Stereoselective synthesis of 3-glycosyl-5-methoxycarbonyl-isoxazolidines from D-galactose and D-glucose

Article abstract of DOI:10.1016/j.tetlet.2004.04.161

Regio- and stereoselective cycloaddition of methyl acrylate to C-glycosyl nitrones derived from D-galactose and D-glucose, giving 5-methoxycarbonyl-3- (pentoglycos-5-yl or pentitol-1-yl)isoxazolidines, is reported. Transformation of one of them into a 4-h

Full text of DOI:10.1016/j.tetlet.2004.04.161

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4835–4839
Stereoselective synthesis of 3-glycosyl-5-methoxycarbonyl-
isoxazolidines from -galactose and -glucose
D
D
*
ꢀ
Pastora Borrachero, Francisca Cabrera-Escribano, Manuel Gomez-Guillen
ꢀ
and Ma Isabel Torres
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica ‘Profesor Garcıa Gonzalez’, Facultad de Quımica, Universidad de Sevilla,
Apartado de Correos No. 553, E-41071 Sevilla, Spain
Received 15 March 2004; revised 23 April 2004; accepted 28 April 2004
Available online 18 May 2004
Abstract—Regio- and stereoselective cycloaddition of methyl acrylate to C-glycosyl nitrones derived from D-galactose and D-glu-
cose, giving 5-methoxycarbonyl-3-(pentoglycos-5-yl or pentitol-1-yl)isoxazolidines, is reported. Transformation of one of them into
a 4-hydroxy-2-(pentoglycos-5-yl)pyrrolidine derivative, potentially useful in a route to polyhydroxy-perhydroazaazulenes, was
achieved.
Ó 2004 Elsevier Ltd. All rights reserved.
Castanospermine (1) and other indolizidine derivatives
are glycomimetics that show, among others, anti-
malarial, antiviral, immunosuppressor, and antidiabetic
activities, probably as a consequence of their glycosidase
inhibitory properties.1;2 This is the main reason why
many synthetic routes have been developed to obtain 1,1
as well as a diversity of stereoisomers and analogues of
1,3;4 since even a change of configuration at a single
hydroxy group could alter the inhibitory properties.4
Readily available monosaccharide derivatives have fre-
quently been used5 as starting materials to obtain this
kind of compound, thus taking advantage from the
configurational variety of sugars and their ability to
exert asymmetric induction in the formation of new
stereogenic centers.
that occurs with high regio- and stereoselectivity. We
have reported the reactions of conveniently protected C-
glycosyl nitrones, derived from
D
D-galactose, D-xylose,
and
-ribose, with nitroalkenes6 and vinyl trimethyl-
silane,7 in which C-glycosyl-isoxazolidines were regio-
and stereoselectively obtained. In the case of vinyl
trimethylsilane as the dipolarophile, the obtained
cycloadducts were transformed into C7 and C8 amino-
dialdoses, direct precursors of higher-chain glycosamino
acids.
2
2
1
1
OH
3
3
8a
4
N
H
4N
9a
OH
8
9
5
5
It is known that, in the 1,3-dipolar cycloaddition of C-
glycosyl nitrones, including cyclic nitrones, with diverse
olefins, glycosyl-isoxazolidines are formed, a reaction
6
7
6
8
HO
OH
7
1
2
A possible route to new potential glycosidase inhibitors
derived from the perhydroazaazulene system (2), which
can be considered as heterocyclic-system homologues of
castanospermine and other related indolizidine deriva-
tives, may start from the isoxazolidines that we obtained
(Scheme 1) in the [3+2] cycloaddition reaction of the
Keywords: C-Glycosyl nitrones; Methyl acrylate; 3-Glycosyl-5-meth-
oxycarbonyl-isoxazolidines; Stereoselective synthesis; Isoxazolidine-
ring cleavage; 6-Amino-6,7-dideoxy-nonopyranosurono-9,6-lactams;
Polyhydroxy-perhydroazaazulene precursors.
* Corresponding author. Tel.: +34-95-4557151; fax: +34-95-4624960;
e-mail: mguillen@us.es
nitrones 3 and 4, prepared from
D-galactose and
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.161

4836
P. Borrachero et al. / Tetrahedron Letters 45 (2004) 4835–4839
COOMe
O
O
COOMe
O
endo Attack:
MeO2C
Bn
Bn
N
Bn
N
+
CO2Me
O
R
N
Bn
N
R
3 R = Gal
4 R = Glu
5
6 R = Gal
7 R = Glu
Gal
Gal
re face
6a
Glu
Gal
COOMe
(3R,5R)
O
Scheme 2. Reagent approach leading to the diastereomer 6a.
O
O
O
OBn
N
Bn
BnO
O
O
Me2C
OBn
OBn
Gal
CMe2
6a (71%)
as formulated (6a, Scheme 1). Anal. Calcd for
C23H31NO8: C, 61.46; H, 6.95; N, 3.12. Found: C, 61.38;
H, 6.78; N, 3.25. HRCIMS: m=z 450.2130 (calcd for
C23H31NO8+H: 450.2128). From the C(3) and C(5)
(R,R) configurations assigned for compound 6a, both
high endo/exo diastereoselectivity and re/si (nitrone 3)
facial diastereoselectivity were evidenced for the reac-
tion (Scheme 2).
CH2OBn
Scheme 1. Regioselective reaction of the nitrones 3 and 4 with methyl
acrylate (5).
D
-glucose derivatives, respectively, with methyl acrylate
(5). This dipolarophile is known to react with nitrones
very regioselectively, so that, with few exceptions, the
unique, or at least the main, product is the 5-methoxy-
carbonyl regioisomer.8;9 Aiming different target mole-
cules, other authors have used the reaction of sugar
nitrones with 5; thus, the isoxazolidine obtained10 from
the N-benzyl-C-glycosyl nitrone derived from 2,3-O-
Scheme 3 summarizes the transformations performed on
6a. Isoxazolidine-ring cleavage was achieved by treat-
ment with hexacarbonylmolybdenum,14;15 affording the
6-benzylamino-6,7-dideoxy-1,2:3,4-di-O-isopropylidene-
L
-threo a-D-galacto-nonopyranosurono-9,6-lactam 7 and
its N-deprotected derivative 8 in 18% and 62% yield,
isopropylidene-
sion about the structure of leptospherin. More recently,
starting from a protected -fucose-derived cyclic nitrone
and methyl acrylate, some indolizidine derivatives
D-glyceraldehyde was used in a discus-
respectively, after column chromatography. Compound
20
20
7: ½aꢀ ꢁ 50 (c 2.7, CHCl3).à Compound 8: ½aꢀ ꢁ 16
D
D
(c 1.0, CHCl3).§ The mass spectral data agree with
the presence of the benzyl group for 7 and its absence
for 8, also corroborated by the 1H and 13C NMR
spectra.
L
have been obtained and their a-L-fucosidase inhibitory
activity measured.11
The synthesis we report herein presents the novelty that
the acyclic nitrones employed were hexose derivatives,
which in their reaction with 5, regio- and stereoselec-
tively afforded isoxazolidines with a C5 sugar chain at
C(3) and the methoxycarbonyl group at C(5), so that
subsequent intermediates having a long enough sugar
chain, might undergo annellation to give polyhydroxy-
perhydroazaazulenes. The configurations of the isoxaz-
olidine new stereogenic centers C(3) and C(5) would be
transferred to C(9a) and C(2) of the perhydro-
azazulene, respectively.
The carbonyl group of 8 was reduced by the action of
lithium aluminum hydride to give (2R,4R)-4-hydroxy-2-
Selected spectral data for 6a: IR (KBr) mmax 1753 cmꢁ1 (ester C@O);
1H NMR (300 MHz, CDCl3) d (locant numerals for the sugar moiety
are maintained, but primed, such as for the starting sugar derivative)
5.48 (d, 1H, J1 ;2 ¼ 5:0, H-10), 4.48 (dd, 1H, J4a;5 ꢂ J4b;5 ¼ 8:4, H-5),
0
0
0
3.76 (s, 3H, MeOCO), 3.66 (m, 1H, H-3), 3.56 (dd, 1H, J3;5 ¼ 9:9, H-
50), 2.86 (ddd, 1H, J4a;4b ¼ 12:3, J3;4a ¼ 1:7, H-4a), 2.62 (ddd, 1H,
J3;4b ¼ 7:0, H-4b); 13C NMR (75.4 MHz, CDCl3) d 173.0 (COOMe),
96.4 (C-10), 77.0 (C-5), 66.6 (C-50), 63.8 (C-3), 52.2 (COOMe), 34.0
(C-4). HRCIMS: m=z 450.2130 (calcd for C23H31NO8+H: 450.2128).
Selected spectral data for 7: IR (KBr) mmax 1686 cmꢁ1 (amide C@O);
1H NMR (300 MHz, CDCl3) d 7.65–7.12 (m, 5H, Ph), 5.55 (d, 1H,
J1;2 ¼ 5:2, H-1), 5.18, 3.96 (each d, each 1H, Jgem ¼ 15:1, CH2Ph),
4.27 (dd, 1H, J7a;8 ¼ 6:8, J7b;8 ¼ 5:2, H-8), 3.98 (dd, 1H, J5;6 ¼ 3:4, H-
5), 3.72 (br m, 1H, HO), 3.60 (ddd, 1H, J6;7a ¼ 5:1, J6;7b ¼ 7:1, H-6),
2.29 (m, 2H, 2H-7); NOE contacts (1D NOESY): H-6, H-5, H-4, H-
8; H-8, HO, H-6; HO, H-8, H-1; 13C NMR (75.4 MHz, CDCl3) d
175.2 (C@O), 135.9 (ipso-C of Ph), 128.6, 127.6, 127.4 (Ph), 96.4 (C-
1), 69.5 (C-8), 64.7 (C-5), 55.3 (C-6), 43.8 (CH2Ph), 30.0 (C-7).
HRCIMS: m=z 420.2008 (calcd for C22H29NO7+H: 420.2022).
Selected spectral data for 8: IR (KBr) mmax 1707 cmꢁ1 (amide C@O);
1H NMR (300 MHz, CDCl3) d 6.27 (br s, 1H, NH), 5.49 (d, 1H,
J1;2 ¼ 5:0, H-1), 4.24 (m, overlapped signal, H-8), 3.68 (dd, 1H,
J5;6 ¼ 2:3, H-5), 3.68 (m, overlapped signal, H-6), 3.34 (br m, 1H,
HO), 2.62 (m, 1H, H-7a), 1.98 (m, 1H, H-7b); 13C NMR (75.4 MHz,
CDCl3) d 177.4 (C@O), 96.0 (C-1), 70.5 (C-5), 69.1 (C-8), 51.1 (C-6),
33.5 (C-7). HREIMS: m=z 329.1475 (calcd for C15H23NO7: 329.1475).
The (Z)-N-benzyl-nitrone 3 was easily prepared as
described,6 while 4, to our knowledge, has not been
described. Therefore, we obtained 4 (52% yield, after
column chromatography) by treatment of 2,3,4,5,6-
à
penta-O-benzyl-aldehydo-D
-glucose12 with N-benzyl-
hydroxylamine, following a procedure similar to that
used6 to obtain 3. [Nitrone 4: oil; HRCIMS: m=z
736.3631 (calcd for C48H49NO6+H: 736.3638). Selected
spectral data: 1H NMR d 6.90 (d, 1H, J1;2 ¼ 7:1,
HC@N); 13C NMR d 138.0 (HC@N)].
The reaction of 3 with 5 in toluene at 35 °C led with total
regioselectivity to only one of the four possible diaste-
reomeric 5-methoxycarbonyl-isoxazolidines, which was
§
isolated as a crystalline compound and recrystallized
25
D
(abs ethanol) [71%, mp 102–104 °C; ½aꢀ ꢁ 44 (c 1.0,
CH2Cl2)]; its X-ray crystallographic analysis13 unam-
biguously showed its (2R,3R,5R) absolute configuration,

P. Borrachero et al. / Tetrahedron Letters 45 (2004) 4835–4839
4837
O
HO
HO
9
OH
COOMe
4
O
(R = H)
ii
Bn
N
R
N
2
6
i
H
O
H
O
HN
H
O
iii
HN
HO
H
O
O
O
O
O
1'
O
O
OH
OH
1'
1
O
O
O
Me2C
Me2C
Me2C
O
O
O
OH
10 (98%)
CMe2
9 (96%)
CMe2
CMe2
6a
7 (R = Bn, 18%)
+ 8 (R = H, 62%)
Scheme 3. Reagents and conditions: (i) Mo(CO)6, MeCN/H2O, reflux; (ii) LiAlH4; (iii) 80% TFA.
(1,2:3,4-di-O-isopropylidene-a-
D
-galacto-pentopyranos-
5-yl)pyrrolidine (9) in 96% yield, after column chroma-
resolution mass spectrometry corroborated the loss of
both isopropylidene protecting groups.**
20
D
tography. Compound 9: ½aꢀ ꢁ 30 (c 1.0, CHCl3).– The
HRCIMS data were in agreement with its structure, also
corroborated by the absences of any carbonyl IR band
and 13C signal (NMR spectrum).
Some conformational features for 6a and its derivatives
(7–10) can be deduced from the spectral data. Thus, the
C(50)H/C(azol ring)H coupling constant takes the values
9.9, 3.4, 2.3, 6.5, and 10.0 Hz, respectively, for 6a, 7, 8, 9,
and 10; among them, first and last high values are
indicative of a preferential anti relationship in solution
between these protons (compounds 6a and 10), while for
compounds 7 and 8, the low values of J suggest that
these protons have a preferential gauche relationship in
solution, and the medium J value for 9 may indicate no
conformational preference in solution.
Compounds 7 and 8 should keep the (6R,8R) configu-
ration, coming from that of isoxazolidine C(3) and C(5)
atoms, respectively. No epimerization at C(3) of 6a is to
be expected, so that 7 and 8 must have the (6R) con-
figuration. However, the C(5) of 6a might have under-
gone epimerization. For compound 7, the C(6)H/C(8)H
and C(8)H/C(6)H contacts (1D NOESY experiments)
and the absence of HO/C(6)H and C(6)H/OH contacts
are in agreement with a 6,8-cis relationship, and there-
fore corroborate the expected (8R) configuration. The
overlapping between some signals in the 1H NMR
spectrum of 8 did not allow us to perform similar 1D
NOESY experiments, but it was possible for its reduc-
tion product 9, for which the C(3a)H/C(2)H, C(3a)H/
C(4)H, C(5b)H/C(2)H, and C(5b)H/C(4)H contacts
observed as well as the absence of both C(3b)H/C(2)H
and C(3b)H/C(4)H contacts indicate the 2,4-cis rela-
tionship again, so that the (2R,4R) configuration is
assigned for 9 and (6R,8R) for 8.
In view of the foregoing, fairly good results, we planned
to extend the 1,3-cycloaddtion reaction with the same
dipolarophile 5 to the nitrone 4, which has a primary
hydroxy group at the terminal carbon atom, and thus
should allow us to save a reduction step of the synthetic
route to polyhydroxy-perhydroazazulenes. A first assay
of its reaction with 5 at 50 °C led to a mixture of
products. Two diastereomeric 3-(penta-O-benzyl-
pentitol-1-yl)isoxazolidines (11a
D
-gluco-
and 11bàà) were
**
Selected spectral data for 10: IR (KBr) mmax 3396 (OH and NH) and
1094 cmꢁ1 (C–OH); 1H NMR (500 MHz, CD3OD) d 4.77 (d, 1H,
Deprotection of 9 with aqueous 80% trifluoroacetic acid
almost quantitatively yielded (2R,4R)-4-hydroxy-2-
J1 ;2 ¼ 6:0, H-10), 4.43 (dddd, 1H, J3a;4 ¼ 5:5, J3b;4 ¼ 4:5, J4;5a ¼ 7:5,
0
0
J4;5b ¼ 7:0, H-4), 3.77 (dd, 1H, J2;5 ¼ 10:0, H-50), 3.18 (dd, 1H,
0
(a-D-galacto-pentopyranos-5-yl)pyrrolidine (10, 98%),
after cation-exchange chromatography; it showed
J5a;5b ¼ 9:5, J4;5a ¼ 7:5, H-5a), 3.06 (dd, 1H, J4;5b ¼ 7:0, H-5b), 3.00
(ddd, 1H, J2;3a ¼ 8:5, J2;3b ¼ 2:5, H-2), 2.35 (ddd, 1H, J3a;3b ¼ 14:0, H-
3a), and 1.75 (ddd, 1H, H-3b); 13C NMR (75.4MHz, CD3OD) d 90.2
(C-10), 71.4 (C-4), 68.4 (C-50), 59.6 (C-2), 58.1 (C-5), and 39.2
(C-3). HRFABMS: m=z 258.0953 (calcd for C9H17NO6+Na: 258.0954).
Selected spectral data for 11a: IR (film) mmax 1751 cmꢁ1 (ester C@O);
1H NMR (500 MHz, CDCl3) d (locant numerals for the sugar
moiety are maintained, but primed, such as for the starting sugar
derivative) 4.38 (dd, 1H, J4a;5 ¼ 8:7, J4b;5 ¼ 7:6, H-5), 3.93 (dd, 1H,
20
D
in agreement with its hemiacetal structure, and high-
mutarotation: ½aꢀ ꢁ 7 to ꢁ 43:6 (24 h; c 0.3, MeOH),
J4 ;5 ꢂ J3 ;4 ꢂ 5:0, H-40), 3.73 (dd, 1H, J2 ;3 ꢂ J3 ;4 ꢂ 5:0, H-30), 3.72
0
0
0
0
0
0
0
0
(s, 3H, COOMe), 3.68 (overlapped signal, 1H, H-20), 3.39 (ddd, 1H,
–
0
Selected spectral data for 9: IR (KBr) mmax 3183 (OH and NH), and
1067 cmꢁ1 (C–OH); 1H NMR (300 MHz, CDCl3) d (locant numerals
for the sugar moiety are maintained, but primed, such as for the
J3;4a ¼ 3:8, J3;4b ¼ 7:7, J2 ;3 ꢂ 0, H-3), 2.78 (ddd, 1H, J4a;4b ¼ 12:7, H-
4a), and 2.46 (ddd, 1H, H-4b); 13C NMR (75.4 MHz, CDCl3) d 172.9
(COOMe), 78.5 (C-20), 76.7 (C-5), 67.2 (C-3), 52.1 (COOMe), and 33.5
(C-4). HRCIMS: m=z 822.3989 (calcd for C52H55NO8+H: 822.4006).
Selected spectral data for 11b: IR (film) mmax 1753 cmꢁ1 (ester C@O);
1H NMR (300 MHz, CDCl3) d 4.62 (overlapped signal, 1H, H-5),
starting sugar derivative) 5.51 (d, 1H, J1 ;2 ¼ 5:0, H-10), 4.27 (m,
0
0
àà
overlapped signal, H-4), 3.70 (dd, 1H, J2;5 ¼ 6:5, H-50), 3.34 (ddd,
0
1H, J2;3a ¼ 9:2, J2;3b ¼ 5:4, H-2), 2.95 (ddd, 1H, J5a;5b ¼ 11:3,
4
3.99 (dd, 1H, J3 ;4 ¼ 4:9, J4 ;5 ¼ 5:0, H-40), 3.89 (dd, 1H, J5 ;6 a ¼ 3:7,
0
0
0
0
0
0
J4;5a ¼ 1:8, J3b;5a ¼ 1:8, H-5a), 2.82 (dd, 1H, J4;5b ¼ 4:1, H-5b),
J6 a;6 b ¼ 9:8, H-60a), 3.82 (dd, 1H, J2 ;3 ¼ 1:4, H-30), 3.77 (dd, 1H,
0
0
0
0
ꢃ2.5 (br s, 2H, NH and OH), 2.14 (ddd, 1H, J3a;3b ¼ 14:6, J3a;4 ¼ 5:8,
H-3a), 1.83 (dddd, J3b;4 ¼ 5:2, H-3b); NOE contacts (1D NOESY):
H-3a, H-2, H-4; H-2, H-3a, H-5b, H-50, H-40; H-5b, H-2, H-4; 13C
NMR (75.4 MHz, CDCl3) d 96.3 (C-10), 71.9 (C-4), 70.2 (C-50), 56.9
(C-2), 55.2 (C-5), 37.7 (C-3). HRCIMS: m=z 316.1757 (calcd for
J2 ;3 ¼ 3:7, H-20), 3.73 (s, 3H, COOMe), 3.12 (ddd, 1H, J3;4a ¼ 5:0,
0
J3;4b ¼ 8:6, H-3), 2.85 (ddd, 1H, J4a;4b ¼ 13:0, J4a;5 ¼ 3:7, H-4a), and
2.61 (ddd, 1H, J4b;5 ¼ 9:9, H-4b); 13C NMR (75.4 MHz, CDCl3) d
77.7 (C-20), 74.8 (C-5), 67.7 (C-3), 51.8 (COOMe), and 33.6 (C-4).
HRCIMS: m=z 822.3995 (calcd for C52H55NO8+H: 822.4006).
C
15H25NO6+H: 316.1760).

4838
P. Borrachero et al. / Tetrahedron Letters 45 (2004) 4835–4839
isolated as oils in 6.9% and 9.0% yield, respectively, after
column chromatography. This poor yield of cyclo-
adducts may be a consequence of the cycloaddition
reversibility or of the lower reactivity of 4 as compared
with 3; nitrone decomposition gave appreciable amounts
of the a,b-unsaturated aldehyde 12, which was isolated
in 7.2% yield. Other fractions eluted from the column
were a mixture of 11a and 11b (4.6%), and a mixture of
the starting nitrone and decomposition products
(ꢃ33%). Configurational assignment for 11a and 11b
was made on the basis of coupling constant values and,
in particular, the NOE contacts (1D NOESY) observed.
For the former compound, NOE contacts were
observed, on the one hand between C(3)H and C(4)Hb,
and on the other hand between C(4)Ha and C(5)H;
hence, C(3)H and C(5)H should have a trans relation-
ship with regard to the isoxazolidine ring, such as that
shown in the formulae 11a and 11d. In order to dis-
criminate between both formulae, the C(4)Ha/C(20)H
and C(3)H/C(40)H contacts were considered, as well as
the following coupling constant values: C(20)H/C(3)H
(ꢂ0 Hz), C(20)H/C(30)H (ꢂ5.0 Hz), and C(30)H/C(40)H
(ꢂ5.0 Hz); molecular models for 11a and 11d indicated
that the best agreement with the foregoing observations
corresponded to 11a (Scheme 4). For the latter diaste-
reomer, C(3)H and C(5)H should have a cis relation-
ship, such as that shown in 11b and 11c, as deduced
from the C(3)H/C(5)H, C(3)H/C(4)Hb, and C(4)Hb/
C(5)H NOE contacts observed, while the assignment of
one of these structures for it was decided taking into
account the C(3)H/C(20)H and C(3)H/C(40)H contacts
and the following coupling0 constant values: C(200)H/
In conclusion, the high stereoselectivity observed in the
cycloaddition reaction of the nitrone 3 with methyl
acrylate leading to a sole diastereomer of cycloadduct in
good yield, is a very convenient feature to undertake a
synthetic route toward stereochemically pure polyhy-
droxy-perhydroazaazulene derivatives, ring homologues
of known, glycosidase inhibitor polyhydroxy-indoliz-
idines, such as castanospermine (1). The here reported
transformations of 6a, leading to the partially protected,
configurationally pure 4-hydroxy-2-(pentopyranos-5-
yl)pyrrolidine 9 and its completely deprotected deriva-
tive 10, will be used as a main part of such synthetic
route. Subsequent steps will imply reduction of the po-
tential aldehydic function to primary alcohol, transfor-
mation of the new hydroxyl group in a good leaving
group, and annellation by nucleophilic attack of the
pyrrolidine N atom. Previous protection of the amino
function could be necessary. With regard to the reaction
of nitrone 4 with 5, we are now working on the opti-
mization of conditions to achieve
a substantial
enhancement of yield, since the stereochemically pure
products 11a and 11b should lead, after a similar
sequence of synthesis, to pure diastereomeric 4-hydroxy-
pyrrolidines having a primary alcohol function at the
end of the sugar chain.
Acknowledgements
ꢀ
We are grateful to the Direccion General de Investi-
gacion, Ministerio de Ciencia y Tecnologıa of Spain
ꢀ
ꢀ
0
_
C(3)H (3.7 Hz), C(2 )H/C(3 )H (1.4Hz), and C(3 )H/
C(40)H (4.9 Hz); molecular models evidenced the best
agreement of 11b with these data (Scheme 4). No con-
clusion about regio- and stereoselectivity can be deduced
for the cycloaddition reaction of 4 with 5 from the
experimental data obtained in this first assay. However,
the isolated products 11a and 11b are configurationally
pure, thus making encouraging the search for better
reaction conditions to increase the yields.
ꢀ
(grant No BQU2000-1155), and the Direccion General
ꢀ
de Universidades e Investigacion, Consejerıa de Edu-
cacion y Ciencia of Andalusia (FQM 142), for financial
ꢀ
ꢀ
support.
References and notes
1. Tyler, P. C.; Winchester, B. G. In Iminosugars as Glyco-
€
sidase Inhibitors. Nojirimycin and Beyond; Stutz, A. E.,
Ed.; Wiley-VCH: Weinheim, 1999; pp 125–156.
2. El Ashry, E. S. H.; Rashed, N.; Shobier, A. H. S.
Pharmazie 2000, 55, 331–348.
3. Ovaa, H.; Stragies, R.; van der Marel, G. A.; van Boom, J.
H.; Blechert, S. Chem. Commun. 2000, 1501–1502.
4. St-Denis, Y.; Chang, T. H. Can. J. Chem. 2000, 78, 776–
783.
Bn
Bn
O
H
Hb
H
H
H
O
O
4'
Hb
H
O
5
4
O
4'
COOMe
Ha
5
3
O3
Bn
5' C
N
COOMe
H
4
3'
Bn
5' C
N 3'
H
2'
Bn
H
H
Ha
2'
6' C
Bn
O
H
5. See, for example: (a) Izquierdo, I.; Plaza, M. T.; Robles,
O
6' C
Bn
ꢀ
ꢀ
R.; Rodrıguez, C.; Ramırez, A.; Mota, A. J. Eur. J. Org.
Chem. 1999, 1269–1274; (b) Carmona, A. T.; Fuentes, J.;
Robina, I. Tetrahedron Lett. 2002, 43, 8543–8546.
Bn
11b
11a
a
a
ꢀ
6. Borrachero, P.; Cabrera, F.; Dianez, M J.; Estrada, M
D.; Gomez-Guillen, M.; Lopez-Castro, A.; Moreno, J.
Scheme 4. NOE (1D NOESY) contacts for 11a and 11b.
ꢀ
ꢀ
ꢀ
BnO
CHO
COOMe
Bn
COOMe
COOMe
Bn N
COOMe
O
O
O
O
Bn
N
N
Bn
N
OBn
OBn
Glu
11a (3R,5R)
Glu
Glu
11c (3S,5R)
Glu
11d (3S,5S)
CH2OBn
11b (3R,5S)
12

P. Borrachero et al. / Tetrahedron Letters 45 (2004) 4835–4839
4839
a
ꢀ
M ; de Paz, J. L.; Perez-Garrido, S. Tetrahedron: Asym-
metry 1999, 10, 77–98.
10. White, J. D.; Badger, R. A.; Kezar, H. S., III; Pallenberg,
A. J.; Schiehser, G. A. Tetrahedron 1989, 45, 6631–6644.
11. Peer, A.; Vasella, A. Helv. Chim. Acta 1999, 82, 1044–1065.
12. Pozsgay, V.; Jennings, H. J. J. Org. Chem. 1988, 53, 4042–
4052.
a
a
ꢀ
7. Borrachero, P.; Cabrera, F.; Dianez, M J.; Estrada, M
D.; Gomez-Guillen, M.; Lopez-Castro, A.; Moreno, J.
ꢀ
ꢀ
ꢀ
a
a
ꢀ
M ; de Paz, J. L.; Perez-Garrido, S.; Torres, M I.
Tetrahedron: Asymmetry 2002, 13, 2025–2038.
8. Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates
in Organic Synthesis. Novel Strategies in Synthesis; VCH:
Weinheim, 1988; pp 29–31.
a
a
ꢀ
ꢀ ꢀ
13. Dianez, M J.; Estrada, M D.; Lopez-Castro, A.; Perez-
Garrido, S., unpublished results.
14. Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351–3354.
ꢀ
9. Perez, P.; Domingo, L. R.; Aurell, M. J.; Contreras, R.
Tetrahedron 2003, 59, 3117–3125.
15. Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.;
Brandi, A. Eur. J. Org. Chem. 2000, 3633–3645.