Oxime-based methods for synthesis of stereodefined acyclic polyfunctionalized δ-azido-nitriles and 5-substituted isoxazoles from carbohydrate derivatives

Article abstract of DOI:10.1016/j.tet.2004.06.050

Hydroxylamine-mediated syntheses of stereodefined acyclic polyfunctionalized δ-azido-nitriles and 5-substituted isoxazoles, bearing a differentially protected glycerol moiety, from 2-deoxysugars and glycals are described.

Full text of DOI:10.1016/j.tet.2004.06.050

Tetrahedron 60 (2004) 6453–6459
Oxime-based methods for synthesis of stereodefined acyclic
polyfunctionalized d-azido-nitriles and 5-substituted isoxazoles
from carbohydrate derivatives
*
Pietro Passacantilli, Simona Pepe, Giovanni Piancatelli, Daniela Pigini and Antonella Squarcia
*
`
Dipartimento di Chimica and Istituto di Chimica Biomolecolare del CNR, Sezione di Roma, Universita ‘La Sapienza’, Piazzale Aldo Moro 5,
00185 Rome, Italy
Received 21 January 2004; revised 17 May 2004; accepted 10 June 2004
Available online 26 June 2004
Abstract—Hydroxylamine-mediated syntheses of stereodefined acyclic polyfunctionalized d-azido-nitriles and 5-substituted isoxazoles,
bearing a differentially protected glycerol moiety, from 2-deoxysugars and glycals are described.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of our continuing exploitation of the reactivity and the
usefulness of carbohydrate derivatives in organic synthesis.7
In the last few years, we have utilised cyclic enol ethers,
easily available from disaccharides, such as lactose,
cellobiose and melibiose, as attractive starting materials
for the construction of unnatural glycosphingolipids.8
Acyclic multifunctional compounds derived from sugars
have played a key role in the field of synthetic organic
chemistry for over 100 years, permitting useful transform-
ations that are not possible with the parent sugars.1
Significant reactions include treatment of sugars with
nitrogen nucleophiles, such as hydroxylamine and phenyl-
hydrazine.2 Such reactions are generally irreversible and
convert the parent sugars into the corresponding oximes and
phenylhydrazones, which then can undergo further reac-
tions.3 It is well known that the construction of versatile
building blocks has been a rewarding research topic, having
provided us with powerful precursors for efficient synthesis
of biologically active natural products.4 Thus, the develop-
ment of new methods in this field remains an important tool
in modern synthetic chemistry.
Here we describe some of our results in the development of
carbohydrate-mediated applications, which have led us to
prepare stereodefined polyfunctionalised hexanenitrile
derivatives, that can be used as precursors in the synthesis
of biologically active compounds, such as glycosylamines,9
1-b-amino-1-deoxynojirimycins10 and D-glucoamidines11
(Fig. 1).
In recent years, carbohydrate derivatives, such as glycals 1,
have shown an increasing synthetic versatility in many
aspects of organic chemistry as valuable starting materials,
allowing a range of preparatively useful applications.5 To
the best of our knowledge, few reports are available in the
literature concerning the reactivity of glycals with nitrogen
nucleophiles.6
Figure 1. Structures of biologically active compounds.
It is worth noting that our particular aim was to find
simplified synthetic strategies, and to be guided by readily
available starting materials in conjunction with straight-
forward chemistry.
Thus, a wide-ranging investigation of the use of glycals
derived from both mono- and disaccharides in the reaction
with nitrogen nucleophiles seemed to be of interest, as part
2. Results and discussion
Keywords: 2-Deoxycarbohydrates; Stereodefined acyclic polyfunctional d-
azido-nitriles; Glycals; Isoxazoles; Glycerols.
2.1. Synthesis of stereodefined acyclic polyfunctional
d-azido-nitriles
*
Corresponding authors. Tel.: þ390649913861; fax: þ3906490631;
e-mail addresses: pietro.passacantilli@uniroma1.it;
giovanni.piancatelli@uniroma1.it
We initially examined the reactivity of the glycals derived
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.050

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P. Passacantilli et al. / Tetrahedron 60 (2004) 6453–6459
from disaccharides, such as perbenzylated melibial 1a,
lactal 1b, cellobial 1c and gentiobial 1d with nitrogen
nucleophiles. To our great surprise, the glycals 1a, b, c, d
were found to be completely unreactive upon treatment with
hydroxylamine, even though the cyclic enol ethers should
be regarded as a masked aldehydic group. However, the
acid-catalysed reaction led to the formation of several
decomposition products. Structures of compounds 1a–d are
as follows
conditions, giving the corresponding d-hydroxynitrile
derivatives 4a, b, c, d with the originally free hydroxyl
group at C5 also protected as a mesylate (85–91%). This
allows displacement of the mesylate and introduction of
other functionality. For instance, the compounds 4 can
easily undergo a nucleophilic substitution by reaction with
sodium azide leading to the formation of the interesting
O-glycosylated derivatives of (3R,4R,5S)-5-azido-3,4,6-
trihydroxy-hexanenitrile, such as 5 (86%). It is worth noting
that all the products 3, 4, 5 prepared according to the
described protocol, are single stereoisomers, multi-
functional compounds.
As described, conveniently protected multifunctional com-
pounds, such as 4 and 5, have been successfully utilised as
key precursors in the asymmetric synthesis of glycosidase
inhibitors,13 sphingoid base scaffold,14 several kinds of
antibiotics,15 unusually hydroxylated amino acids16 and
other biologically active compounds.17 The results show the
flexibility of the strategy, which allows variation of the
stereochemistry of multifunctional compounds, by selecting
the correct starting sugars, and allowing an easy access to a
library of stereochemically pure chiral synthons.
Recently, we described a short and valuable synthesis of
2-deoxysugars from glycals: protected glycals, derived from
mono-, di- and trisaccharides were easily converted in
excellent yields into the corresponding 2-deoxysugars, by
treatment with aqueous mercuric(II) acetate/sodium boro-
hydride in one reaction flask and on a large scale.12
Stimulated by these results, we turned our attention to
exploring the reactivity of 2-deoxysugars with nitrogen
nucleophiles, particularly with the aim of finding strategies
for the preparation of enantiomerically pure, multi-
functional compounds.
2.2. Synthesis of 5-substituted isoxazoles
Stemming from the above results, we wanted to explore the
reactivity of the cyclic enol ethers by introducing a keto
group at C3 of the glycals to enhance its capability as a
Michael acceptor. Recently, the conjugate additions of
nucleophiles to cyclic enol ethers of glycals, such as
2-nitrogalactal, have received increasing interest, due to
their high reactivity in this field of reaction, and permitting
the synthesis of useful intermediates.18
Reaction of 2-deoxysugars 2a, b, c, d with two equivalents
of hydroxylamine, prepared from hydroxylamine hydro-
chloride and triethylamine as an ethanolic solution, afforded
the oxime derivatives 3a, b, c, d as an inseparable E/Z
mixture (70/30) in good yields (85–90%) (Scheme 1). The
following dehydration was carried out in high yield by
treatment with mesyl chloride in pyridine under described
The enones, such as 10, were prepared following a modified
procedure previously described by Kirschning.19 Unfortu-
nately, only the perbenzylated melibial 1a and gentiobial 1d
could be oxidized to the corresponding enones (70% and
60% respectively) by treatment with bis-acetoxyiodo-
benzene (BAIB) and para-toluenesulfonic acid. The
Scheme 1. Synthesis of 5a–c.

P. Passacantilli et al. / Tetrahedron 60 (2004) 6453–6459
6455
perbenzylated lactal 1b and cellobial 1c, which possess a
glycosyl moiety at C4, were completely recovered
unchanged.
4. Experimental
4.1. General
Indeed, the enones 10, when treated with two equivalents of
hydroxylamine were able to undergo conjugate addition at
C1. However, the reaction directly afforded the isoxazolines
11 (80–83%) as an inseparable epimeric mixture, and
containing a differentially functionalised glycerol moiety
(Scheme 2). The results can be explained by initial attack of
the nucleophile at C1, opening of the cyclic enol ether,
formation of the oxime derived from the aldehydic group
and its intramolecular ring closure on the keto group at C3.
Then, the dehydration reaction, carried out by treatment
with para-toluenesulfonic acid in dichloromethane at room
temperature, gave isoxazole derivatives 12 (92–95%). The
1H NMR (200 MHz) and 13C NMR (50.3 MHz) spectra
were recorded on a Varian Gemini 200 spectrometer with
CDCl3 as the solvent and as the internal standard. IR spectra
were recorded on IR-470 infrared spectrophotometer
Shimadzu. HRMS spectra were recorded with Micromass
Q-TOF micro Mass Spectrometer (Waters). Optical
rotations were measured using sodium D line on DIP 370
Jasco digital polarimeter. Yields are given for isolated
products after column chromatography showing a single
spot on TLC and no detectable impurities in 1H NMR
spectra. All reactions were performed under an inert
atmosphere of N2 in flame-dried glassware. All solvents
and commercially available reagents were used without
purification unless otherwise noted. All reactions were
monitored by thin-layer chromatography (TLC) carried out
on Merck F-254 silica glass plates visualized with UV/light
and heat-gun treatment with 2 M H2SO4 solution. Column
chromatography was performed with Merck silica gel 60
(230–400 mesh).
1
structure was completely in agreement with the H NMR
spectroscopy data: for instance, 12a showed two doublets at
8.24 d (J¼2.0 Hz, 1H, 3-H) and at 6.36 d (J¼2.0 Hz, 1H,
4-H) respectively, typical of 5-substituted isoxazoles.7a
The transformation should be considered valuable, since
isoxazole-containing natural and non-natural compounds
show interesting biological properties,20 such as nicotinic
acetylcholine receptor ligands,21 glutamic receptors
agonists22 or fungicides and herbicides.23
4.2. Starting materials
All glycosyl glycals 1a–d were prepared from their
corresponding disaccharides.21 Since the compounds 1d
and 2d were never described before, we report their
analytical data in the Section 4.
3. Conclusion
In conclusion, the exploration of the reactivity of carbo-
hydrate derivatives, such as 2-deoxysugars and glycals, has
led us to disclose a concise and efficient entry to a variety of
stereodefined polyfunctionalised hexanenitrile derivatives,
potentially valuable chiral molecules in the synthesis of
biologically active compounds. Since the d-azido-hexane-
nitriles were obtained in three simple steps from the
corresponding reducing 2-deoxysugars, the methodology
appears to be practical for large scale application. Various
transformations of the multifunctional compounds are in
progress and will be presented in due course.
4.3. General procedure for preparation of azide
derivates
To a solution of 2 (1 mmol) in absolute ethanol (10 mL) was
added triethylamine (3 mmol) and hydroxylamine hydro-
chloride (2 mmol) at 0 8C. The solution was stirred at room
temperature for 12 h; thereafter the solution, concentrated in
vacuo, was purified by silica gel chromatography (hexane/
ethyl acetate 7:3) to give 3 as an inseparable E/Z mixture
(70/30; yield 86–90%). Mesyl chloride (2.7 mmol) was
Scheme 2. Synthesis of the isoxazoles 12a and 12d.

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P. Passacantilli et al. / Tetrahedron 60 (2004) 6453–6459
added to 3 (0.9 mmol) in dry pyridine (3.5 mL) at 0 8C.
After stirring at room temperature for 1 h, the reaction
mixture was diluted with diethyl ether and, after treatment
with ice-cold 6 M hydrochloric acid (9 mL) and saturated
NaHCO3, was washed with water, brine and, after dried over
Na2SO4, the organic solution, concentrated in vacuo, was
purified on silica gel chromatography (hexane/ethyl acetate
7.5:2.5) to give 4 (yield 86–91%). The mesyl derivative 4
(0.85 mmol) and NaN3 (14 mmol) in dry DMF (12 mL)
were stirred for 36 h at 100 8C. The reaction mixture was
diluted with ethyl ether, washed with water, brine and, after
dried over Na2SO4, was concentrated in vacuo and
chromatographed on silica gel (hexane/ethyl acetate 4:1)
to give 5 (yield 82–86%).
(1H, m); 2.65 (1H, m). 13C NMR, d (CDCl3): 150.2 (C1);
138.8, 138.5, 138.3, 138.0 (Cquat., Ph); 128.5–127.6 (Ph);
103.9 (C10); 82.5; 79.4; 77.8; 77.4; 77.2; 76.9; 75.3; 074.7;
73.8; 73.6; 73.3; 73.0; 72.5, 72.3 (CH2Ph, C3, C4, C2 ,C30,
C40, C50); 70.8, 70.6 (C5); 68.8, 68.9 (C6, C60); 30.4, 26.2
(C2). HRMS Calcd for C54H59NO10 [MþNH4]þ 899.4139,
found 899.4143.
Compound 4b, viscous colorless oil (0.81 mmol, 0.77 g,
yield 91%); IR nmax (CHCl3)/cm21: 3090, 3082, 3067,
2016, 1610, 1520, 1348, 1160, 1080. [a]D þ7.0 (c 1.0,
1
CHCl3). H NMR, d (CDCl3): 7.50–7.20 (30H, m); 5.10–
4.42 (15H, m); 4.28 (2H, s); 4.20–3.46 (7H, m); 2.93 (3H,
s); 2.93 (1H, dd, A of ABX system, JAB¼12.0 Hz,
JAX¼4.5 Hz); 2.72 (1H, dd,
B of ABX system,
4.3.1. (3R,4R,5S)-3,4-Di-O-benzyl-5-azide-6-O-(2,3,4,6-
tetra-O-benzyl-a-D-galactopyranosyl) hexanenitrile 5a.
Compound 3a (E/Z mixture), viscous colorless oil
JBA¼12.0 Hz, JBX¼7.5 Hz). 13C NMR, d (CDCl3): 138.8,
138.7, 138.4, 137.9, 137.6, 137.3 (Cquat., Ph); 128.6–127.6
(Ph); 118.4 (CN); 103.3 (C10); 082.6, 80.1, 79.2, 77.2, 74.5;
73.6, 73.5 (C3, C4, C5, C20, C3 , C40, C50); 75.4, 740.8, 73.7,
73.6, 73.2, 73.0, 72.9, 68.2 (CH2Ph, C6, C6 ); 38.1
(CH3SO2); 19.6 (C2). HRMS Calcd for C55H59NO11S
[MþNH4]þ 959.3809, found 959.3805.
(0.90 mmol, 0.79 g, yield 90%); IR nmax (CHCl3)/cm21
:
3570, 3350, 3090, 3080, 1500, 1460, 1095, 1070, 1030. 1H
NMR, d (CDCl3): 7.30–7.0 (30H, m); 6.83 (0.5H, t,
J¼4.5 Hz), 6.65 (0.5H, t, J¼4.5 Hz); 4.82–4.22 (13H, m);
4.05–3.22 (10.5H, m); 2.89 (0.5H, q, J¼8.5 Hz); 2.65 (1H,
t, J¼4.5 Hz); 2.43 (1H, t, J¼4.5 Hz). 13C NMR, d (CDCl3):
149.3, 149.2 (C1); 139.4–138.0 (Cquat., Ph); 129.4–125.9
(Ph); 99.2 (C10); 80.5; 79.0; 77.4; 76.7; 74.9; 74.1; 74.0;
73.9; 73.9; 73.6; 72.9; 72.9; 70.8, 70.7, 70.4, 70.3 (CH2Ph,
C3, C4, C20,C30, C40, C50, C6, C60); 69.9, 69.0 (C5); 42.9,
40.0 (C2). HRMS Calcd for C54H59NO10 [MþNH4]þ
899.4139, found 899.4133.
Compound 5b, viscous colorless oil (0.78 mmol, 0.69 g,
yield 86%); IR nmax (CHCl3)/cm21: 2920, 2898, 2099,
2122, 1500, 1460, 1368, 1190, 1015. [a]D þ5.8 (c 1.4,
1
CHCl3). H NMR, d (CDCl3): 7.49–7.20 (30H, m); 5.01–
4.35 (15H, m); 4.10 (1H, m, H-2) 3.95–3.45 (8H, m); 2.98
(1H, dd, A of ABX system, JAB¼12.2 Hz, JAX¼4.5 Hz);
2.80 (1H, dd, B of ABX system, JAB¼12.2 Hz,
JBX¼7.5 Hz). 13C NMR, d (CDCl3): 138.7, 138.6, 138.4,
137.9, 137.7, 137.3 (Cquat., Ph); 128.5–127.7 (Ph); 119.1
(CN); 105.0 (C10); 82.5; 79.1, 75.5; 75.2; 74.7 73.0 (C3, C4,
C20, C30, C40, C50); 73.7, 73.6, 73.2, 73.1 (CH2Ph); 69.2;
68.9 (C6, C60); 59.6 (C5); 19.7 (C2). HRMS Calcd for
C54H56N4O8 [MþNH4]þ 906.4098, found 906.4094.
Compound 4a, viscous colorless oil (0.80 mmol, 0.75 g,
yield 89%); IR nmax (CHCl3)/cm21: 3093, 3090, 3080,
2020, 1600, 1500, 1350, 1165, 1075. [a]D þ16.0 (c 1.2,
1
CHCl3). H NMR, d (CDCl3): 7.60–7.25 (30H, m): 5.18–
4.30 (15H, m); 4.22–3.89 (7H, m); 3.60 (2H, m); 2.86 (3H,
s); 2.58 (2H, t, J¼4.5 Hz). 13C NMR, d (CDCl3): 138.7,
138.6, 138.5, 138.1, 137.2, 137.1 (Cquat., Ph); 128.8–128.7
(Ph); 117.8 (CN); 98.0 (C10); 80.7;0 79.3; 78.5; 76.4; 75.1;
74.0, 70.2 (C3, C4, C5, C20,C030, C4 , C50); 74.8, 74.7, 73.8,
73.7, 73.4 (CH2Ph); 69.2 (C6 ); 65.9 (C6); 38.7 (CH3SO2);
19.9 (C2). HRMS Calcd for C55H59NO11S [MþNH4]þ
959.3809, found 959.3803.
4.3.3. (3R,4R, 5S)-3,6-Di-O-benzyl-5-azide-4-O-(2,3,4,6-
tetra-O-benzyl-b-D-glucopyranosyl) hexanenitrile (5c).
Compound 3c (E/Z mixture), viscous colorless oil
(0.86 mmol, 0.76 g, yield 86%); IR nmax (CHCl3)/cm21
:
3577, 3355, 3090, 3080, 1610, 1460, 1095, 1075, 1040. 1H
NMR, d (CDCl3): 7.62 (0.5H, t, J¼4.5 Hz); 7.55–7.22
(30H, m); 7.0 (0.5H, t, J¼4.5 Hz); 5.09–4.40 (13H, m);
4.30–3.40 (11H, m); 3.0–2.63 (2H, m). 13C NMR, d
(CDCl3): 150.2, 150.1 (C1); 138.8, 138.5, 138.3, 138.1
(Cquat., Ph); 128.5–127.1 (Ph); 103.4 (C10); 84.9, 82.3, 77.4,
75.7, 75.0, 74.8, 73.5, 73.4, 72.6, 72.4 (CH2Ph, C3, C4,
C20,C30, C40, C50); 72.5, 72.4 (C5); 69.6, 68.1 (C6, C60);
30.5, 28.1 (C2). HRMS Calcd for C54H59NO10 [MþNH4]þ
899.4139, found 899.4131.
Compound 5a, viscous colorless oil (0.68 mmol, 0.61 g,
yield 86%); IR nmax (CHCl3)/cm21: 2990, 2985, 2099,
1510, 1460 1360, 1240, 1094, 1042. [a]D þ22.0 (c 1.6,
CHCl3). 1H NMR, d, (CDCl3): 7.58–7.30 (30H, m); 5.09–
4.45 (15H, m); 4.12–3.68 (8H, m); 3.60 (1H, m,); 2.65 (2H,
t, J¼4.5 Hz). 13C NMR, d (CDCl3): 138.8, 138.7, 138.1,
137.5, 137.3 (Cquat., Ph); 128.7–127.7 (Ph); 118.1 (CN);
99.1 (C10); 78.9; 78.6; 76.6; 75.2; 75.1 (C3, C4, C20, C30,
C50); 74.9, 74.7, 73.7, 73.6, 73.2, 73.2 (CH2Ph); 70.2 (C40);
69.3 (C60); 63.3 (C6); 60.4 (C5); 19.6 (C2). HRMS Calcd
for C54H56N4O8 [MþNH4]þ 906.4098, found 906.4091.
Compound 4c, viscous colorless oil (0.73 mmol, 0.69 g,
yield 85%); IR nmax (CHCl3)/cm21: 3091, 3082, 3067,
2013, 1613, 1523, 1343, 1161, 1080. [a]D þ7.7 (c 1.2,
1
CHCl3). H NMR, d (CDCl3): 7.52–7.20 (30H, m); 5.13–
4.3.2. (3R,4R,5S)-3,6-Di-O-benzyl-5-azide-4-O-(2,3,4,6-
tetra-O-benzyl-b-D-galactopyranosyl) hexanenitrile 5b.
Compound 3b (E/Z mixture), viscous colorless oil
5.40 (13H, m); 4.34 (2H, s); 4.18 (1H, m, H-2); 3.85–3.36
(8H, m); 3.03 (1H, dd, A of ABX system, JAB¼11.8 Hz,
JAX¼4.5 Hz); 3.92 (3H, s); 2.70 (1H, dd, B of ABX system,
JBA¼11.8 Hz, JBX¼7.0 Hz). 13C NMR, d (CDCl3): 138.4,
138.2, 138.1, 137.2, (Cquat., Ph); 128.4–127.6 (Ph); 118.1
(CN); 102.6 (C10); 84.7, 81.8, 79.6, 75.5, 74.8 (C3, C4, C20,
C30, C50); 74.8, 74.7, 73.3 (CH2Ph); 72.9, 72.8 (C5, C40);
(0.90 mmol, 0.79 g, yield 90%); IR nmax (CHCl3)/cm21
:
3575, 3350, 3090, 3080, 1600, 1460, 1095, 1075, 1040. 1H
NMR, d (CDCl3): 7.65–7.25 (30.5H, m); 6.90 (0.5H, t,
J¼4.5 Hz); 5.05–4.37 (13H, m); 4.25–3.40 (11H, m); 2.85

P. Passacantilli et al. / Tetrahedron 60 (2004) 6453–6459
6457
68.4, 67.8 (C6, C60); 38.9 (CH3SO2); 19.4 (C2). HRMS
Calcd for C55H59NO11S [MþNH4]þ 959.3809, found
959.3808.
(C1); 139.4–138.0 (Cquat., Ph); 129.4–125.9 (Ph); 103.7
(C10); 83.9, 82.3, 77.5, 75.7, 75.1, 74.8, 73.5, 73.4, 72.6,
72.4, 72.5, 72.4 (C3, C4, C5, C20, C30, C40, C50, CH2Ph);
69.6, 68.1 (C6, C60); 30.4, 28.2 (C2). HRMS Calcd for
C54H59NO10 [MþNH4]þ 899.4139, found 899.4141.
Compound 5c, viscous colorless oil (0.60 mmol, 0.53 g,
yield 82%); IR nmax (CHCl3)/cm21: 3010, 2890, 2100,
1665, 1509, 1458, 1399, 1365, 1094. [a]D þ4.3 (c 1.5,
Compound 4d, viscous colorless oil (0.72 mmol, 0.68 g,
yield 91%); IR nmax (CHCl3)/cm21: 3091, 3067, 2990,
2013, 1613, 1523, 1343, 1161, 1080. [a]D þ18.7 (c 1.4,
1
CHCl3). H NMR, d (CDCl3): 7.46–7.18 (30H, m); 4.98–
4.38 (13H, m); 4.36 (2H, s); 4.13 (1H, m, H-2); 3.78 (8H,
m); 2.98 (1H, dd, A of ABX system, JAB¼11.8 Hz,
1
CHCl3). H NMR, d (CDCl3): 7.52–7.20 (30H, m); 5.13–
JAX¼4.5 Hz); 2.80 (1H, dd,
B
of ABX system,
5.40 (13H, m); 4.34 (2H, s); 4.18 (1H, m, H-2); 3.85–3.36
(8H, m); 3.92 (3H, s); 3.03 (1H, m, HA-1); 2.70 (1H, m, HB-
JBA¼11.8 Hz, JBX¼7.0 Hz). 13C NMR, d (CDCl3): 138.4,
138.1, 137.3 (Cquat., Ph); 128.5–127.6 (Ph); 118.9 (CN);
104.4 (C10); 84.8, 81.9, 75.7, 75.3, 74.9 (C3, 0C4, C20, C30,
C50); 73.6, 73.26, 73.13, 72.92 (CH2Ph, C4 ); 69.2; 69.0
(C6, C60); 59.9 (C5); 19.5 (C2). HRMS Calcd for
C54H56N4O8 [MþNH4]þ 906.4098, found 906.4098.
1). 13C NMR, d (CDCl3): 138.4, 138.2, 138.1, 137.2, (Cquat.
,
Ph); 128.4–127.6 (Ph); 117.3 (CN); 102.7 (C10); 83.7, 81.7,
79.6, 75.6, 74.4 (C3, C4, C20, C30, C50); 74.8, 74.7, 73.3
(CH2Ph); 72.8, 72.8 (C5, C40); 68.5, 67.6 (C6, C60); 38.9
(CH3SO2); 19.3 (C2). HRMS Calcd for C55H59NO11S
[MþNH4]þ 959.3809, found 959.3807.
4.3.4. 3,4-Di-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-b-D-
glucopyranosyl)-1,5-anhydro-2-deoxy-D-arabino-hex-1-
enitol (gentiobial) 1d. The compound 1d was prepared
from the commercially available gentiobiose according to a
described procedure.24 Starting from gentiobiose
(14.6 mmol, 5.0 g), 1d was obtained as amorphous white
Compound 5d, viscous colorless oil (0.61 mmol, 0.54 g,
yield 85%); IR nmax (CHCl3)/cm21: 2950, 2890, 2100,
1680, 1500, 1450, 1360, 1099. [a]D þ31.0 (c 1.7, CHCl3).
1H NMR, d, (CDCl3): 7.58–7.30 (30H, m); 5.09–4.45
(15H, m); 4.12–3.68 (8H, m); 3.60 (1H, m,); 2.65 (2H, t,
J¼4.5 Hz). 13C NMR, d (CDCl3): 138.83, 138.77, 138.15,
137.56, 137.27 (Cquat., Ph); 128.71–127.71 (Ph); 118.11
(CN); 104.28 (C100); 82.57; 79.06; 75.57; 75.25; 74.77 (C2,
C3, C20, C30, C4 ); 73.70, 73.61, 73.23, 73.17 (CH2Ph);
73.10 (C50); 69.24; 68.94 (C5, C60); 59.62 (C4); 19.70 (C1).
HRMS Calcd for C54H56N4O8 [MþNH4]þ 906.4098, found
906.4096.
solid (7.5 g, 8.9 mmol, yield 60%); IR nmax (CHCl3)/cm21
:
3090, 3080, 1650, 1610, 1460, 1095, 1075, 1040. [a]D
1
þ44.3 (c 1.1, CHCl3). H NMR, d (CDCl3): 7.52–7.20
(30H, m); 6.56 (1H, d, J¼6,2 Hz); 5.20–4.7 [15H, m,
CH2Ph (12H), H-2, H-10, H-30]; 4.40–4.20 (4H, m, H-3,
H-4, H-20, H-40); 4.10–3.57 (6H, m, H-5, H-50, 2H-6, 2H-
60). 13C NMR, d (CDCl3):145.02 (C1); 138.83, 138.78,
138.20, 137.47 (Cquat., Ph); 128.77–127.63 (Ph); 104.27
(C10); 99.86 0(C2); 84.78, 82.13, 79.06, 75.77, 75.25, (C3,
C4, C20, C3 , C40); 73.70, 73.61, 73.23, 73.17 (CH2Ph);
73.15 (C5, C50); 69.24; 68.94 (C6, C60). HRMS Calcd for
C54H56O9 [MþNH4]þ 866.3924, found 866.3930.
4.4. General procedure for preparation of isoxazoles
To a solution of 1 (1.16 mmol) in dry CH3CN (20 mL) and
in the presence of molecular sieves, BAIB (450 mg,
1.15 mmol) was added and stirred for 10 min at room
temperature. Then, p-TSOH (265 mg, 1.4 mmol) was added
portionwise under stirring during 45 min, until no starting
material was detectable and filtered through a pad of Celite.
The filtrate was concentrated in vacuo and the residue was
purified by flash chromatography on silica gel (hexane/ethyl
ether 7:3) to give pure compound 10 (yield 60–70%). To a
solution of 10 (0.73 mmol) in absolute ethanol (5 ml) were
added triethylamine (2.7 mmol) and hydroxylamine hydro-
chloride (1.8 mmol). The solution was stirred at room
temperature for 4 h; thereafter the solution was evaporated,
the crude product was purified by flash column chromato-
graphy on silica gel (hexane/ethyl acetate 7:3) to give 11 as
inseparable epimeric mixture (yield 80–83%). A solution of
11 in dry CH2Cl2 (4 mL) was stirred with 5 mg of para-
toluensulfonic acid for 6–8 h at room temperature; the
reaction was diluted with diethyl ether and, after cold-ice
treatment with saturated NaHCO3, was washed with water,
brine and, after dried over Na2SO4, the organic solution,
concentrated in vacuo, was purified on silica gel chroma-
tography (hexane/ethyl ether 6:4) to give 12 (yield
92–95%).
4.3.5. 3,4-Di-O-benzyl-2-deoxy-6-O-(2,3,4,6-tetra-O-ben-
zyl-b-D-glucopyranosyl)-D-glucopyranose 2d. Compound
2d was prepared from the perbenzylated gentiobial 1d
following our previous method.12 Starting from 1d (1 mmol,
0.85 g), 2d was obtained as viscous colorless oil
(0.90 mmol, 0.78 g, yield 90%); IR nmax (CHCl3)/cm21
:
3577, 3355, 3090, 3080, 1610, 1460, 1095, 1075, 1040. [a]D
1
þ12.3 (c 1.3, CHCl3). H NMR, d (CDCl3): 7.52–7.20
(30H, m); 5.25 (1H, bs, H-1); 5.10–4.25, [14H, m, CH2Ph
(12H), H-10, H-30]; 4.40–4.200 (4H, m, H-3, H-4, H-20, H-40);
4.10–3.57 (6H, m, H-5, H-5 , 2H-6, 2H-60); 2.27–1.92 (2H,
m, 2H-2). 13C NMR, d (CDCl3): 138.8–137.4 (Cquat., Ph);
128.2–126.1 (Ph); 103.3, 102.6 (C10); 93.0, 92.7 (C1); 82.3,
80.2, 79.1, 75.8, 73.8, 73.1, 72.3,0 72.0, 71.8, 71.6, 70.2,
69.5, 67.1, (C3, C4, C5, C6, C20, C3 , C40, C50, C60, CH2Ph);
36.6, 34.4 (C2). Anal. CALCD. for C54H58O10: C, 74.80, H,
6.74. Found: C, 74.82, H, 6.59.
4.3.6. (3R,34,5S)-3,4-Di-O-benzyl-5-azide-6-O-(2,3,4,6-
tetra-O-benzyl-b-D-glucopyranosyl)-hexanenitrile 5d.
Compound 3d, (E/Z mixture), viscous colorless oil,
(0.79 mmol, 0.70 g, yield 88%); IR nmax (CHCl3)/cm21
:
3575, 3350, 3090, 3080, 1630, 1460, 1095, 1075, 1040. 1H
NMR, d (CDCl3): 7.65–7.25 (30.5H, m); 6.82 (0.5H, t,
J¼4.5 Hz); 5.13–4.28 (13H, m); 4.25–3.40 (11H, m); 2.85
(1H, m); 2.65 (1H, m). 13C NMR, d (CDCl3):149.8, 149.6
4.4.1. 5-[(1R,2R)-1-Benzyl-2-hydroxy-3-(2,3,4,6-tetra-O-
benzyl-a-D-galactopyranosyl)]isoxazole (12a). Com-
pound 10a, viscous colorless oil (0.81 mmol, 0.61 g, yield
70%); IR nmax (CHCl3)/cm21: 2950, 2890, 1680 (CvO),

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P. Passacantilli et al. / Tetrahedron 60 (2004) 6453–6459
1
1500, 1450, 1360, 1099. [a]D þ7.0 (c 1.2, CHCl3). H
NMR, d (CDCl3): 7.53–7.20 [26H, m, (5xPh, H-1)]; 5.37
(1H, d, J¼3.5 Hz, H-10); 5.08–4.40 [13H, m, (5£CH2Ph,
H-2, 0 H-4, H-30)]; 4.18–3.80 [5H, m, (H-5, H-20, H-40,
2H-6 )]; 3.65–3.40 [3H, m, (H-50, 2H-6)]. 13C NMR, d
(CDCl3): 193.0 (C3); 161.8 (C1); 138.5–137.4 (Cquat., Ph);
128.4–127.4 (Ph); 105.0 (C2); 98.1 (C10); 81.1, 78.4,
76.9, 76.6, 74.9, 74.6 (C4, C5, C20, C30, C40, C50); 74.04,
74.2, 73.3, 73.1, 72.9 (CH2Ph); 69.6, 68.3 (C6, C6 ).
HRMS Calcd for C47H48O9 [MþNH4]þ 774.3298, found
774.3296.
Compound 12d, viscous colorless oil (0.5 mmol, 0.39 g,
yield 92%); IR nmax (CHCl3)/cm21: 3560, 3090, 3010,
2980, 1630, 1440, 1095, 1090, 1040. [a]D þ126.0 (c 1.5,
CHCl3). 1H NMR, d (CDCl3): 8.22 (1H, d, J¼2.0 Hz, H-4);
7.41–7.25 (25H, m, 5xPh); 6.31 (1H, d, J¼2.0 Hz, H-4);
5.04–4.42 (13H, m); 4.25 (2H, m); 4.20–3.45 (6H, m); 2.55
(1H, bs, OH). 13C NMR, d (CDCl3): 170.5 (C5); 150.1 (C3);
138.6–137.3 (Cquat., Ph); 128.5–127.7 (Ph); 104.5 (C100);
102.4 (C4); 84.6, 82.2, 77.8, 74.8, 73.8, 72.0 (C10, C20, C200,
C300, C400, C50000); 75.7, 75.0, 73.6, 72.6, 72.1 (CH2Ph); 70.1,
68.8 (C30, C6 ). HRMS Calcd for C47H49NO9 [MþNH4]þ
789.3407, found 789.3411.
Compound 11a, viscous colorless oil (0.67 mmol, 0.53 g,
yield 83%); IR nmax (CHCl3)/cm21: 3575, 3350, 3090,
1
3080, 2990, 1650, 1450, 1095, 1075, 1040. H NMR, d
Acknowledgements
(CDCl3): 7.52–7.25 [26H, m, (5xPh, H-1)]; 5.10–4.30
(16H, m); 4.20–3.40 (5H, m); 2.80 (2H, m). 13C NMR, d
(CDCl3): 147.2, 147.1 (C3); 138.4,137.7, 137.6, 137.5,
136.8 (Cquat., Ph); 128.3–127.4 (Ph); 108.0, 106.8 (C5);
99.9, 99.6 (C100); 80.0, 78.7, 76.3, 74.6, 74.4, 074.1, 73.4,
72.7, 720.02, 71.4, 70.7, 70.1, 69.0 (C10, C20, C3 C200, C300,
C400, C5 , C600 CH2Ph); 43.2, 42.9 (C4). HRMS Calcd for
C47H51NO10 [MþNH4]þ 807.3513, found 807.3508.
We thank the University ‘La Sapienza’ of Rome for
financial support.
References and notes
Compound 12a, viscous colorless oil (0.63 mmol, 0.49 g,
yield 95%); IR nmax (CHCl3)/cm21: 3575, 3090, 2995,
1660, 1458, 1100, 1075, 1040. [a]D þ12.0 (c 1.2, CHCl3).
1H NMR, d (CDCl3): 8.24 (1H, d, J¼2.0 Hz, H-3);
7.43–7.25 (25H, m, 5xPh); 6.36 (1H, d, J¼2.0 Hz, H-4);
4.98–4.40 (15H, m); 4.18–3.40 (6H, m); 2.68 (1H, bs, OH).
13C NMR, d (CDCl3): 170.08 (C5); 150.21 (C3); 138.08–
137.17 (Cquat., Ph); 128.56–127.57 (Ph); 102.56 (C4); 99.58
(C100); 78.86, 77.98, 76.84, 76.50, 75.02, 74.86 (C10, C20,
C200, C300, C400, C500); 73.86,0 73.77, 73.50, 73.30, 73.15
(CH2Ph); 70.82, 69.67 (C3 , C600). HRMS Calcd for
C47H49NO9 [MþNH4]þ 789.3407, found 789.3997.
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10d, viscous colorless oil (0.69 mmol, 0.53 g, yield 60%);
IR nmax (CHCl3)/cm21: 3010, 2985, 1670 (CvO), 1510,
1460 1360, 1240, 1094, 1042. [a]D þ97.0 (c 1.2, CHCl3).
1H NMR, d (CDCl3): 7.50–7.24 [26H, m, (5£Ph, H-1)];
5.08–4.40 [14H, m, (5£CH2Ph, H-2, H-4, H-10, H-30)];
4.18–3.80 [50H, m, (H-5, H-20, H-40, 2H-60)]; 3.65–3.40
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Compound 11d, viscous colorless oil (0.55 mmol, 0.44 g,
yield 80%); IR nmax (CHCl3)/cm21: 3575, 3350, 3010,
1650, 1455, 1091, 1077, 1050. 1H NMR, d (CDCl3): 7.58–
7.25 [26H, m, (5xPh, H-1)]; 5.0–4.33 (16H, m); 4.20–3.45
(5H, m); 2.90 (2H, m). 13C NMR, d (CDCl3): 147.3, 147.1
(C3); 138.3, 138.1, 137.9, 137.7, 137.5, 137.3 (Cquat., Ph);
128.3–127.6 (Ph); 108.0, 106.9 (C5); 104.3, 104.1 (C100);
84.4, 82.01, 79.5, 77.5, 75.6, 74.6, 74.4, 070 3.5, 70.8, 70.1, 68.7
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