminocyclitols were discovered as natural
products, although they were difficult to isolate, at least in
multigram scale. In the last 15 years, much effort has been di-
rected to the synthesis of five-, six-, and seven-membered
monocyclic and bicyclic polyhydroxyalkyl iminocycli-
tols,6,7 in many cases sugar derivatives being the starting
materials for these syntheses. However, much less effort
has been put into the synthesis of bicyclic iminocyclitols
with an ether bridge (1) (Fig. 1), in spite of the restricted
conformational properties of these compounds, which can
be interesting for possible biological studies. A dihydroxy-
3,6-anhydro iminoheptitol was prepared by Kilonda8 starting
from 1-amino-1-deoxy-D-glucitol; the same compound was
later obtained starting from a dibenzyloxy-dihydroxy-perhy-
droazepane.9 At the same time, the iminocyclitols 1 are
Now, we report the synthesis of the iminocyclitols with an
ether bridge 9, 13, and 16 starting from the glycofuranosyl
cyanide 3.14 Compounds 13 and 16 are homoaminoaza-
sugars,15 and can be useful for preparing azasugar-isothio-
cyanates, homonucleosides, and related compounds.16
2. Results and discussion
The 6-O-benzyl-2-cyanopsicofuranose derivative 3,14 which
is easily prepared from 1,2:4,5-di-O-isopropylidene-b-D-
fructopyranose, was reduced with lithium aluminum hydride
to obtain (Scheme 1) the amino derivative 4, which was in
situ acetylated to give 5 in 87% yield from 3. The position
6 of 5 was debenzylated by hydrogenation (Pd–C) to get 6,
in which was introduced a good leaving group by treatment
with mesyl chloride (/7).
O
NH
R
N
OH
Tables 1 and 2 show selected 1H and 13C NMR data of pre-
pared compounds, respectively. The spectra of 5 showed sig-
nals for two acetyl groups (see also Section 3) and its 13C
NMR spectrum had no signal for a C^N group. The reso-
nance of C-6 in 6 showed a shielding of 7.5 ppm with respect
to the same signal in 5, indicative of the deprotection of the
corresponding hydroxyl group. The presence of the mesyl
group in 7 was evident from the signals at 3.09 (1H) and
1
2
Figure 1.
Keywords: Iminocyclitols; Bicyclic azasugars; Atropoisomerism.
* Corresponding author. Tel.: +34 954557150; fax: +34 954624960; e-mail:
jfuentes@us.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.097

4696
F. J. Sayago et al. / Tetrahedron 63 (2007) 4695–4702
OBn
O
OBn
O
OH
OMs
O
OBn
O
NHAc
OAc
NH2
OH
NHAc
OAc
NHAc
OAc
CN
O
O
O
O
O
iv
ii
OH
iii
i
O
O
O
O
O
O
5
3
4
7
6
O
O
O
O
O
H
N
O
N
O
N
O
N
O
N
O
v
vi
iii
vii
OMs
iv
N3
NH2
NH2
OH
O
O
O
O
O
OH
13
HO
O
O
10a, 10b
11a, 11b
12a, 12b
8a, 8b
viii
O
vii
O
H
N
O
Et
N
O
Et
N
O
N
O
OH
i
N
vii
NH2
NH2
O
OH
HO
O
O
OH
HO
9
14a, 14b
15
16
Scheme 1. Compounds showing atropoisomerism are indicated as na and nb. The major (Z, na) compound is showed. Reagents and conditions: (i) LiAlH4,
Et2O; (ii) Ac2O/Py; (iii) H2, Pd–C, AcOEt; (iv) CIMs/Py, rt; (v) NaH, DMF; (vi) NaN3, DMF; (vii) MeOH, HCl; (viii) KCN, DMF.
38.1 (13C) ppm and from the deshielding of the signals for
H6a and H6b (0.27–0.33 ppm) and C-6 (6.3 ppm).
Scheme 2) on C-6. Reaction of 8 with HCl in methanol
yielded the N- and O-unprotected target compound 9. The
NMR spectra (1H and 13C) of compound 8 showed two series
of signals corresponding to two atropoisomers, 8a and 8b, by
restricted rotation of the N–CO bond (see below). The 2D
NOESY spectrum showed EXSY18 peaks relating signals
of the two different spin systems. No significant changes
Treatment of the mesyloxy derivative 7 with sodium hydride
in DMF produced the tricyclic compound 8. The reaction
involves O-deacylation and cyclization by intramolecular
nucleophilic attack of a stabilized amide ion13,17 (17,
Table 1. Selected 1H NMR data (d ppm, J Hz) for compounds 5–16 at 500 MHz in CDCl3
H1a
H1b
H3
H4
H5
H6a
H6b
CH2NH
J3,4
J4,5
J5,6a
J5,6b
5
6
7
4.26
4.39
4.33
4.23
4.17
4.18
4.52
4.66
4.63
4.79
4.97
4.66
4.09
4.11
4.16
3.82
3.79
4.52
3.67
3.64
4.31
3.83, 3.17
3.81, 2.98
3.62, 3.36
6.0
6.0
6.5
6.0
4.5
5.0
0
0
2.5
2.5
—
3.5
CH2OH
H7
H6
H5
H4a
3.63
4.03
2.84
H4b
3.12
2.62
2.73
H2a
H2b
2.60
3.16
2.83
J6,7
5.9
5.9
6.5
J5,6
0
0
J4a,5
z0a
z0a
2.5
J4b,5
2.5
2.5
1.4
8a
8b
9
3.60, 3.42
3.60, 3.45
3.71, 3.60
4.23
4.50
4.30
4.64
4.38
4.25
4.11
4.15
4.02
4.21
3.68
2.87
0
CH2OMs
4.42, 4.23
4.42, 4.23
H7
4.32
4.61
H6
4.73
4.45
H5
4.24
4.27
H4a
3.67
4.06
H4b
3.16
2.65
H2a
4.20
3.75
H2b
2.71
3.26
J6,7
5.8
5.8
J5,6
0
0
J4a,5
z0a
z0a
J4b,5
2.4
2.4
10a
10b
CH2N3
3.53
3.53
H7
4.25
4.53
H6
4.70
4.43
H5
4.20
4.24
H4a
3.66
4.04
H4b
3.14
2.64
H2a
4.14
3.68
H2b
2.66
3.20
J6,7
5.9
5.9
J5,6
0
0
J4a,5
z0a
z0a
J4b,5
2.5
2.5
11a
11b
CH2NH2
2.80, 2.66
2.80, 2.66
2.90, 2.84
H7
H6
H5
H4a
3.63
4.03
2.81
H4b
3.11
2.61
2.70
H2a
4.28
3.79
2.76
H2b
2.54
3.07
2.64
J6,7
5.9
5.9
6.5
J5,6
0
0
J4a,5
z0b
z0b
2.5
J4b,5
2.5
12a
12b
13
4.24
4.50
4.28
4.64
4.38
4.26
4.12
4.15
4.03
2.5
0
z0b
CH2CN
2.87, 2.71
2.81
H7
4.43
4.44
H6
4.60
4.61
H5
4.34
4.36
H4a
3.57
4.33
H4b
3.39
2.87
H2a
4.48
3.75
H2b
2.94
3.40
J6,7
5.5
5.5
J5,6
0
0
J4a,5
z0b
z0b
J4b,5
2.3
—
14a
14b
CH2CH2NH2
3.18, 2.18, 1.86
H7
4.18
H6
4.26
H5
4.12
H4a
2.76
H4b
2.11
H2a
2.73
H2b
2.01
J6,7
6.3
J5,6
0
J4a,5
J4b,5
2.0
16
z0b
1
a
The 2D COSY long range showed a correlation between H4a and H5, but this small coupling was not resolved in the H NMR spectrum, precluding the
determination of the value of J4a,5
The lineshape of both, H-4a (H4b for 13) and H-5, suggest the existence of a small coupling (<1 Hz) between these protons.
.
b

F. J. Sayago et al. / Tetrahedron 63 (2007) 4695–4702
Table 2. Selected 13C NMR data (125 MHz) for 5–14, 16
4697
for the internal rotation was measured at the coalescence
of H-5 (Fig. 2, Tc¼333 K). Despite the small rotamer popu-
lation difference (Dp¼0.06), the data were treated as an
exchange between two unequally populated sites.19 The
chemical shift separation at 303 K for this proton between
the two rotamers is 17.7 Hz. From these data, the rate con-
stants for the conversions 8a/8b and 8b/8a were calcu-
lated as 33.3 sꢀ1 and 37.5 sꢀ1, respectively, and the
substitution of these values into the Eyring equation19 gave
the values 17.3 and 17.2 kCal/mol for DGsa (8a/8b) and
DGsb (8b/8a), respectively.
C1
C2
C3
C4
C5
C6
CH2NH
5
6
7
64.2
63.0
63.0
84.9 83.6 80.8 83.7 69.8 43.7
85.1 84.0 81.6 86.1 62.3 43.1
85.3 83.0 80.6 81.1 68.6 42.5
CH2OH
60.5
60.5
C1
C7
C6
C5
C4
C2
8a
8b
9
83.3 81.8 82.5 77.7 47.1 45.5
82.8 82.6 81.8 77.9 42.7 49.9
85.6 75.3 75.1 84.2 48.0 51.0
63.8
CH2OMs
C1
C7
C6
C5
C4
C2
10a 69.1
10b 69.3
81.0 81.9 82.5 78.5 46.7 44.4
80.6 82.0 82.6 78.8 42.2 48.7
Treatment of 8 with mesyl chloride in pyridine gave the
mesyl derivative 10a (10b), which by reaction with sodium
azide in DMF yielded 11a (11b). Catalytic hydrogenation of
11 produced 12a (12b), which by simultaneous deacetyl-
ation and deacetalation with HCl in methanol was trans-
formed into the target methyl aminoazasugar 13. The
signals at 3.09 (3.07) (1H) and 36.6 (36.7) ppm (13C) in
the NMR spectra of 10a (and its rotamer 10b), together
with the deshielding in the resonances of the CH2OMs group
supported the presence of the mesyl group. The azido group
of 11a (11b) was evident from the IR absorption at
2105 cmꢀ1, which was not present in the IR spectrum of
CH2N3
11a 51.4
11b 51.5
C1
C7
C6
C5
C4
C2
82.4 81.9 82.6 78.2 46.7 45.1
82.0 81.9 82.8 78.5 42.3 49.5
CH2NH2
12a 42.7
12b 42.7
C1
C7
C6
C5
C4
C2
83.2 81.9 82.6 77.9 47.1 45.9
83.7 81.9 82.7 77.9 42.8 50.5
84.3 76.1 75.6 84.3 48.1 52.5
13
44.3
CH2CN
14a 21.3
14b 21.0
C1
C7
C6
C5
C4
C2
80.8 82.4 83.5 79.1 47.4 46.9
80.2 82.3 83.4 79.9 42.7 51.7
CH2CH2NH2 C1
30.8, 37.0 84.6 76.0 75.7 83.7 55.5 61.7
C7
C6
C5
C4
C2
16
3
were observed by comparison of the corresponding JH,H
values (see Table 1 and Section 3) of 8a and 8b, which is in-
dicative of no conformational changes in the tricyclic sys-
1
393 K
383 K
tem. The H and 13C NMR spectra of N-acetyl derivatives
10–12 and 14 (see below) also show two series of signals,
and their NOESY spectra also have EXSY peaks. However,
the same spectra of the amino compounds 9, 13, and 16 have
only one signal series and no EXSY peaks were observed;
consequently the atropoisomerism is due to restricted rota-
tion of the N–CO amido bond.
373 K
363 K
353 K
343 K
In order to characterize the interconversion of the atro-
poisomers of 8, a variable-temperature H NMR study was
1
performed. Ten experiments were carried out in DMSO-d6
at different temperatures from 303 to 393 K. These spectra
showed broadening of the signals with increasing tempera-
ture, and coalescence at different temperatures for different
kinds of protons. At the highest temperature employed, some
signals were still very broad, which suggests a high-energy
barrier between the two atropoisomers. This observation is
also supported by NOESY experiments carried out in
CDCl3 at 253 K. Under these conditions, no interchange
(EXSY) peaks were observed, and d and J values of the
two series of signals were similar to those measured in the
spectrum obtained at 303 K, indicating no conformational
changes on decreasing the temperature. The energy barrier
333 K
323 K
313 K
303 K
ppm
4.18
4.17
4.16
4.15
4.14
4.13
4.12
Figure 2. 1H NMR peaks corresponding to H-5 in the two rotamers of 8 in
DMSO-d6 at various temperatures.
O
O
O
O
N
O
N
O
N
O
H2O
-OH
OH
OH
7
OAc
MsO
O
O
O
O
O
8b
8a
Scheme 2. Mechanism of the cyclization step.

4698
F. J. Sayago et al. / Tetrahedron 63 (2007) 4695–4702
R
1
12a (12b). The NMR spectra of 13 showed signals for only
one spin system.
3
N
2
R
1
Ac
2
8 O
8 O
3
N
Ac
4
5
7
5
6
4
The reaction of the mesyl derivative 10 with potassium cya-
nide afforded in high yield the azasugar acetonitrile 14a
(14b), which was treated with lithium aluminum hydride
to give 15. During this reaction, the cyano and acetyl groups
were simultaneously reduced. Compound 15 was directly O-
deprotected to produce the azasugar ethylamino derivative
16 in 92% yield. The presence of C^N group of 14a
(14b) was evident from the signals at 2300 cmꢀ1 (IR spec-
trum) and 116.0 ppm (13C NMR spectrum). The 13C NMR
spectrum of compound 16 had no signals for an isopropyli-
dene group, the resonances for the N-ethyl group appeared at
52.8 (CH2) and 12.0 (CH3) ppm, and the signals for the
amino-ethyl group were at 37.0 and 30.8 ppm.
7
6
O
O
O
O
8C3
B8,3
Scheme 3. Conformations of the oxazine ring of compounds 8, 10–12,
and 14.
range experiments confirmed the expected coupling by the
observation of a cross peak between H2a and H4a. These
data clearly indicate an C3 conformation. Unfortunately,
the crucial 1,3-diaxial NOEs could not be detected in the
NOESY spectra due to the proximity of these expected cor-
relations to the more intense EXSY peaks. Only in the case
of 8a/8b, which was also studied in chloroform at low tem-
perature (253 K), did the absence of exchange peaks in these
conditions permit the observation of the NOE between
8
The NOESYexperiments were conclusive for the Z, E assign-
ment of the N-acetyl derivatives 8a/8b, 10a/10b, 11a/11b,
12a/12b, and 14a/14b (a is the major isomer and b the mi-
nor). In all cases, the observed NOEs for the methyl group
of the N-Ac moiety were key for this determination. Thus,
the observation of NOE interactions for this methyl group
with protons H4a and H6, for the major atropoisomer (com-
pounds a), and with protons H2a and H7 for the minor (com-
pounds b), clearly indicates a Z and E configuration for the
major and minor, respectively. Furthermore, these NOEs, to-
gether with those observedfor H6 and H7, allowed the stereo-
specific assignment of the prochiral protons H4a/H4b and
H2a/H2b. For these diastereotopic methylene protons, the
8
H2b and H4b, confirming the C3 conformation. Since the
1H and 13C NMR spectra of 8a/8b indicate that there is no
conformational change either by changing the solvent
from DMSO-d6 to CDCl3, or by lowering the temperature
from 303 K to 253 K in the latter solvent, we could expect
8
the same C3 conformation in all cases. Additionally, the
aforementioned closer proximity of the carbonyl group to
H2a and H4a for the E and the Z isomer, respectively, to-
gether with the observed NOEs between the methyl group
of the N-Ac and H6 for the Z isomer and H7 for the E isomer,
can be considered as an exclusive features of the 8C3 confor-
mation, since for the B8,3 conformation the N-Ac group
should be located far away from H6 and H7. The coupling
pattern observed for H5 and the vicinal protons H4a and
H4b is also in agreement with this conformation, since for
the B8,3 conformation we would expect a higher value for the
J4a,5 rather than lower and similar values observed for J4a,5
and J4b,5. Figure 3 shows the energy-minimized structure20
of the major rotamer 8a.
1
most-deshielded signals in the H NMR spectra, that is,
H2a and H4a, correspond to the protons located in the con-
cavity (endo protons) of the nor-tropane related part of the
structure (H2a is the pro-S proton at C2 and H4a is the pro-
R at C4). As an exception, only for 8a/8b in CDCl3 was the
E isomer observed as the major product, at 303 K as well
as at 253 K. This assignment is coherent with the observed
chemical shifts in the 1H and 13C NMR spectra of these com-
pounds, specially for the methylene groups located at the vic-
inal positions of the N-Ac (positions 2 and 4), from which we
can deduce the opposite effect that the anisotropy of the car-
bonyl group exerts in these positions in both atropoisomers.
Comparing the Z and E isomer, a shielding effect was con-
stantly observed at C4 (approx. 4.5 ppm) in all cases, and
a corresponding opposite effect at C2 (deshielding of approx.
4.5 ppm). Similarly, H4a for the Z isomer and H2a for the E
isomer, were the protons most affected by the deshielding
effect of the carbonyl, in agreement with a closer proximity
of the carbonyl to these protons.
For the bicyclic compounds 9, 13, and 16 the NMR data were
also in agreement with the 8C3 conformation. In the case of
the fully deprotected compounds 9 and 13, the most notice-
able difference in comparison with the other bi- or tricyclic
compounds was the change in the order of appearance in the
These products have semirigid structures, whose most prob-
8
able conformations are C3 and B8,3 (Scheme 3). There are
various NMR data that allow us to distinguish between
both conformations. For an 8C3 conformation, a long-range
coupling through a W pathway between H2a and H4a would
be expected, as well as a 1,3-diaxial NOE between H2b and
H4b, whereas for a B8,3 conformation, the small coupling
would be between H2b and H4b and the NOE would relate
H2a and H4a. Despite all 1H NMR spectra showing broad-
ened signals for H2a and H4a, attributable to a hidden small
coupling constant, in no case was the resolution enough to
determine the value of this coupling constant. For com-
pounds 8a/8b, 10a/10b, and 11a/11b, the 2D COSY long-
Figure 3. Main conformation (oxazine ring and amido bond) of rotamer 8a.

F. J. Sayago et al. / Tetrahedron 63 (2007) 4695–4702
4699
1H NMR spectra of the signals corresponding to the methyl-
enes 2 and 4. Thus, in both compounds the pro-R proton at
C4 is H-4b, instead of H-4a, and for 9 the pro-S proton at C-2
is H-2b, instead of H-2a. For all these bicyclic structures, and
likewise the other studied compounds, the signals corre-
sponding to the long-range coupled protons characteristic
2 (257 mg, 0.805 mmol) in super-dry diethyl ether (8.7 mL).
The resulting suspension was stirred at room temperature for
3 h and afterward 414 mL of a 1 M solution of K2CO3 was
carefully added. The reaction mixture was filtered through
Celite, dried (MgSO4), and evaporated to dryness. The ob-
tained residue was dissolved in dry pyridine (3.3 mL) and
cooled to 0 ꢁC. Acetic anhydride (1.7 mL) was added and
the mixture was kept stirred at 0 ꢁC for 3 h. The solution
was poured into ice water and extracted with CH2Cl2, the or-
ganic layer was separated, washed with 2 N H2SO4, saturated
aqueous sodium hydrogencarbonate, and water, dried
(MgSO4), filtered, and evaporated to dryness. The residue
was purified by column chromatography using ether/hexane
4:1 and ether as eluents to give a syrup. Yield 87%; [a]D25
+33 (c 0.9, CH2Cl2); CIMS m/z 408 [(M+H)+]; IR 3311,
3097, 2964, 2874, 1746, 1651, 1547, 1460, 1397, 1262,
8
of the C3 conformation (H2b/H4b for 9, H2a/H4b for 13,
and H2a/H4a for 16) presented a broadened lineshape, indic-
ative of the presence of this small coupling. For compound
13, a further confirmation was provided by the 2D NOESY
spectrum, which showed a small correlation between H2b
and H4a, the 1,3-diaxial interaction characteristic of the pro-
posed conformation.
In conclusion, the glycosyl cyanide 3 is a suitable starting
material to prepare conformationally restricted iminocycli-
tols with an ether bridge, with nor-tropane related structure,
and different functionalizations on C-1. The key step is a
cyclization reaction using a stabilized amide ion. All the
reactions are highly stereoselective. The 8C3 is the main con-
formation for prepared compounds in DMSO-d6 and/or
CDCl3.
1
1087, 880, 809 cmꢀ1; H NMR (500 MHz, CDCl3) d 7.29–
7.38 (m, 5H, Ph), 6.51 (m, 1H, NHAc), 4.79 (t, 1H,
J3,4¼J3,4¼6.0, H-4), 6.91 (d, 1H, Jgem¼11.0, HCHPh), 4.52
(m, 2H, H-3,HCHPh), 4.26, 4.23(eachd, each1H, Jgem¼12.0,
H-1a, H-1b), 4.09 (m, 1H, H-5), 3.83 (dd, 1H, Jgem¼14.0,
JNH;CH ¼9.0,
HCHNH),
3.82
(d,
1H,
J6a,6b
¼
2
11.0, H-6a), 3.67 (dd, 1H, J5,6b¼2.5, H-6b), 3.17 (dd, 1H,
JNH;CH ¼3.0, HCHNH), 2.09, 1.52 (each s, each 3H,
2
3. Experimental
CH3CO), 1.50, 1.30 (each s, each 3H, (CH3)2C); 13C NMR
(125.7 MHz, CDCl3) d 170.9, 170.8 (2CO), 137.7–127.9
(Ar), 114.1 ((CH3)2C), 84.9 (C-2), 83.7 (C-5), 83.6 (C-3),
80.8 (C-4), 74.2 (CH2Ph), 69.8 (C-6), 64.2 (C-1), 43.7
(CH2NH), 27.2, 25.4 (2(CH3)2C), 22.5, 21.0 (2CH3CO);
HRCIMS m/z obsd 408.2010 calcd for C21H30NO7 408.2022.
3.1. General methods
Melting points were determined with a Gallenkamp appara-
tus and are uncorrected. A Perkin–Elmer Model 141 MC po-
larimeter, 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 spectrophotometer. Mass spectra (EI, CI, and FAB)
wererecordedwithaKratosMS-80RFAoraMicromassAuto-
SpecQ 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 charring with H2SO4. Silica Gel 60 (Merck, 70–230 and
230–400 mesh) was used for preparative chromatography.
3.1.2. 1-Acetyl-2-acetylaminomethyl-2-deoxy-3,4-O-iso-
propylidene-b-D-psicofuranose (6). To a stirred solution
of 5 (241 mg, 0.592 mmol) in ethyl acetate (40 mL), 10%
Pd–C (40 mg) was added. The obtained solution was kept
at room temperature and stirred under hydrogen atmosphere
for 2.5 h. The mixture was filtered through Celite and evap-
orated to dryness. The resulting crude was purified by col-
umn chromatography on silica gel using dichloromethane/
methanol 25:1 as eluent to give an amorphous solid. Yield
96%; [a]2D4 +18 (c 1.4, CH2Cl2); FABMS m/z 340
[(M+Na)+]; IR 3451, 3285, 3090, 2986, 2938, 2901, 1740,
1651, 1572, 1443, 1377, 1292, 1211, 1072, 974, 864,
NMR experiments were recorded on a Bruker Avance 500
spectrometer (500.13 MHz for 1H and 125.75 MHz for
13C) equipped with a 5 mm inverse detection probe. All
experimentswereperformedat303 K, exceptforthevariable-
temperature 1H NMR study of 8. The samples were thermi-
cally equilibrated at the corresponding temperature before
measurement. The probe temperature was calibrated with
a standard sample of 80% ethyleneglycol in DMSO-d6. Sam-
ple concentrations were typically in the range 10–15 mg per
0.6 mL of the deuterated solvent. Chemical shifts are given
in parts per million, using the residual protonated solvent
signal as reference. 1H and 13C assignments were confirmed
by 2D conventional COSY and HSQC experiments. 2D
NOESYexperiments were carried out by using conventional
pulse sequence with a mixing time of 400 ms, a recycle delay
of 2 s, and 2048 transients per spectrum in all cases.
783 cmꢀ1 1H NMR (500 MHz, CDCl3) d 6.59 (d, 1H,
;
JNH;CH ¼5.0, NHAc), 4.97 (dd, 1H, J3,4¼6.0, J4,5¼4.5,
2
H-4), 4.46 (d, 1H, H-3), 4.39 (d, 1H, J1a,1b¼11.0, H-1a),
4.23 (m, 1H, OH), 4.17 (d, 1H, H-1b), 4.11 (m, 1H, H-5),
3.81 (d, 1H, Jgem¼14.0, HCHNH), 3.79 (d, 1H, J6a,6b
¼
14.5, H-6a), 3.64 (m, 1H, H-6b), 2.98 (dd, 1H, HCHNH),
2.12, 2.02 (each s, each 3H, CH3CO), 1.53, 1.34 (each s,
each 3H, (CH3)2C); 13C NMR (125.7 MHz, CDCl3)
d 171.7, 171.6 (2CO), 113.9 ((CH3)2C), 86.1 (C-5), 85.1
(C-2), 84.0 (C-3), 81.6 (C-4), 63.0 (C-1), 62.3 (C-6), 43.1
(CH2NH), 26.9, 25.2 (2(CH3)2C), 23.5, 21.2 (2CH3CO);
Anal. Calcd for C14H23NO7: C, 52.99; H, 7.31; N, 4.41.
Found: C, 52.87; H, 7.08; N, 4.34.
3.2. General procedure for the synthesis of compounds
7 and 10
3.1.1. 1-Acetyl-2-acetylaminomethyl-6-O-benzyl-2-deoxy-
3,4-O-isopropylidene-b-D-psicofuranose (5). Lithium alu-
minum hydride (159 mg) was added at 0 ꢁC to a solution of
Compound 6 or 8 (m mg) was dissolved in dry pyridine
(x mL) and mesyl chloride (y mL) was added dropwise at
0 ꢁC. The mixture was stirred at room temperature for

4700
F. J. Sayago et al. / Tetrahedron 63 (2007) 4695–4702
24 h. The reaction crude was poured into saturated aqueous
sodium hydrogencarbonate at 0 ꢁC, and extracted with ethyl
acetate. The organic layer was dried (MgSO4), filtered, and
evaporated to dryness. The resulting residue was purified by
silica gel column chromatography using dichloromethane/
methanol 40:1 as eluent.
added to a solution of 7 (226 mg, 0.572 mmol) in dry
DMF (6 mL) containing molecular sieves, and the mixture
was stirred at room temperature for 12 h. The crude was
poured into water and coevaporated to dryness with ethanol
and toluene. The resulting residue was purified by column
chromatography on silica gel using dichloromethane/metha-
nol 30:1 as eluent to give 6 as a mixture of two rotamers (8a
and 8b) in a ratio of 1.25:1. Amorphous solid; yield 82%;
[a]2D5 ꢀ55 (c 1.0, CH2Cl2); CIMS m/z 258 [(M+H)+]; IR
3428, 2990, 2936, 2872, 1649, 1458, 1371, 1275, 1204,
1172, 1069, 878 cmꢀ1; NMR data for rotamer 8a: 1H NMR
3.2.1. 1-Acetyl-2-acetylaminomethyl-2-deoxy-3,4-O-iso-
propylidene-6-O-mesyl-b-D-psicofuranose
(7).
M¼
234 mg (0.738 mmol), x¼3.2 mL, y¼280 mL, z¼28 mL.
Amorphous solid; yield 76%; [a]2D5 +37 (c 0.93, CH2Cl2);
FABMS m/z 418 [(M+Na)+]; IR 3420, 3079, 2928, 2856,
1752, 1657, 1561, 1521, 1466, 1371, 1116, 1069, 989,
(500 MHz, DMSO-d6) d 4.80 (t, 1H, JOH;CH ¼5.5, OH), 4.64
2
(d, 1H, J6,7¼5.9, H-6), 4.23 (d, 1H, H-7), 4.21 (d, 1H,
1
751 cmꢀ1; H NMR (500 MHz, CDCl3) d 6.30 (m, 1H,
J2a,2b¼13.5, H-2a), 4.11 (m, 1H, H-5), 3.63 (d, 1H, J4a,4b¼
NHAc), 4.66 (dd, 1H, J3,4¼6.5, J4,5¼5.0, H-4), 4.63 (d,
1H, H-3), 4.52 (dd, 1H, J5,6a¼2.5, J6a,6b¼11.5, H-6a), 4.33
(d, 1H, J1a,1b¼12.0, H-1a), 4.31 (dd, 1H, J5,6b¼3.5, H-6b),
4.18 (d, 1H, H-1b), 4.16 (m, 1H, H-5), 3.62 (dd, 1H,
12.9, H-4a), 3.60 (m, 1H, CH2OH), 3.42 (dd, 1H, Jgem¼11.0,
CH2OH), 3.12 (dd, 1H, J4b,5¼2.5, H-4b), 2.60 (d, 1H, H-2b),
1.98 (s, 3H, CH3CO), 1.35, 1.23 (each s, each 3H, (CH3)2C);
13C NMR (125.7 MHz, DMSO-d6) d 169.8 (CO), 110.5
((CH3)2C), 83.3 (C-1), 82.5 (C-6), 81.8 (C-7), 77.7 (C-5),
60.5 (CH2OH), 47.1 (C-4), 45.5 (C-2), 25.9, 24.4
Jgem¼14.5, JNH;CH ¼8.0, HCHNH), 3.36 (dd, 1H,
2
JNH;CH ¼5.0, HCHNH), 3.09 (s, 3H, CH3SO2), 2.09, 2.01
2
1
(each s, each 3H, CH3CO), 1.51, 1.31 (each s, each 3H,
(CH3)2C); 13C NMR (125.7 MHz, CDCl3) d 171.0 (2CO),
115.1 ((CH3)2C), 85.3 (C-2), 83.0 (C-3), 81.1 (C-5), 80.6
(C-4), 68.6 (C-6), 63.0 (C-1), 42.5 (CH2NH), 38.1
(CH3SO2), 26.8, 25.1 (2(CH3)2C), 23.2, 21.0 (2CH3CO);
Anal. Calcd for C15H25NO9S: C, 45.56; H, 6.37; N, 3.54;
S, 8.11. Found: C, 45.39; H, 6.33; N, 3.58; S, 7.86.
((CH3)2C), 21.3 (CH3CO); NMR data for rotamer 8b: H
NMR (500 MHz, DMSO-d6) d 4.83 (t, 1H, JOH;CH ¼5.5,
2
OH), 4.50 (d, 1H, J6,7¼5.9, H-7), 4.38 (d, 1H, H-6), 4.15
(m, 1H, H-5), 4.03 (d, 1H, J4a,4b¼13.3, H-4a), 3.68 (d, 1H,
J2a,2b¼12.9, H-2a), 3.60 (m, 1H, CH2OH), 3.45 (dd, 1H,
Jgem¼11.0, CH2OH), 3.16 (d, 1H, H-2b), 2.62 (dd,
1H, J4b,5¼2.5, H-4b), 1.98 (s, 3H, CH3CO), 1.35, 1.23 (each
s, each 3H, (CH3)2C); 13C NMR (125.7 MHz, DMSO-d6)
d 169.9 (CO), 110.6 ((CH3)2C), 82.8 (C-1), 82.6 (C-7),
81.8 (C-6), 77.9 (C-5), 60.5 (CH2OH), 49.9 (C-2), 42.7
(C-4), 25.9, 24.4 ((CH3)2C), 21.3 (CH3CO). HRCIMS calcd
for C12H20NO5: 258.1341. Found: 258.1339.
3.2.2. (1R,5R,6R,7R)-3-N-Acetyl-3-aza-7,8-(dimethyl-
methylenedioxy)-1-mesyloxymethyl-8-oxabicyclo[3.2.1]-
octane (10). M¼166 mg (0.646 mmol), x¼2.8 mL,
y¼245 mL, z¼25 mL. Amorphous solid; yield 85%; mixture
of two rotamers (10a and 10b) in a ratio of 1.25:1; [a]2D4 ꢀ60
(c 0.92, CH2Cl2); FABMS m/z 358 [(M+Na)+]; IR 2990,
2962, 2863, 1655, 1544, 1425, 1353, 1210, 1171, 1131,
3.2.4. (1R,5R,6R,7R)-3-N-Acetyl-3-aza-1-azidomethyl-
7,8-(dimethylmethylenedioxy)-8-oxabicyclo[3.2.1]octane
(11). To a stirred solution of 10 (100 mg, 0.299 mmol) in dry
DMF (7.5 mL), sodium azide (150 mg, 2.30 mmol) was
added and the mixture was kept stirring for 2 h at 155 ꢁC.
The reaction was monitored by TLC using ethyl acetate as
eluent. When the starting product was completely con-
sumed, the reaction mixture was poured into ice water and
extracted with ethyl acetate. The organic layer was dried
over MgSO4, filtered, and evaporated to dryness. The ob-
tained residue was purified by silica gel column chromato-
graphy using ethyl acetate as eluent. Amorphous solid;
yield 86%; [a]2D6 ꢀ77 (c 1.2, CH2Cl2); mixture of two ro-
tamers (11a and 11b) in a ratio of 1.25:1; CIMS m/z 283
[(M+H)+]; IR 3416, 2995, 2931, 2105, 1644, 1422, 1374,
1358, 1215, 1112, 1072, 874 cmꢀ1; NMR data for rotamer
11a: 1H NMR (500 MHz, DMSO-d6) d 4.70 (d, 1H,
J6,7¼5.9, H-6), 4.25 (d, 1H, H-7), 4.20 (m, 1H, H-5), 4.14
(d, 1H, J2a,2b¼13.0, H-2a), 3.66 (d, 1H, J4a,4b¼12.9, H-
4a), 3.53 (m, 2H, CH3N3), 3.14 (dd, 1H, J4b,5¼2.5, H-4b),
2.66 (d, 1H, H-2b), 1.99 (s, 3H, CH3CO), 1.38, 1.24 (each
s, each 3H, (CH3)2C); 13C NMR (125.7 MHz, DMSO-d6)
d 169.9 (CO), 111.1 ((CH3)2C), 82.6 (C-6), 82.4 (C-1),
81.9 (C-7), 78.2 (C-5), 51.4 (CH2N3), 46.7 (C-4), 45.1 (C-
2), 25.8, 24.4 ((CH3)2C), 21.3 (CH3CO); NMR data for ro-
1
1075, 980, 877, 829 cmꢀ1; NMR data for rotamer 10a: H
NMR (500 MHz, DMSO-d6) d 4.73 (d, 1H, J6,7¼5.8, H-6),
4.42 (d, 1H, Jgem¼11.0, HCHOMs), 4.32 (d, 1H, H-7),
4.24 (m, 1H, H-5), 4.23 (d, 1H, HCHOMs), 4.20 (d, 1H,
J2a,2b¼13.4, H-2a), 3.67 (d, 1H, J4a,4b¼13.0, H-4a), 3.16
(dd, 1H, J4b,5¼2.4, H-4b), 2.71 (d, 1H, H-2b), 2.00 (s, 3H,
CH3CO), 1.38, 1.25 (each s, each 3H, (CH3)2C); 13C NMR
(125.7 MHz, DMSO-d6) d 170.0 (CO), 111.2 ((CH3)2C),
82.5 (C-6), 81.9 (C-7), 81.0 (C-1), 78.5 (C-5), 69.1
(CH2OMs), 46.7 (C-4), 44.4 (C-2), 36.6 (CH3SO2), 25.8,
24.3 ((CH3)2C), 21.3 (CH3CO); NMR data for rotamer
10b: 1H NMR (500 MHz, DMSO-d6) d 4.61 (d, 1H,
J6,7¼5.8, H-7), 4.45 (d, 1H, H-6), 4.42 (d, 1H, Jgem¼11.0,
HCHOMs), 4.23 (d, 1H, HCHOMs), 4.27 (m, 1H, H-5),
4.06 (d, 1H, J4a,4b¼13.3, H-4a), 3.75 (d, 1H, J2a,2b¼12.7,
H-2a), 3.26 (d, 1H, H-2b), 2.65 (dd, 1H, J4b,5¼2.4, H-4b),
2.00 (s, 3H, CH3CO), 1.38, 1.25 (each s, each 3H,
(CH3)2C); 13C NMR (125.7 MHz, DMSO-d6) d 170.0
(CO), 111.2 ((CH3)2C), 82.6 (C-6), 82.0 (C-7), 80.6 (C-1),
78.8 (C-5), 69.3 (CH2OMs), 48.7 (C-2), 42.2 (C-4), 36.7
(CH3SO2), 25.8, 24.3 ((CH3)2C), 21.2 (CH3CO);
HRFABMS calcd for C13H21NO7NaS: 358.0936. Found:
358.0943. Anal. Calcd for C13H21NO7S: C, 46.56; H, 6.31;
N, 4.18; S, 9.56. Found: C, 46.47; H, 6.15; N, 4.19; S, 9.48.
1
tamer 11b: H NMR (500 MHz, DMSO-d6) d 4.53 (d, 1H,
J6,7¼5.9, H-7), 4.43 (d, 1H, H-6), 4.24 (m, 1H, H-5), 4.04
(d, 1H, J4a,4b¼13.4, H-4a), 3.68 (d, 1H, J2a,2b¼12.7, H-
2a), 3.53 (m, 2H, CH3N3), 3.20 (d, 1H, H-2b), 2.64 (dd,
1H, J4b,5¼2.5, H-4b), 1.99 (s, 3H, CH3CO), 1.38, 1.24
3.2.3. (1R,5R,6R,7R)-3-N-Acetyl-3-aza-1-hydroxymeth-
yl-7,8-(dimethylmethylenedioxy)-8-oxabicyclo[3.2.1]-
octane (8). Sodium hydride (60 mg, 60% in paraffin) was

F. J. Sayago et al. / Tetrahedron 63 (2007) 4695–4702
4701
(each s, each 3H, (CH3)2C); 13C NMR (125.7 MHz, DMSO-
d6) d 169.9 (CO), 111.1 ((CH3)2C), 82.8 (C-6), 82.0 (C-1),
81.9 (C-7), 78.5 (C-5), 51.5 (CH2N3), 49.5 (C-2), 42.3 (C-
4), 25.8, 24.4 ((CH3)2C), 21.2 (CH3CO); HRCIMS calcd
for C12H19N4O4: 283.1406. Found: 283.1407.
4.41 (d, 1H, H-7), 4.33 (m, 1H, H-5), 4.29 (d, 1H, Jgem¼12.9,
H-4a), 3.72 (d, 1H, Jgem¼12.6, H-2a), 3.36 (d, 1H, H-2b),
2.83 (d, 1H, H-4b), 2.77 (m, 2H, H-10a and H-10b), 2.10 (s,
3H, COCH3), 1.48, 1.30 (each s, each 3H, (CH3)2C). 13C
NMR (125.7 MHz, CDCl3) d 170.5 (CO), 116.0 (CN),
113.1 ((CH3)2C), 83.4 (C-6), 82.3 (C-7), 80.2 (C-1), 79.9
(C-5), 51.7 (C-2), 42.7 (C-4), 25.9, 24.6 ((CH3)2C), 21.5
(CH3CO), 21.0 (CH2CN); HRCIMS calcd for C13H19N2O4:
267.1345 Found: 267.1330.
3.2.5. (1S,5R,6R,7R)-3-N-Acetyl-1-aminomethyl-3-aza-
7,8-(dimethylmethylenedioxy)-8-oxabicyclo[3.2.1]octane
(12). To a stirred solution of 11 (52 mg, 0.184 mmol) in ethyl
acetate (5.3 mL), 10% Pd–C (18 mg) was added. The ob-
tained suspension was kept at room temperature and stirred
under hydrogen atmosphere for 3 h. The mixture was filtered
through Celite and evaporated to dryness. Amorphous solid;
yield 98%; [a]2D9 ꢀ71 (c 0.7, CH2Cl2); mixture of two ro-
tamers (12a and 12b) in a ratio of 1.25:1; FABMS m/z 279
[(M+Na)+]; IR 3396, 2999, 2928, 2864, 1649, 1458, 1434,
1371, 1212, 1116, 1069, 1013, 870 cmꢀ1; NMR data for ro-
3.2.7. (1S,5R,6R,7R)-1-(20-Aminoethyl-3-aza-7,8-(di-
methylmethylenedioxy)-3-N-ethyl-8-oxabicyclo[3.2.1]-
octane (15). Lithium aluminum hydride (100 mg) was added
at 0 ꢁC to a solution of 14 (50 mg, 0.188 mmol) in super-dry
diethyl ether (7.0 mL). The resulting suspension was stirred
at room temperature for 18 h and afterward 1 mL of a 1 M so-
lution of K2CO3 was carefully added at 0 ꢁC. The reaction
mixture was filtered through Celite, dried (MgSO4), and
evaporatedtodryness. Theresiduewasusedasobtainedinthe
next reaction step. Amorphous solid; yield 64%; HRCIMS
calcd for C13H25N2O3: 257.1865. Found: 257.1878.
1
tamer 12a: H NMR (500 MHz, DMSO-d6) d 4.64 (d, 1H,
J6,7¼5.9, H-6), 4.28 (d, 1H, J2a,2b¼13.3, H-2a), 4.24 (d,
1H, H-7), 4.12 (m, 1H, H-5), 3.63 (d, 1H, J4a,4b¼12.9, H-
4a), 3.23 (s, 2H, NH2), 3.11 (dd, 1H, J4b,5¼2.5, H-4b),
2.80, 2.66 (each d, each 1H, Jgem¼13.0, CH2NH2), 2.54 (d,
1H, H-2b), 1.98 (s, 3H, CH3CO), 1.36, 1.24 (each s, each
3H, (CH3)2C); 13C NMR (125.7 MHz, DMSO-d6) d 169.8
(CO), 110.6 ((CH3)2C), 83.2 (C-1), 82.6 (C-6), 81.9 (C-7),
77.9 (C-5), 47.1 (C-4), 45.9 (C-2), 42.7 (CH2NH2), 25.8,
24.4 ((CH3)2C), 21.4 (CH3CO); NMR data for rotamer
12b: 1H NMR (500 MHz, DMSO-d6) d 4.50 (d, 1H,
J6,7¼5.9, H-7), 4.38 (d, 1H, H-6), 4.15 (m, 1H, H-5), 4.03
(d, 1H, J4a,4b¼13.4, H-4a), 3.79 (d, 1H, J2a,2b¼12.9, H-2a),
3.23 (s, 2H, NH2), 3.07 (d, 1H, H-2b), 2.80, 2.66 (each d,
each 1H, Jgem¼13.0, CH2NH2), 2.61 (dd, 1H, J4b,5¼2.5, H-
4b), 1.98 (s, 3H, CH3CO), 1.36, 1.24 (each s, each 3H,
(CH3)2C); 13C NMR (125.7 MHz, DMSO-d6) d 169.8
(CO), 110.6 (CH3)2C), 83.7 (C-1), 82.7 (C-6), 81.9 (C-7),
77.9 (C-5), 50.5 (C-2), 42.8 (C-4), 42.7 (CH2NH2), 25.8,
24.4 ((CH3)2C), 21.3 (CH3CO); HRFABMS: calcd for
C12H20N2O4Na: 279.1321. Found: 279.1327.
3.3. Preparation of compounds 9, 13 and 16
To a solution of 8, 12 or 15 (m mg) in methanol (x mL),
concd HCl (y mL) was added. The resulting solution was
stirred at 65 ꢁC for 4 h and then evaporated to dryness.
The obtained residue was purified by ion-exchange resin
chromatography (Dowex50W8X) using 2 N aqueous ammo-
nia as eluent.
3.3.1. (1R,5R,6R,7S)-3-Aza-6,7-dihydroxy-1-hydroxy-
methyl-8-oxabicyclo[3.2.1]octane
(9).
M¼51 mg
(0.198 mmol), x¼5.2 mL, y¼420 mL. Amorphous solid;
yield 98%; [a]2D4 ꢀ23 (c 2.4, MeOH); CIMS m/z 176
[(M+H)+]; IR 3420, 2928, 2856, 1649, 1450, 1355, 1116,
1045, 854, 767, 711 cmꢀ1; H NMR (500 MHz, MeOD)
1
d 4.30 (d, 1H, J6,7¼6.5, H-7), 4.25 (d, 1H, H-6), 4.02 (m, 1H,
H-5), 3.71, 3.60 (each d, each 1H, Jgem¼11.5, CH2OH), 2.87
3.2.6. (1S,5R,6R,7R)-3-N-Acetyl-3-aza-1-cyanomethyl-
7,8-(dimethylmethylenedioxy)-8-oxabicyclo[3.2.1]octane
(14). To a solution of 10 (110 mg, 0.328 mmol) in dry DMF
(7.9 mL), KCN (165 mg, 2.53 mmol) and crown ether (18-
crown-6) (175 mg, 0.656 mmol) were added. The mixture
was stirred at 155 ꢁC for 4 h and then poured into ice water,
extracted with ethyl acetate, dried over MgSO4, filtered,
and evaporated to dryness. The obtained residue was purified
by silica gel column chromatography using CH2Cl2/MeOH
40:1 as eluent to give 12 as a mixture of two rotamers (14a
and 14b) in a ratio of 1.2:1. Yield 85%; [a]2D0 ꢀ26 (c 2.2,
CH2Cl2); CIMS m/z 267 [(M+H)+]; IR 2919, 2840, 2300,
1654, 1443, 1374, 1358, 1266, 741 cmꢀ1; NMR data for
(d, 1H, Jgem¼12.5, H-2a), 2.84 (dd, 1H, Jgem¼12.0, J4a,5¼
2.5, H-4a), 2.83 (d, 1H, H-2b), 2.73 (dd, 1H, J4b,5¼1.4,
H-4b); 13C NMR (125.7 MHz, MeOD) d 85.6 (C-1), 84.2
(C-5), 75.3 (C-7), 75.1 (C-6), 63.8 (CH2OH), 51.0 (C-2),
48.0 (C-4); HRCIMS calcd for C7H14NO4: 176.0923.
Found: 176.0919.
3.3.2. (1S,5R,6R,7S)-1-Aminomethyl-3-aza-6,7-di-
(13).
hydroxy-8-oxabicyclo[3.2.1]octane
M¼42 mg
(0.164 mmol), x¼4.3 mL, y¼348 mL. Amorphous solid;
yield 98%; [a]2D9 ꢀ49 (c 1.5, MeOH); CIMS m/z 175
[(M+H)+]; IR 3390, 2938, 2850, 1636, 1559, 1429, 1373,
1107, 1072, 866 cmꢀ1; 1H NMR (500 MHz, MeOD) d 4.28
(d, 1H, J6,7¼6.5, H-7), 4.26 (d, 1H, H-6), 4.03 (m, 1H, H-5),
2.90, 2.84 (each d, each 1H, Jgem¼13.0, CH2NH2), 2.81
(dd, 1H, Jgem¼13.0, J4a,5¼2.5, H-4a), 2.76(d, 1H, Jgem¼12.0,
H-2a), 2.70 (d, 1H, H-4b), 2.64 (d, 1H, H-2b); 13C NMR
(125.7 MHz, MeOD) d 84.3 (C-5), 84.3 (C-1), 76.1 (C-7),
75.6 (C-6), 52.5 (C-2), 48.1 (C-4), 44.3 (CH2NH2); HRCIMS
calcd for C7H15N2O3: 175.1083. Found: 175.1079.
1
rotamer 14a: H NMR (500 MHz, CDCl3) d 4.56 (d, 1H,
J6,7¼5.9, H-6), 4.45 (d, 1H, Jgem¼13.3, H-2a), 4.39 (d, 1H,
H-7), 4.31 (m, 1H, H-5), 3.54 (d, 1H, Jgem¼12.9, H-4a),
3.39 (dd, 1H, J4b,5¼2.4, H-4b), 2.91 (d, 1H, H-2b), 2.83 (d,
1H, Jgem¼17.0, H-10a), 2.67 (d, 1H, H-10b), 2.09 (s, 3H,
COCH3), 1.48, 1.30 (each s, each 3H, (CH3)2C). 13C NMR
(125.7 MHz, CDCl3) d 170.5 (CO), 116.0 (CN), 113.1
((CH3)2C), 83.5 (C-6), 82.4 (C-7), 80.8 (C-1), 79.1 (C-5),
47.4 (C-4), 46.9 (C-2), 25.9, 24.6 ((CH3)2C), 21.6
3.3.3. (1S,5R,6R,7S)-1-(20-Aminoethyl)-3-aza-6,7-di-
hydroxy-3-N-ethyl-8-oxabicyclo[3.2.1]octane (16). M¼
31 mg (0.164 mmol), x¼5.2 mL, y¼900 mL. Amorphous
1
(CH3CO), 21.3 (CH2CN); NMR data for rotamer 14b: H
NMR (500 MHz, CDCl3) d 4.57 (d, 1H, J6,7¼5.9, H-6),

4702
F. J. Sayago et al. / Tetrahedron 63 (2007) 4695–4702
solid; yield 92%; [a]2D0 ꢀ26 (c 0.8, MeOH); CIMS m/z 217
;
1336, 1185, 1096, cmꢀ1 1H NMR (500 MHz, MeOD)
Asymmetry 2002, 13, 1743–1753; (c) Chabeaud, L.; Landais,
Y.; Renaud, P. Org. Lett. 2005, 7, 2587–2590; (d) Li, H.;
[(M+H)+]; IR 3761, 3423, 2932, 2810, 1634, 1561, 1402,
ꢀ
Bleriot, Y.; Chantereau, C.; Mallet, J. M.; Sollogoub, M.;
Zhang, Y.; Rodriguez-Garcıa, E.; Vogel, P.; Jimenez-Barbero,
ꢀ
d 4.26 (d, 1H, J6,7¼6.3, H-6), 4.18 (d, 1H, H-7), 4.12 (m,
1H, H-5), 3.18 (m, 2H, H-20a and H-20b), 2.76 (m, 1H, H-
J.; Sinay, P. Org. Biomol. Chem. 2004, 2, 1492–1499.
8. Kilonda, A.; Dequeker, E.; Compernolle, F.; Delbeke, P.;
Toppet, S.; Babady, B.; Hoornaert, G. J. Tetrahedron 1995,
51, 849–858.
9. Poitout, L.; Le Merrer, Y.; Depezay, J. C. Tetrahedron Lett.
1996, 37, 1613–1616.
10. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2005, 12, 1239–1287.
11. Asano, N.; Kato, A.; Miyauchi, M.; Kizu, H.; Tamimori, T.;
Matsui, K.; Nash, R. J.; Molyneux, R. J. Eur. J. Biochem.
1997, 248, 296.
3
4a), 2.73 (d, 1H, Jgem¼10.9, H-2a), 2.35 (q, 2H, JH,H
¼
0
0
7.5, NCH2CH3), 2.18 (dt, 1H, Jgem¼14.5, J1 a,2 a
¼
J1 a,2 b¼7.0, H-10a), 2.11 (dd, 1H, Jgem¼11.0, J4b,5¼2.0, H-
0
0
0
0
0
0
4b), 2.01 (d, 1H, H-2b), 1.86 (dt, 1H, J1 b,2 a¼J1 b,2 b¼7.0,
H-10b), 1.06 (t, 3H, NCH2CH3); 13C NMR (125.7 MHz,
MeOD) d 84.6 (C-1), 83.7 (C-5), 76.0 (C-7), 75.7 (C-6),
61.7 (C-2), 55.5 (C-4), 52.8 (NCH2CH3), 37.0 (C-20), 30.8
(C-10), 12.0 (NCH2CH3). HRCIMS calcd for C10H21N2O3:
217.1552. Found: 217.1553.
12. Ball, C. P.; Barret, A. G. M.; Poitout, L. F.; Smith, M. L.; Thorn,
Z. E. Chem. Commun. 1998, 2453–2454.
Acknowledgements
13. Fuentes, J.; Illangua, J. M.; Sayago, F. J.; Angulo, M.; Gasch,
C.; Pradera, M. A. Tetrahedron: Asymmetry 2004, 15, 3783–
3789.
ꢀ
We thank the Secretarıa General de Polıtica Cientıfica y
Tecnica of Spain and the Junta de Andalucia for financial
ꢀ
ꢀ
ꢀ
14. Sano, H.; Mio, S.; Kitagawa, J.; Sugai, S. Tetrahedron:
Asymmetry 1994, 5, 2233–2240.
15. Wong, C. H.; Proveucher, L.; Porco, J. A.; Jung, S. H.; Wang,
Y. F.; Chen, L.; Wang, R.; Steensma, D. H. J. Org. Chem. 1995,
60, 1492–1501.
support (grant numbers CTQ 2005-01830, with FEDER par-
ꢀ
ticipation, and FQM-134), and the Ministerio de Educacion
y Ciencia, for the award of a fellowship to F.J.S.
References and notes
ꢀ
16. Fuentes, J.; Salameh, B. A. B.; Pradera, M. A.; Fernandez de
Cordoba, F. J.; Gasch, C. Tetrahedron 2006, 62, 97–111 and
ꢀ
1. See as examples: (a) Afarinkia, K.; Bahar, A. Tetrahedron:
Asymmetry 2005, 12, 1239–1287; (b) Lillelund, V. H.;
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3. Winchester, B.; Fleet, G. W. G. Glycobiology 1992, 2,
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17. Sayago, F. J.; Pradera, M. A.; Gasch, C.; Fuentes, J.
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1998, 63, 3411–3416; (b) Fuentes, J.; Gasch, C.; Olano, D.;
Pradera, M. A.; Repetto, G.; Sayago, F. J. Tetrahedron:
20. The minimization was performed through the MM2 force field
as implemented in the program ChemOffice. Chem3D version
Ultra 9.0. CambridgeSoft Corporation: Cambridge, MA. See:
Burkert, H.; Allinger, N. L. Molecular Mechanics; ACS
Monography 177; American Chemical Society: Washington,
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