A short and highly stereoselective route to polyhydroxy-perhydroazaazulenes via a C-(D-galacto-pentopyranos-5-yl)isoxazolidine

Article abstract of DOI:10.1016/j.tetasy.2005.10.023

A short and efficient route to enantiomerically pure hexahydroxy- and pentahydroxy-perhydroazaazulenes, ring-homologues of castanospermine, starting from the sole isoxazolidine derivative obtained in the 1,3-dipolar cycloaddition of a D-galactose-derived

Full text of DOI:10.1016/j.tetasy.2005.10.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3897–3907
A short and highly stereoselective
route to polyhydroxy-perhydroazaazulenes via
a C-(D-galacto-pentopyranos-5-yl)isoxazolidine
a
a
a
a
´
M Isabel Torres-Sanchez, Pastora Borrachero, Francisca Cabrera-Escribano,
a,
b
a
c
´
c
*
´
´
´
Manuel Gomez-Guillen, Manuel Angulo-Alvarez, M Jesu´s Dianez,
a
c
c
´
´
´
M Dolores Estrada, Amparo Lopez-Castro and Simeon Perez-Garrido
aDepartamento de Quı´mica Orga´nica ꢀProfesor Garcı´a Gonza´lezꢁ, Facultad de Quı´mica, Universidad de Sevilla,
Apartado de Correos No. 553, E-41071 Seville, Spain
bServicio de RMN, Centro de Investigacio´n, Tecnologı´a e Innovacio´n de la Universidad de Sevilla (C.I.T.I.U.S.),
Avda. Reina Mercedes, s/n, E-41012 Seville, Spain
cInstituto de Ciencias de Materiales de Sevilla and Departamento de Fı´sica de la Materia Condensada,
C.S.I.C.-Universidad de Sevilla, Apartado de Correos No. 1065, E-41080 Seville, Spain
Received 26 September 2005; accepted 14 October 2005
Available online 14 November 2005
Abstract—A short and efficient route to enantiomerically pure hexahydroxy- and pentahydroxy-perhydroazaazulenes, ring-homo-
logues of castanospermine, starting from the sole isoxazolidine derivative obtained in the 1,3-dipolar cycloaddition of a D-galactose-
derived nitrone and methyl acrylate, is established. The procedure allows both backbone and stereochemical modulation of the
products by choice of the starting monosaccharide. Structural assignment was based on crystallographic analysis of the starting
isoxazolidine and NMR techniques. The products were tested for inhibitory activity against several glycosidases.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tion of new stereogenic centers. A very useful type of
reaction for the synthesis of higher-chain amino sugars
is the 1,3-dipolar cycloaddition reaction of olefins with
C-glycosyl nitrones, including cyclic nitrones, in which
glycosyl-isoxazolidines are regio- and stereoselectively
formed.9,10 Opening the isoxazolidine ring of the cyc-
loadducts affords diverse kinds of higher-chain sugars;
thus, we have described11 the synthesis of C7 and C8
aminodialdoses by opening the cycloadduct obtained
from conveniently protected C-glycosyl nitrones and
vinyl trimethylsilane.
Polyhydroxy-indolizidines are a group of natural and
synthetic compounds belonging to the wider class of
the iminosugars (azasugars). Many of them show inter-
esting biological activities, such as glycosidase inhibitory
properties, and therefore therapeutic applications, such
as immunosuppressive, anti-malarial, anti-viral, anti-
cancer, and anti-diabetic agents.1–3 Extensive efforts
have been reported to obtain compounds of this kind,
castanospermine 1 being one of the most representative,
and a natural member of the series.2 Analogues of 1
have also been synthesized in order to study their bio-
logical properties. The topic has been extensively
reviewed in the last few years.4–7 Diverse synthetic
routes start from monosaccharide derivatives,8 taking
advantage of the configurational variety of sugars and
their ability to exert asymmetric induction in the forma-
The perhydroazaazulene system 2 is a higher-ring homo-
logue of indolizidine. A possible general route to new
potential glycosidase inhibitors derived from 2 starts
from methyl acrylate 3 (as the dipolarophile) and hexose
N-benzyl-nitrones (as the 1,3-dipoles). Compound 3 is
known to add to nitrones with high regioselectivity, so
that, with few exceptions, the sole (or at least the main)
product is the 5-methoxycarbonyl regioisomer.12,13 We
have briefly reported14,15 that the cycloaddition reaction
of 3 with the nitrone 4, derived from D-galactose, affords
*
Corresponding author. Tel.: +34 95 4557151; fax: +34 95 4624960;
e-mail: mguillen@us.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.023

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M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
only one of the possible diastereomeric N-benzyl-3-(O-
protected pentosyl)-5-methoxycarbonyl-isoxazolidines,
whose hydrogenolysis, followed by reduction of the
resulting lactam, leads to a 5-(O-protected pentosyl)-3-
hydroxypyrrolidine. The chain of the sugar moiety in
these compounds is long enough to undergo annellation
in a subsequent step of the synthesis, giving rise to a
seven-membered ring. This methodology might allow
modulating both the ring size and the stereochemistry
of the products. The synthetic versatility of this strategy
is shown in Figure 1. Hence, the designed pathway
would also allow the synthesis of polyhydroxy-indolizi-
dines analogous to 1, as well as their 5-hydroxy
precursors.
MeO2C
CO2Me
O
N Bn
a
O
N
+
Bn
Gal
Gal
4
3
5
Gal:
O
O
O
O
Me2C
O
CMe2
Scheme 1. Reagents and conditions: (a) Toluene, 35 ꢁC, under Ar
atmosphere (3 h), 71%.
Compound 5 was subjected to isoxazolidine-ring cleav-
age by treatment with hexacarbonylmolybdenum18,19
to afford (3R,5R)-3-hydroxy-5-(1,2:3,4-di-O-isopropyl-
idene-a-D-galacto-pentopyranos-5-yl)-2-oxopyrrolidine
6 and its N-benzyl derivative 7 in 62% and 18% yield,
respectively, after column chromatography (Scheme 2).
These nonopyranos-uronolactam derivatives should
keep the (3R,5R) configuration coming from that of
isoxazolidine C(5) and C(3) atoms, respectively. The
(R) configuration assigned to C(5) for compounds 6
and 7 must be considered sure, since no epimerization
of this center is to be expected. However, the C(3) of
these compounds might have undergone epimerization.
A correct assignment required the use of NMR tech-
niques, as explained below.
2
2
1
3
HO
3
1
8a N 4
8
9a
4
N
H
HO
9
5
5
7
6
8
6
HO
OH
7
1
2
We now report in detail the synthesis of two poly-
hydroxy-perhydroazaazulenes. To our knowledge, only
one indolizidine homologue of this type has been synthe-
sized.16 We also include here a thorough configurational
study of these molecules and their precursors, as well as
the results of their biological evaluation. The first
selected hexose nitrone was the O-protected D-galactose
derivative 4, which we have used for [3+2] cycloaddition
reactions with other dipolarophiles.10,11
O
O
HO
HO
MeO2C
O
a
+
N
N
N
Bn
Bn
H
Gal
Gal
6 (62%)
Gal
7 (18%)
Oxidation
level
HO
5
H
N
Configurational
diversity
HO
R
Scheme 2. Reagents and conditions: (a) Mo(CO)6, MeCN/H2O, reflux
(7 h), yields: 62% for 6; 18% for 7.
R = H, OH
n = 1, 2
HO
OH
n
Ring size
As we have previously reported,14,15 the major product 6
of the foregoing reaction was reduced with lithium alu-
minum hydride in ether to afford 96%, after column
chromatography, of (2R,4R)-4-hydroxy-2-(1,2:3,4-di-O-
isopropylidene-a-D-galacto-pentopyranos-5-yl)pyrroli-
dine 8, whose treatment with trifluoroacetic acid (TFA),
followed by cation-exchange chromatography, led to a
product initially14,15 formulated as the O-deprotected
compound 9 (Scheme 3).
Figure 1. The synthetic versatility of the procedure, expressed on a
general formula of the expected products.
2. Results
The reaction of 3 with the (Z)-N-benzyl-nitrone 4 (2:1
molar ratio) in toluene at 35 ꢁC led with total regioselec-
tivity to only one of the four possible diastereomeric
cycloadducts—that coming from the endo attack of 3
to the re face of 4—which was isolated as a crystalline
compound 5 in 71% yield (Scheme 1). X-ray crystallo-
graphic analysis of 5 unambiguously showed, as dis-
cussed below, that it is the (2R) invertomer of the
(3R,5R) configured diastereomer.ꢂ
HO
O
HO
HO
a
b
N
O
H
N
N
H
H
H
HO
Gal
Gal
OH
OH
6
8
OH
9
ꢂ Compound 5 and the opening of its isoxazolidine ring under
conditions different from those used by us have been described17
after our first communication.14
Scheme 3. Reagents and conditions: (a) LiAlH4, ether, reflux (3 h),
96%; (b) 80% TFA, rt (24 h), 98%.

M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
3899
HO
HO
HO
HO
a
b
N
N
O
NH
Gal
N
Cbz
Cbz
Cbz
OH
H
HO
H
Gal
10
HO
OH
OH
OH
8
OH
11
HO
c
CHO
d
HO
HO
d
H
H
N
N
HO
OH
OH
HO
HO
HO
OH
OH
OH
12
13
Scheme 4. Reagents and conditions: (a) CbzCl, NaHCO3, 1:1 EtOH/H2O, rt, 96%; (b) 80% TFA, rt (24 h), 95%; (c) H2, 10% Pd/C, EtOH, rt (24 h),
99.5%; (d) H2, 10% Pd/C, EtOH, HOAc, rt (2 h).
We aimed to complete our earlier route15 to a castano-
spermine ring-homologue by selectively protecting the
pyrrolidine N atom of compound 8 before trying to
reduce the potential aldehyde group of the sugar moiety;
the subsequent reduction and selective transformation
of the expected primary alcohol into its O-tosyl deriva-
tive, followed by N-deprotection, should lead to the 5-
deoxy annellated compound. Therefore, 8 was treated
with benzyloxycarbonyl chloride (Scheme 4) to obtain
10 (96%), which was then O-deprotected by the action
of 80% TFA at room temperature for 24 h, giving 95%
of compound 11, after column chromatography. When
11 was subjected to catalytic hydrogenation (Pd/C)
using ethanol as the sole solvent, internal nucleophilic
addition of the amine nitrogen to the aldehyde group
took place to give the hexahydroxy-perhydroazaazulene
derivative 12 in 99% yield, whereas in the presence of an
additional amount of acetic acid, the hydrogenation
gave (2R,6S,7R,8S,9R,9aR)-2,6,7,8,9-pentahydroxy-
perhydroazaazulene 13, isolated as a product containing
1 mol equiv of acetic acid, which could be totally
removed by co-evaporation with ethanol–water to give
pure 13 in high yield (99%). Hydrogenation of com-
pound 12 under acid conditions also gave rise to 13. This
latter compound may be considered a castanospermine
ring-homologue. The foregoing findings made unneces-
sary the planned aldehyde reduction and tosylation
before deprotecting the pyrrolidine nitrogen.
When we started from 6 (Scheme 3), a thorough struc-
tural analysis of the product obtained in the hydrolysis
of 8 with TFA, made us realize that its structure was
not the one previously assigned 9,15 but 12, isolated in
high yield (98%) (Scheme 5). Compound 9 is very likely
HO
HO
O
HO
HO
a
b
N
O
N
H
H
N
N
H
H
H
HO
H
HO
Gal
Gal
OH
OH
OH
OH
6
8
OH
HO
9
CHO
HO
HO
c
H
H
N
N
HO
OH
OH
HO
HO
HO
OH
OH
OH
12
13
Scheme 5. Reagents and conditions: (a) LiAlH4, ether, reflux (3 h), 96%; (b) 80% TFA, rt (24 h), 98%; (c) H2, 10% Pd/C, EtOH, HOAc, rt (7 h), 98%.

3900
M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
O
HO
HO
HO
12
13
a
b
c
N
N
N
O
Bn
Bn
Bn
OH
H
HO
d
d
Gal
Gal
14
OH
7
OH
15
Scheme 6. Reagents and conditions: (a) LiAlH4, ether, reflux (3 h), 99%; (b) 80% TFA, rt (15 h), 96%; (c) H2, 10% Pd/C, EtOH, rt (24 h), 99%; (d)
H2, 10% Pd/C, EtOH, HOAc, rt (2 h), 99%.
an intermediate in equilibrium with the free aldehyde
form of the sugar moiety, and the isolated product
should arise from annellation of 9 by nucleophilic addi-
tion of the N atom to the carbonyl group. Here again,
when 12 was subjected to Pd/C-catalyzed hydrogenation
in the presence of acetic acid, 13 was isolated as a
product containing acetic acid, which could be totally
removed by co-evaporation with toluene–water or etha-
nol–water to give pure 13 in high yield (98%). Therefore,
the route summarized in Scheme 5 is shown to be the
shortest one toward compounds 12 and 13.
relationship. As expected, the hydroxyl proton did not
show contact with the C(5)H. Furthermore, a long-
range contact between the hydroxyl proton and the ano-
meric proton of the sugar moiety, as well as a C(5)H/
C(40)H contact, were observed, which allowed establish-
ing the relative pyrrolidine/pyranose steric relationship.
All that led us to conclude that our product is identical
with the one obtained by reduction of 5 using another
reagent.17
For the N-deprotected lactam 6, the overlapping
between some signals in its 1H NMR spectrum pre-
vented performing 1D NOESY experiments. These were
possible, however, in the case of its reduction product 8,
for which C(3a)ꢃH/C(2)H and C(3a)H/C(4)H contacts
were evidenced, but no C(2)H/C(4)H contact; further-
more, C(3b)H did not show any contact with either
C(2)H or C(4)H. Therefore, the 2,4-cis relationship
was also determined here, so that the (2R,4R) configura-
tion was assigned for 8 and (3R,5R) for 6.
In order to obtain additional amounts of the new com-
pounds 12 and 13, a route similar to that applied to the
N-benzyloxycarbonyl-pyrrolidine derivative 10 was car-
ried out with the N-benzyl lactam 7. Its reduction with
lithium aluminum hydride in ether (Scheme 6) afforded
(2R,4R)-1-benzyl-4-hydroxy-2-(1,2:3,4-di-O-isopropyli-
dene-a-D-galacto-pentopyranos-5-yl)pyrrolidine 14 in
99% yield after purification, whose treatment with TFA
led to 96% of the O-deprotected compound 15. Catalytic
(Pd/C) hydrogenation of 15 in ethanol originated the
hydrogenolysis of the N-benzyl bond, making possible
the annellation to give the azabicyclic compound 12 in
99% yield. When acetic acid was added to the solvent
for the hydrogenation of compound 15, the castanosper-
mine homologue 13 was again obtained in high yield
after purification of the crude product by co-evaporation
of the equimolar amount of acetic acid that it contained.
A similar analysis of the NOESY spectra of the N-benz-
yloxycarbonyl-pyrrolidine derivative 10 was not possi-
ble since the H-2 and H-4 signals were too close to
allow a fine observation of the cross peaks in the 2D-
NOESY spectrum or to allow a suitable selection for
1D spectra. Selection of the H-3b signal evidenced a
strong C(3b)H/C(2)H contact, and a weak C(3a)H/
C(2)H contact; hence, the pro-(S) designation was
attributed to C(3b)H, and the pro-(R) one to C(3a)H.
However, the C(3a)H/C(4)H and C(3b)H/C(4)H con-
tacts observed were of very similar magnitude, thus pre-
venting any configurational assignment to C(4). The
problem was solved by a semiquantitative analysis of
the NOE data. Four 2D NOESY experiments at mixing
times 100, 200, 300, and 400 ms were performed, and the
integration volumes of the cross-peaks corresponding to
the C(3a)H/C(2)H, C(3b)H/C(2)H, C(3a)H/C(4)H, and
C(3b)H/C(4)H interactions were determined. The aver-
age value of the two cross-peaks observed for each inter-
action was used to obtain the NOE build-up curves. For
every case, the range of mixing times used was checked
as fitting into the lineal zone of the NOE build-up. Lin-
eal regression analysis led to the slope for each interac-
tion, and this value was used as a comparative
estimation of the internuclear distances. The highest
slope values corresponded to the C(3b)H/C(2)H and
3. Discussion
The conditions used to open the isoxazolidine ring of 5
[Mo(CO)6 as the reducing reagent in 16:1 acetonitrile/
water at reflux] proved to be very suitable, since the
major product was the N-deprotected lactam 6 (62%),
a key intermediate in the shortest synthetic route
(Scheme 5), while the N-benzyl derivative 7 was the
minor product (18%). The (R) absolute configuration
of C(5) for both compounds comes from that of C(3)
in the isoxazolidine derivative 5, and should not change
under the reduction conditions. However, the stereo-
genic center C(3) of these pyrrolidin-2-ones could have
undergone epimerization. A thorough structural study
of 7 by NMR spectroscopic techniques allowed us to
assign the (R)-configuration to C(3) of this compound.
We carried out 1D-Double Pulse Field Gradient Spin
Echo (DPFGSE)-NOE experiments, which showed
C(3)H/C(5)H, C(3)H/C(ortho-arom.)H, and C(5)H/
C(ortho-arom.)H contacts, in accordance with a 3,5-cis
ꢃ For diastereotopic protons, that showing the highest d value is named
ꢀaꢁ; the other one is named ꢀbꢁ.

M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
3901
C(3b)H/C(4)H interactions, indicative of a 2,3b,4-cis
relationship and, hence, the (4R) configuration.
lose a water molecule, giving an iminium cation, hydro-
genation of which, involving the loss of a proton, would
lead to 13.
Assignment of an annellated structure to compound 12
was based on the heteronuclear multiple bond correla-
tion (HMBC) spectrum performed, where a C(5)/
C(3b)H correlation peak was observed, in agreement
with the presence of the new N–C(5) bond. The (R)-con-
figuration was assigned to C(9a) on the basis of the high
C(9a)H/C(9)H coupling constant value observed (10
Hz), corresponding to a 9,9a-anti disposition. Therefore,
the configuration at this stereogenic center—C(3) in the
starting isoxazolidine 5—is maintained in every step of
the synthesis, as expected. In addition, the diastereotopic
C(1b) and C(1a) protons of 12 were designated pro-(R)
and pro-(S), respectively, taking into account the
C(9)H/C(1b)H contact observed in the 2D NOESY spec-
trum, and the absence of any C(9)H/C(1a)H contact.
From that conclusion and the strong C(2)H/C(1a)H con-
tact observed, we assigned the (R)-configuration to C(2).
Analogously, from the contacts observed between C(2)H
on the one hand, and C(3a)H or C(3b)H on the other, it
was possible to assign the pro-(S) and pro-(R) designa-
tions to the diastereotopic C(3a)H and C(3b)H, respec-
tively. Additionally, a C(9)H/C(3b)H contact was
observed, corroborating the foregoing prochiral designa-
tions attributed to the C(3a) and C(3b) protons. This
long-range contact, and that between C(9)H and
C(1b)H commented on above, indicated the proximity
of the respective pentagonal and heptagonal ring faces,
in agreement with the (R)-configuration assigned to
C(9a). Lastly, C(5)H/C(3a)H and C(5)H/C(3b)H con-
tacts of similar intensities were also observed, preventing
any configurational assignment for C(5); therefore, the
C(5) configuration was tentatively assigned by applying
the CS Chem3D Ultraꢂ (CambridgeSoft) molecular
modeling approach (force field MM2), to build the two
energetically minimized structures of the (5R) and (5S)
diastereomers. A study of the compatibility of each
structure with the 2D NOESY data led us to conclude
that all the theoretical (5S)-diastereomer interactions
were in agreement with the contact set observed, whereas
for the (5R)-diastereomer model, a C(5)H/C(3b)H con-
tact stronger than the C(5)H/C(3a)H one, as well as
another C(5)H/C(9)H contact, should have been observed.
3.1. X-ray structure analysis of crystalline compound 5
A perspective view of the molecule, showing the abso-
lute configuration together with the atomic labeling
scheme, is shown in Figure 2. The pyranose ring shows
˚
the anomeric effect [O5–C5 = 1.447(10) A and O5–
˚
C1 = 1.395(12) A]. The geometry observed for the pyra-
nose, dioxolane, and isoxazolidine rings is shown in
Table 1. The pyranose ring adopts an approximate
twist-boat conformation. The two dioxolane rings show
conformations intermediate between envelope (E) and
twist (T), but one tends to the E conformation and the
other to the T. The crystal cohesion is governed by
van der Waals forces. The molecular pack to form a
compact structure with a network of H-bonds is shown
in Table 2, and the packing of the molecule, viewed
down the c-axis, is shown in Figure 3, where hydrogen
bonds are indicated by dashed lines.
Figure 2. An ORTEP view of crystalline compound 5 showing the
atomic numbering. The ellipsoids enclose 30% probability.
3.2. Glycosidase inhibitory essays
Compounds 12 and 13 were tested for inhibitory activity
against a series of glycosidases (a-L-fucosidase, a-galacto-
sidase, a-glucosidase, amyloglucosidase, b-glucosidase,
a-mannosidase, b-mannosidase, b-xylosidase, a-N-acet-
ylgalactosaminidase, and b-N-acetylgalactosaminidase)
from diverse sources. For a 1 mM concentration, com-
pound 12 showed 38% and 65% of inhibition against
The observation that the catalytic hydrogenation of 11
or 15 in the absence of any acid led to the 5-hydroxy
derivative 12, whilst in the presence of acetic acid the
reaction proceeded up to the 5-deoxy product 13, could
be explained as shown in Scheme 7, that is, the proton-
ation of 12 would generate an ammonium cation able to
HO
HO
-H2O
H
H
H2
-H
H
N
N H
12
13
HO
HO
OH
HO
OH
HO
OH
OH
OH
Scheme 7. The action of acid on the catalytic hydrogenation of 11 or 15 through 12 up to 13.

3902
M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
Table 1. Puckering coordinates, amplitudes and phase magnitudes, and asymmetry parameters for 5
˚
Ring
Q (A)
u(ꢁ)
h (ꢁ)
DC2
DCs
Sequence
Pyranose
0.642(8)
0.231(9)
0.261(9)
0.409(8)
ꢀ38.9(8)
78.8(8)
—
—
(C1) = 0.075
(O5–C5) = 0.056(4)
O5–C1–C2–C3–C4–C5
O2–C10–O1–C1–C2
O3–C13–O4–C4–C3
O6–N1–C6–C7–C8
Dioxolane
Dioxolane
Isoxazolidine
8(2)
(O1) = 0.061
(C4) = 0.028(3)
(C8) = 0.064(3)
—
—
—
28(2)
70(1)
—
Table 2. Hydrogen bonding geometry
D–Hꢁ ꢁ ꢁA
˚
˚
˚
D–H (A)
Hꢁ ꢁ ꢁA (A)
Dꢁ ꢁ ꢁA (A)
D–Hꢁ ꢁ ꢁA angle (ꢁ)
C17–H17Bꢁ ꢁ ꢁO8i
0.970(10)
0.980(8)
0.980(11)
0.930(11)
2.580(7)
2.718(8)
2.218(7)
2.460(6)
3.278(12)
3.427(12)
3.163(13)
3.326(12)
129
129
161
154
C6–H6ꢁ ꢁ ꢁO8ii
C1–Hꢁ ꢁ ꢁO8iii
C19–H19ꢁ ꢁ ꢁO2iv
Symmetry codes: (i) x, y, z; (ii) ꢀx + 1, y + 1/2, ꢀz; (iii) ꢀx + 2, y ꢀ 1/2, ꢀz; (iv) x, y + 1, z.
product—a feature present in natural products such as
castanospermine—catalytic hydrogenation of the 2-(gly-
cos-5-yl)pyrrolidine intermediate is required to be per-
formed in the presence of acetic acid, since the product
of the reaction in the absence of acid is the 5-hydroxy
compound, a hemiaminal. The new perhydroazaazulene
derivatives were subjected to glycosidase inhibitory
studies, and showed a rather low activity against bovine
liver b-galactosidase (EC 3.2.1.23), Rhizopus mold amy-
loglucosidase, and A. niger amyloglucosidase.
5. Experimental
5.1. General
Hexane and ether were distilled from sodium prior to
use. TLC was performed on silica gel plates (DC-Alufo-
lien F254, E. Merck, or Alugram Sil G/UV254, Mache-
rey-Nagel), and preparative TLC on Kieselgel 60 F254
DC-Platten 105715 HR; detection of compounds was
accomplished with UV light (254 nm) and by charring
with H2SO4 and phosphomolybdic reagent. Silica gel
60 (E. Merck, 230–400 mesh) was used for column
chromatography. Solutions were concentrated under
diminished pressure at <40 ꢁC. Melting points were
determined on a Gallenkamp MFB-595 apparatus and
are uncorrected. A Perkin–Elmer 241 MC polarimeter
was used for measurement of optical rotations. IR spec-
tra (neat or on a KBr disc) were obtained on a FTIR
Bomem Michelson MB-120 spectrophotometer. NMR
experiments were recorded on a Bruker AMX-300 (or
500) or a Bruker Avance-300 (or 500) spectrometer;
chemical shifts (d) are given in ppm, using the residual
protonated solvent signal as reference. Assignments
were confirmed by selective homonuclear decoupling,
homonuclear 2D COSY, NOESY (1D or 2D), 1D
TOCSY, heteronuclear multiple (or single) quantum
correlation (HMQC or HSQC), and heteronuclear mul-
tiple bond correlation (2D-HMBC) spectra. Selective
inversion in 1D experiments were performed by using
the Double Pulse Field Gradient Spin Echo (DPFGSE)
module. For the NOESY experiments, the mixing times
was 400 ms in all cases, except for compound 12, for
Figure 3. Packing of 5 viewed down the c-axis. Hydrogen bonds are
indicated by dashed lines.
bovine liver b-galactosidase (EC 3.2.1.23) and Rhizopus
mold amyloglucosidase, respectively, whilst compound
13 reached 36% and 62% against the same glycosidases,
and 56% against Aspergillus niger amyloglucosidase.
4. Conclusion
In conclusion, we establish here a short, highly stereo-
selective route to ring-homologues of polyhydroxy-
indolizidines. When the synthesis started from a
D-galactose-derived nitrone and methyl acrylate, the dif-
ferent steps of the synthesis took place in good to high
yields. The synthetic procedure allows modulating both
the backbone and the stereochemistry of the products by
selection of the starting monosaccharide. Diverse poly-
ols derived from the perhydroazaazulene heterocyclic
system might be obtained by starting from other hexose
nitrones, while from pentose derivatives, the products
would be polyhydroxy-indolizidines. For the 5-deoxy

M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
3903
which a set of mixing times of 100, 200, 300, and 400 ms
was used. EI mass spectra (70 eV) were measured with a
Kratos MS-80RFA instrument, with an ionizing current
of 100 lA, an accelerating voltage of 4 kV, and a resolu-
tion of 10,000 (10% valley definition). Fast-atom bom-
bardment mass spectrometry (FABMS) was performed
on the same instrument; ions were produced by a beam
of xenon atoms (6–7 keV) using a matrix consisting of
m-nitrobenzyl alcohol or thioglycerol and NaI as salt.
HRCIMS (150 eV) and HRLSIMS experiments were
performed with a Micromass AutoSpecQ instrument
with a resolution of 10,000 (5% valley definition).
for 12 h, filtered through Celite, and the solid thor-
oughly washed with ethyl acetate. Evaporation of the
solvent afforded a crude residue (0.300 g), which was
subjected to column chromatography (40:1, 30:1, and
20:1 dichloromethane/methanol, successively); first
eluted the N-benzyl-lactam 7 (0.049 g, 18%) and second
the N-deprotected product 6 (0.128 g, 62%).
Compound 6 was an oil; Rf 0.46 (15:1 dichloromethane/
20
25
methanol); ½aꢂD ¼ ꢀ16 (c 1.0, CHCl3); {lit.17 ½aꢂD ¼ ꢀ29
(c 0.65, CHCl3)}; IR (KBr) mmax 3262 (OH and NH),
1707 (amide C@O), 1379 (CMe2), and 1067 cmꢀ1 (C–
1
OH); H NMR (300 MHz, CDCl3): d 6.27 (br s, 1H,
NH), 5.49 (d, 1H, J1 ,2 = 5.0, H-10), 4.61 (dd, 1H,
0
0
5.2. Reaction of (Z)-N-benzyl-(1,2:3,4-di-O-isopropyli-
dene-a-D-galactopyranos-6-ylidene)amine N-oxide, 4 with
methyl acrylate. Preparation of methyl (2R,3R,5R)-
2-benzyl-3-(1,2:3,4-di-O-isopropylidene-a-D-galacto-
pentopyranos-5-yl)isoxazolidine-5-carboxylate, 5
J2 ,3 = 2.6, J3 ,4 = 7.9, H-30), 4.31 (dd, 1H, H-20), 4.24
0
0
0
0
(dd, 1H, J4 ,5 = 1.6, H-40), 4.24 (m, overlapped signal,
0
0
H-3), 3.68 (dd, 1H, J5,5 = 2.3, H-50), 3.68 (m, over-
0
lapped signal, H-5), 3.34 (br m, 1H, HO), 2.62 (m, 1H,
H-4a), 1.98 (m, 1H, H-4b), 1.49, 1.42, 1.32, and 1.30
(each s, each 3H, 2CMe2); 13C NMR (75.4 MHz,
CDCl3): d 177.4 (C@O), 109.6, 108.8 (2CMe2), 96.0
(C-10), 70.7 (C-20), 70.5 (C-30), 70.5 (C-50), 70.1 (C-40),
69.1 (C-3), 51.1 (C-5), 33.5 (C-4), 29.5, 25.7, 24.8, and
24.3 (2CMe2); HREIMS: m/z 329.1475 (calcd for
C15H23NO7: 329.1475).
A solution of nitrone 410 (0.400 g, 1.10 mmol) and
methyl acrylate (207 lL, 0.198 g, 2.30 mmol) in toluene
(3.6 mL) was stirred under argon atmosphere at 35 ꢁC.
Monitoring of the reaction (TLC, 3:1 hexane/ethyl
acetate) indicated a complete conversion after 3 h.
The solution was then concentrated to give a crude res-
idue (0.437 g, 88%), which was crystallized (absolute
ethanol) to afford pure 5 (0.350 g, 71%); mp 102–
104 ꢁC; crystallographic analysis evidenced its (2R,3R,
Compound 7 was an amorphous material; Rf 0.60 (15:1
20
dichloromethane/methanol); ½aꢂD ¼ ꢀ50 (c 2.7, CHCl3);
25
5R) absolute configuration; Rf 0.48 (3:1 hexane/
{lit.17 mp 124–126 ꢁC; ½aꢂD ¼ þ47 (c 0.40, CHCl3)}; IR
25
ethyl acetate); ½aꢂD ¼ ꢀ44 (c 1.0, CH2Cl2); {lit.17
(KBr) mmax 3316 (OH), 1686 (amide C@O), 1377
25
mp 117–119 ꢁC; ½aꢂD ¼ ꢀ82 (c 0.40, CHCl3)}; IR
(CMe2), 1069 (C–OH), and 899, 752, and 700 cmꢀ1
(KBr) mmax 1753 (ester C@O), 1377 (CMe2), 1209 and
(arom dC–H); 1H NMR (300 MHz, CDCl3): d 7.65–
1173 cmꢀ1 (C–O–C); 1H NMR (300 MHz, CDCl3): d
7.12 (m, 5H, Ph), 5.55 (d, 1H, J1 ,2 = 5.2, H-1 ), 5.18,
0
0
0
7.39–7.22 (m, 5H, Ph), 5.48 (d, 1H, J1 ,2 = 5.0, H-10),
3.96 (each d, each 1H, Jgem = 15.1, CH2Ph), 4.55 (dd,
0
0
4.51 (dd, 1H, J2 ,3 = 2.2, J3 ,4 = 8.0, H-30), 4.48 (dd,
1H, J2 ,3 = 2.2, J3 ,4 = 8.0, H-30), 4.29 (dd, 1H, H-20),
4.27 (dd, 1H, J3,4a = 6.8, J3,4b = 5.2, H-3), 4.09 (dd,
0
0
0
0
0
0
0
0
0
0
1H, J4a,5 ꢃ J4b,5 = 8.4, H-5), 4.42 (dd, 1H, J4 ,5 = 1.5,
H-40), 4.23 (dd, 1H, H-20), 4.23, 3.85 (each d, each 1H,
Jgem = 12.9, CH2Ph), 3.76 (s, 3H, MeOCO), 3.66 (m,
1H, J4 ,5 = 1.9, H-40), 3.98 (dd, 1H, J5,5 = 3.4, H-50),
3.72 (br m, 1H, HO), 3.60 (ddd, 1H, J4a,5 = 5.1,
J4b,5 = 7.1, H-5), 2.29 (m, 2H, 2H-4), 1.40, 1.30, 1.26,
and 1.21 (each s, each 3H, 2CMe2); 1D-DPFGSE-
NOE contacts: H-3, H-5, ortho-H of Ph; H-5, H-40, H-
3, ortho-H of Ph; 13C NMR (75.4 MHz, CDCl3): d
175.2 (C@O), 135.9 (ipso-C of Ph), 128.6, 127.6, 127.4
(Ph), 109.2, 108.4 (2CMe2), 96.4 (C-10), 71.3 (C-40),
70.9 (C-30), 70.2 (C-20), 69.5 (C-3), 64.7 (C-50), 55.3
(C-5), 43.8 (CH2Ph), 30.0 (C-4), 25.9, 25.6, 24.5, and
23.9 (2CMe2); HRCIMS: m/z 420.2008 (calcd for
C22H29NO7+H: 420.2022).
0
0
0
1H, H-3), 3.56 (dd, 1H, J3,5 = 9.9, H-50), 2.86 (ddd,
0
1H, J4a,4b = 12.3, J3,4a = 1.7, H-4a), 2.62 (ddd, 1H,
J3,4b = 7.0, H-4b), and 1.45, 1.29, 1.29, 1.27 (each s, each
3H, 2CMe2); 13C NMR (75.4 MHz, CDCl3): d 173.0
(COOMe), 137.3 (ipso-C of Ph), 129.3, 128.0, 127.1
(Ph), 108.7, 108.4 (2CMe2), 96.4 (C-10), 77.0 (C-5),
70.8 (C-20), 70.4, and 70.3 (C-30/C-40), 66.6 (C-50), 63.8
(C-3), 61.5 (CH2Ph), 52.2 (COOMe), 34.0 (C-4), 26.0,
25.6, 24.8, and 24.0 (2CMe2); HRCIMS: m/z 450.2130
(calcd for C23H31NO8+H: 450.2128). Anal. Calcd for
C23H31NO8: C, 61.46; H, 6.95; N, 3.12. Found: C,
61.38; H, 6.78; N, 3.25.
5.4. (2R,4R)-4-Hydroxy-2-(1,2:3,4-di-O-isopropylidene-
a-D-galacto-pentopyranos-5-yl)pyrrolidine, 8
5.3. (3R,5R)-3-Hydroxy-5-(1,2:3,4-di-O-isopropylidene-
a-D-galacto-pentopyranos-5-yl)-2-oxopyrrolidine, 6, and
(3R,5R)-1-benzyl-3-hydroxy-5-(1,2:3,4-di-O-isopropylid-
ene-a-D-galacto-pentopyranos-5-yl)-2-oxopyrrolidine, 7
To a solution of 6 (0.27 g, 0.82 mmol) in ether (6.6 mL),
cooled in an ice bath, a 1 M solution of lithium alumi-
num hydride in ether (2.45 mL; 2.45 mmol) was slowly
added, and the mixture was then heated at reflux under
stirring for 3 h. After destroying the excess of hydride by
adding saturated aqueous sodium sulfate, the mixture
was filtered through Celite, and the solid thoroughly
washed with ethyl acetate and ether. The filtrate was
concentrated and the residue was subjected to column
chromatography (30:1 dichloromethane/methanol) to
afford the reduced product 8 as an oil (0.248 g, 96%);
To a solution of 5 (0.286 g, 0.63 mmol) in a mixture of
acetonitrile (9.6 mL) and water (0.6 mL), hexa-
carbonylmolybdenum18,19 (0.120 g) was added and the
mixture was heated at reflux (85 ꢁC). Monitoring of
the reaction (TLC, 15:1 dichloromethane/methanol)
indicated a complete conversion after 7 h. Silica gel
(0.250 g) was then added and the suspension was stirred

3904
M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
20
Rf 0.10 (15:1 dichloromethane/methanol); ½aꢂD ¼ ꢀ30 (c
kept at room temperature, monitoring the reaction
by TLC (15:1 dichloromethane/methanol). After 24 h,
all the starting material had been transformed, and
the mixture was concentrated. The residue was
subjected to column chromatography (15:1 dichloro-
methane/methanol) to obtain 11 as a colorless oil
(0.454 g, 95%); Rf 0.25 (8:1 dichloromethane/metha-
nol); IR (KBr) mmax 3362 (OH), 1746 (carbamate
C@O), 1684 (arom), 1454 and 1430 (C–O), and
1016 cmꢀ1 (C–OH); HRFABMS: m/z 392.1321 (calcd
for C17H23NO8+Na: 392.1326).
1.0, CHCl3); IR (KBr) mmax 3183 (OH and NH), 1377
(CMe2), and 1067 cmꢀ1 (C–OH); H NMR (300 MHz,
1
CDCl3): d 5.51 (d, 1H, J1 ,2 = 5.0, H-10), 4.57 (dd, 1H,
0
0
J2 ,3 = 2.4, J3 ,4 = 8.0, H-30), 4.32 (dd, 1H, J4 ,5 = 1.8,
0
0
0
0
0
0
H-40), 4.27 (dd, 1H, H-20), 4.27 (m, overlapped signal,
H-4), 3.70 (dd, 1H, J2,5 = 6.5, H-50), 3.34 (ddd, 1H,
0
J2,3a = 9.2, J2,3b = 5.4, H-2), 2.95 (ddd, 1H,
J5a,5b = 11.3, J4,5a = 1.8, J3b,5a = 1.8, H-5a), 2.82 (dd,
4
1H, J4,5b = 4.1, H-5b), ꢄ2.5 (br s, 2H, NH and OH),
2.14 (ddd, 1H, J3a,3b = 14.6, J3a,4 = 5.8, H-3a), 1.83
(dddd, 1H, J3b,4 = 5.2, H-3b), and 1.49, 1.41, 1.30,
1.29 (each s, each 3H, 2CMe2); 1D-DPFGSE-NOESY
contacts: H-3a, H-2, H-4; 13C NMR (75.4 MHz,
CDCl3): d 109.0, 108.6 (2CMe2), 96.3 (C-10), 71.9 (C-
4), 71.3 (C-40), 70.6 (C-20), 70.4 (C-30), 70.2 (C-50),
56.9 (C-2), 55.2 (C-5), 37.7 (C-3), 25.8, 25.7, 24.8, and
24.1 (2CMe2); HRCIMS: m/z 316.1757 (calcd for
C15H25NO6+H: 316.1760).
5.7. Catalytic hydrogenation of (2R,4R)-1-benzyloxy-
carbonyl-4-hydroxy-2-(D-galacto-pentos-5-yl)pyrrolidine,
11, in neutral medium. Synthesis of (2R,5S,6R,7S,8S,9R,
9aR)-2,5,6,7,8,9-hexahydroxy-perhydroazaazulene, 12
To a solution of compound 11 (0.252 g, 0.683 mmol) in
ethanol (23.5 mL), 10% Pd/C catalyst (39.25 mg) was
added. The mixture was shaken at room temperature
under hydrogen for 24 h, and then filtered through Cel-
ite, which was washed with ethyl acetate and methanol.
The combined filtrate and washings were concentrated
and the residue was subjected to column chromatogra-
phy (5:1 ! 4:1 gradient, dichloromethane/methanol) to
5.5. (2R,4R)-1-Benzyloxycarbonyl-4-hydroxy-2-(1,2:3,4-
di-O-isopropylidene-a-D-galacto-pentopyranos-5-yl)-
pyrrolidine, 10
Sodium hydrogen carbonate (0.117 g, 1.39 mmol) and
benzyl chlorocarbonate (126.56 lL, 0.896 mmol) were
added to a solution of 8 (0.258 g, 0.818 mmol) in 1:1 eth-
anol/H2O (5.3 mL). The mixture was left to cool down
to room temperature, then poured into saturated aque-
ous sodium hydrogen carbonate (17 mL) and extracted
with ethyl acetate (3 · 20 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The resi-
due was purified by column chromatography (40:1
dichloromethane/methanol) to afford 10 as an amor-
give 12 (0.160 g, 99.5%); white, amorphous material;
20
Rf 0.33 (3:1 dichloromethane/methanol); ½aꢂD ¼ þ58:9
(c 0.45, MeOH); IR (KBr) mmax 3396 (OH), 1094 (C–
O), and 1017 cmꢀ1 (C–N); 1H NMR (500 MHz,
CD3OD): d 4.76 (d, 1H, J5,6 = 6.0, H-5), 4.42 (dddd,
0
0
1H, J1,2 = 8.5, J1 ,2 = 4.5, J2,3 ꢃ J2,3 ꢃ 6.5, H-2), 4.12
(d, 1H, J6,7 = 2.5, J7,8 ꢃ 0, H-7), 4.10 (dd, 1H, H-6),
3.87 (d, 1H, J8,9 = 4.5, H-8), 3.77 (dd, 1H, J9,9a = 10.0,
0
H-9), 3.18 (dd, 1H, J3,3 = 9.5, H-3), 3.06 (dd, 1H, H-
30), 3.00 (ddd, 1H, J1,9a = 8.0, J1 ,9a = 2.0, H-9a), 2.33
0
phous white material (0.352 g, 96%); Rf 0.50 (30:1
24
(ddd, 1H, J1,1 = 14.0, H-1), and 1.75 (ddd, 1H, H-10);
0
dichloromethane/methanol); ½aꢂD ¼ þ4:5 (c 3.1,
CH2Cl2); IR (KBr) mmax 3180 (OH and NH), 1416 (C–
O), 1370 (CMe2), and 1069 cmꢀ1 (C–OH); 1H NMR
(500 MHz, CDCl3): d 7.34–7.29 (m, 5H, Ph), 5.59 (d,
HMBC experiments: H-3b, C-5; NOE contacts (2D-
NOESY): H-9, H-1b; H-9a, H-1a; H-2, H-1a; H-3b,
H-9; H-3a, H-2; 13C NMR (125.7 MHz, CD3OD): d
88.8 (C-5), 85.4 (C-8), 80.1 (C-7), 76.2 (C-6), 70.2 (C-
2), 67.4 (C-9), 57.9 (C-9a), 56.7 (C-3), and 37.9 (C-1);
HRFABMS: m/z 258.0953 (calcd for C9H17NO6+Na:
258.0954), 236.1116 (calcd for C9H17NO6+H:
236.1134).
1H, J1 ,2 = 5.0, H-10), 5.18, 5.10 (each d, each 1H,
0
0
0
0
Jgem = 12.5, CH2Ph), 4.62 (dd, 1H, J2 ,3 = 2.5,
J3 ,4 = 8.0, H-30), 4.49 (s, 1H, J2,5 ꢃ J4 ,5 ꢃ 0, H-50),
4.38 (d, 1H, H-40), 4.33 (dd, 1H, H-20), 4.28 (m, 1H,
H-4), 4.20 (d, 1H, J2,3a ꢃ 0, J2,3b = 10.5, H-2), 3.57 (d,
1H, J5a,5b = 12.0, J4,5a ꢃ 0, H-5a), 3.49 (dd, 1H,
J4,5b = 4.0, H-5b), 2.56 (d, 1H, J3a,3b = 15.5, J3a,4 ꢃ 0,
H-3a), 2.22 (ddd, J3b,4 = 5.5, H-3b), and 1.49, 1.39,
1.36, 1.31 (each s, each 3H, 2CMe2); NOE contacts
(1D-NOESY): H-3b, H-2; 2D-NOESY (four experi-
ments at 100, 200, 300, and 400 ms; see Section 3): High-
er slope values: H-3b/H-2, H-3b/H-4; 13C NMR
(124.5 MHz, CDCl3): d 155.4 (C@O), 136.9 (ipso-C of
Ph), 128.6–127.0 (Ph), 109.5 (2CMe2), 96.4 (C-10), 72.3
(C-40), 71.6 (C-30), 70.8 (C-20), 70.3 (C-4), 66.9 (C-50),
66.7 (CH2Ph), 59.2 (C-2), 56.4 (C-5), 34.4 (C-3), and
25.8 and 24.1 (2CMe2); HRFABMS: m/z 472.2127
(calcd for C23H32NO8+Na: 472.2125).
0
0
0
0
0
5.8. Catalytic hydrogenation of (2R,4R)-1-benzyloxycar-
bonyl-4-hydroxy-2-(D-galacto-pentos-5-yl)pyrrolidine, 11,
in the presence of acetic acid. Synthesis of (2R,6S,7R,
8S,9R,9aR)-2,6,7,8,9-pentahydroxy-perhydroazaazulene
hydroacetate, 13ÆHOAc, and (2R,6S,7R,8S,9R,9aR)-
2,6,7,8,9-pentahydroxy-perhydroazaazulene, 13
To a solution of compound 11 (0.050 g, 0.136 mmol) in
ethanol (5 mL), acetic acid (three drops, ꢃ0.025 g,
0.42 mmol) and 10% Pd/C catalyst (15 mg) were added.
The mixture was shaken at room temperature under
hydrogen for 2 h and then filtered through Celite, which
was washed with methanol. The combined filtrate and
washings were concentrated, and the residue was repeat-
edly dissolved in ethanol and water, and concentrated.
The residue was purified by column chromatography
(5:1 dichloromethane/methanol) to afford 13ÆHOAc
(29 mg, 99.5%); Rf 0.25 (3:1 dichloromethane/metha-
5.6. (2R,4R)-1-Benzyloxycarbonyl-4-hydroxy-2-
(D-galacto-pentos-5-yl)pyrrolidine, 11
Compound 10 (0.534 g, 1.30 mmol) was treated with
80% trifluoroacetic acid (40 mL) and the mixture was

M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
3905
20
nol); ½aꢂD ¼ ꢀ1:4 (c 0.5, MeOH); IR (KBr) mmax 3390
concentrated, and the acetic acid was co-evaporated with
ethanol and water to afford 13 (0.062 g, 98%), which
showed NMR and MS data, respectively, identical with
those of compound obtained from 11 (Section 5.8).
(OH), 1094 (C–O), and 1018 cmꢀ1 (C–N); 1H NMR
(300 MHz, CD3OD): d 4.41 (m, 1H, H-2), 4.19 (ddd,
0
1H, J6,7 = 6.6, J5,6 = 5.7, J5 ,6 = 6.0, H-6), 4.04 (dd,
1H, J7,8 = 1.2, H-7), 3.90 (dd, 1H, J8,9 = 7.2, H-8),
3.82 (dd, 1H, J9,9a = 9.3, H-9), 3.70 and 2.94 (each dd,
5.11. Reduction of (3R,5R)-1-benzyl-3-hydroxy-5-
(1,2:3,4-di-O-isopropylidene-a-D-galacto-pentopyranos-5-
yl)-2-oxopyrrolidine, 7, with lithium aluminum hydride.
Synthesis of (2R,4R)-1-benzyl-4-hydroxy-2-(1,2:3,4-di-O-
isopropylidene-a-D-galacto-pentopyranos-5-yl)pyrrol-
idine, 14
each 1H, J5,5 = 13.2, H-5 and H-50), 3.38 (d, 1H,
0
0
J3,3 = 11.4, H-3), 3.32 (m, 1H, H-9a), 3.15 (dd, 1H,
J2,3 = 3.9, H-30), 2.55 (ddd, 1H, J1,1 = 14.4, J1,2 = 5.4,
0
0
0
0
J1,9a = 9.6, H-1), 2.12 (ddd, 1H, J1 ,2 = 2.7, J1 ,9a = 5.4,
H-10), and 1.99 (s, 3H, OCOCH3); 13C NMR
(75.4 MHz, CD3OD): d 178,5 (C@O), 78.1 (C-8), 77.6
(C-7), 76.7 (C-9), 72.1 (C-2), 71.2 (C-9a), 70.7 (C-6),
68.0 (C-3), 61.4 (C-5), 42.6 (C-1), and 23.7 (OCOCH3);
HRFABMS: m/z 220.1181 (calcd for C9H17NO5+H:
220.1184). The acetic acid of the remainder 13ÆHOAc
was several times co-evaporated with ethanol and water,
and the residue was purified by column chromatography
Lithium aluminum hydride (1 M ethereal solution,
1.58 mL, 1.58 mmol) was added to a cold (ice bath) solu-
tion of 7 (0.182 g, 0.434 mmol) in ether (3.5 mL), and
the mixture was heated to reflux under stirring until
no longer progress of the reaction was observed (3 h,
TLC, 15:1 dichloromethane/methanol). Then, saturated
aqueous sodium sulfate (554 lL) was added to eliminate
the excess of reductive reagent. The mixture was filtered
through Celite, and this successively washed with ethyl
acetate and ether. The combined filtrate and washings
(5:1 dichloromethane/methanol) to give pure 13; Rf 0.37
20
(3:1 dichloromethane/methanol); ½aꢂD ¼ þ6:1 (c 1.55,
MeOH); IR (KBr) mmax 3380 (OH), 1092 (C–O), and
1024 cmꢀ1 (C–N); 1H NMR (300 MHz, CD3OD): d
4.29 (m, 1H, H-2), 4.09 (ddd, 1H, J6,7 = J5,6 = 6.9,
were concentrated to obtain 14 (0.176 g, 99%); Rf 0.34
20
0
J5 ,6 = 7.2, H-6), 3.87 (d, 1H, J7,8 ꢃ 0, H-7), 3.83 (d,
(15:1 dichloromethane/methanol); ½aꢂD ¼ ꢀ29:7 (c 0.3,
1H, J8,9 = 6.6, H-8), 3.70 (dd, 1H, J9,9a = 9.0, H-9),
CH2Cl2); IR (KBr) mmax 1092 (C–OH) and 1032 cmꢀ1
1
0
3.43 (dd, 1H, J5,5 = 13.2, H-5), 3.12 (br d, 1H,
(C–N); H NMR (300 MHz, CDCl3):0 d 7.39–7.24 (m,
0
0
0
0
J3,3 = 10.2, J2,3 ꢃ 0, H-3), 2.76 (dd, 1H, J2,3 = 3.6, H-
30), 2.71 (overlapped m, 1H, J1,9a = 5.1, H-9a), 2.53
(overlapped dd, 1H, H-50), 2.50 (overlapped ddd, 1H,
H-1), and 1.92 (m, 1H, H-10); 13C NMR (75.4 MHz,
CD3OD): d 77.0 (C-8), 76.7 (C-7 and C-9), 70.7 (C-2),
69.8 (C-6 and C-9a), 65.5 (C-3), 60.4 (C-5), and 41.5
(C-1); HRFABMS: m/z 220.1183 (calcd for
C9H17NO5+H: 220.1184).
5H, Ph), 5.65 (d, 1H, J1 ,2 = 4.8, H-1 ), 4.64 (dd, 1H,
J2 ,3 = 2.4, J3 ,4 = 8.1, H-30), 4.34 (overlapped dd, 1H,
H-20 or H-40), 4.33 (overlapped dd, 1H, H-40 or H-20),
4.18, 3.47 (each d, each 1H, Jgem = 13.5, CH2Ph), 4.13
0
0
0
0
0
(m, overlapped signal, H-4), 3.93 (dd, 1H, J2,5 = 3.0,
J4 ,5 = 1.8, H-50), 3.02 (ddd, 1H, J2,3a = 3.0,
J2,3b = 10.2, H-2), 2.95 (br s, 1H, OH), 2.89 (dd, 1H,
0
0
J5a,5b = 9.9, J4,5a = 2.1, H-5a), 2.32 (dd, 1H, J4,5b
=
3.3, H-5b), 2.28 (ddd, 1H, J3a,3b = 12.9, J3a,4 = 2.4, H-
3a), 2.13 (m, 1H, H-3b), and 1.49,1.36, (each s, each
6H, 2CMe2); 13C NMR (75.4 MHz, CDCl3): d 140.0
(ipso-C of Ph), 128.6–126.9 (Ph), 109.1, 108.6 (2CMe2),
96.7 (C-10), 72.2 (C-40), 70.8 (C-20), 71.1 (C-30), 71.1
(C-4), 68.1 (C-50), 62.5 (C-2), 61.3 (C-5), 58.6 (CH2Ph),
35.6 (C-3), and 26.2, 25.8, 25.0, and 24.1 (2CMe2);
HRCIMS: m/z 406.2219 (calcd for C22H32NO6+H:
406.2229).
5.9. (2R,5S,6R,7S,8S,9R,9aR)-2,5,6,7,8,9-Hexahydroxy-
perhydroazaazulene, 12
An 80% solution of trifluoroacetic acid (20 mL) was
added to compound 8 (0.200 g, 0.63 mmol) and the mix-
ture was kept at room temperature, monitoring the reac-
tion by TLC (15:1 dichloromethane/methanol). After 24
h, all the starting material had been transformed, and
the mixture was applied to a Dowex 50W · 8 (H+) resin
column, then eluting with methanol (150 mL), water
(150 mL), and 10% aqueous ammonia. The fractions
eluted by ammonia were concentrated to afford pure
12 as an oil (0.148 g, 98%); Rf 0.51 (8:4:1 dichlorometh-
ane/methanol/10% aqueous ammonia); NMR and MS
data, respectively, identical with those of compound
obtained from 11 (Section 5.7).
5.12. O-Deprotection of (2R,4R)-1-benzyl-4-hydroxy-2-
(1,2:3,4-di-O-isopropylidene-a-D-galacto-pentopyranos-5-
yl)pyrrolidine, 14. Synthesis of (2R,4R)-1-benzyl-4-
hydroxy-2-(D-galacto-pentos-5-yl)pyrrolidine, 15
An 80% solution of trifluoroacetic acid (5 mL) was
dropwise added to 0.080 g (0.197 mmol) of compound
14, and the mixture was stirred at room temperature
until the starting material was totally consumed
(15 h, TLC). The solution was concentrated under
diminished pressure, and the residue was dissolved in
dichloromethane and washed with aqueous 10%
sodium hydrogen carbonate until pH ꢄ7.5. After drying
(Na2SO4), the solvent was evaporated at reduced pres-
sure to afford 15 as an oil (0.061 g, 96%); Rf 0.40
(3:1 dichloromethane/methanol); HRFABMS: m/z
348.1423 (calcd for C16H23NO6+Na: 348.1449). This
product was used for other transformations without
more purification.
5.10. (2R,6S,7R,8S,9R,9aR)-2,6,7,8,9-Pentahydroxy-
perhydroazaazulene, 13
To a solution of compound 12 (0.068 g, 0.289 mmol) in
ethanol (10 mL), glacial acetic acid (five drops,
ꢃ0.042 g, 0.70 mmol) and 10% Pd/C catalyst (0.020 g)
were added. The mixture was shaken at room tempera-
ture under hydrogen for 7 h (TLC monitoring, 3:1
dichloromethane/methanol) and then filtered through
Celite, which was washed several times with ethanol
and methanol. The combined filtrate and washings were

3906
M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
5.13. N-Deprotection of (2R,4R)-1-benzyl-4-hydroxy-
2-(D-galacto-pentos-5-yl)pyrrolidine, 15. Synthesis of
(2R,5S,6R,7S,8S,9R,9aR)-2,5,6,7,8,9-hexahydroxy-per-
hydroazaazulene, 12
I > 2r(I0); final R, 0.07: final xR(F2), 0.16, goodness-
of-feet S, 0.88. Corrections were made for Lorentz-
polarization effects, but not for extinction and absorp-
tion. This effect was not taken into account because
the crystal absorption with Mo radiation was practically
negligible. The structure was solved by direct methods
using SIR200220 and refined with SHELX97.21 All geo-
metric calculations were performed using PARST97.22
To a solution of 15 (0.180 g, 0.553 mmol) in abs ethanol
(20 mL), 10% Pd/C catalyst (0.020 g) was added, and the
mixture was shaken under hydrogen atmosphere for
24 h. The suspension was filtered through a plug of Cel-
ite, and the solids were washed with methanol. The com-
bined filtrate and washings were concentrated at reduced
pressure to give 12 (0.129 g, 99%), which showed NMR
and MS data, respectively, identical with those of the
compound obtained from 8 (Section 5.5).
Acknowledgements
We are grateful to Prof. P. Vogel (EPF Lausanne,
Switzerland), for the glycosidase inhibitory essays.
´
We are thankful to the Direccion General de Investi-
´ ´
gacion, Ministerio de Ciencia y Tecnologıa of Spain
5.14. Preparation of compound 13 by catalytic hydro-
genation of 15 in the presence of acetic acid
´
(Grant No. BQU2000-1155), and the Direccion General
´
´
de Universidades e Investigacion, Consejerıa de Edu-
´
To a solution of compound 15 (0.080 g, 0.246 mmol) in
abs ethanol (10 mL), 10% Pd/C catalyst and acetic acid
(three drops, ꢃ0.025 g, 0.42 mmol) were added, and the
mixture was shaken under hydrogen atmosphere for 2 h.
After filtration through a plug of Celite and washing of
the solids with methanol, the combined filtrate and
washings were concentrated, and the acetic acid was
co-evaporated with ethanol and water, to afford 13
(0.0535 g, 99%), which showed NMR and MS data,
respectively, identical with those of the product obtained
from 12 (Section 5.6) or from 11 (Section 5.10).
cacion y Ciencia of Andalusia (FQM 142), for financial
support.
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M.a I. Torres-Sa´nchez et al. / Tetrahedron: Asymmetry 16 (2005) 3897–3907
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