Formyl C-glycosides as precursors to glycosyl nitrile oxides and nitrones

Article abstract of DOI:10.1055/s-2002-33643

Formyl C-glycosides, prepared via the thiazole-based formylation of sugar lactones in three steps, are readily condensed with N-benzylhydroxylamine and hydroxylamine to give the corresponding glycosyl nitrones and oximes respectively. The latter imino derivatives are the precursors to nitrile oxides via the N-bromosuccinimide method.

Full text of DOI:10.1055/s-2002-33643

PAPER
1701
Formyl C-Glycosides as Precursors to Glycosyl Nitrile Oxides and Nitrones
Formyl
C-
Glycosid
l
e
s
as
P
e
recursors
t
s
G
lycosy
s
l
Nitrile
O
a
xides,
N
itr
n
ones dro Dondoni,* Pier Paolo Giovannini
Laboratorio di Chimica Organica, Dipartimento di Chimica, Università di Ferrara, Via Borsari 46, 44100 Ferrara, Italy
E-mail: adn@dns.unife.it
Received 2 April 2002; revised 5 June 2002
tial of this synthetic method by showing the access to ei-
Abstract: Formyl C-glycosides, prepared via the thiazole-based
formylation of sugar lactones in three steps, are readily condensed
with N-benzylhydroxylamine and hydroxylamine to give the corre-
sponding glycosyl nitrones and oximes respectively. The latter imi-
ther the - or -anomers through the control of the
stereochemistry of the deoxygenation step, i.e. 2 to 3, us-
ing polar or radical conditions.9 For example, the deoxy-
no derivatives are the precursors to nitrile oxides via the N- genation of mannofuranose bis-acetonide with
bromosuccinimide method.
trimethylsilyl triflate and triethylsilane affords the
-
linked formyl C-mannofuranoside whereas the use of sa-
marium iodide and ethylene glycol leads to the -formyl
anomer. Hence, it appears that formyl C-glycosides pos-
sess several interesting features, such as the ready access
as to either - or -anomers, sufficient stability, high reac-
tivity and therefore present themselves as convenient re-
agents in carbohydrate chemistry. Nevertheless, a recent
paper by Paton and co-workers10 put some doubts on the
synthetic utility of these compounds as they were defined
to be plagued by ‘instability and lack of ready access’. In
order to remove that misleading belief, we would like to
report herein a convenient preparation of compounds
which belong to the same class of N-derivatives of formyl
C-glycosides, i.e. oximes and nitrile oxides, which were
considered to be difficult to access starting from sugar al-
dehydes. Moreover, as a further demonstration of the po-
tential of sugar aldehydes as precursors to 1,3-dipolar
systems, we will also describe their direct transformation
into glycosyl nitrones.
Key words: sugar aldehydes, glycosyl nitrile oxides, glycosyl ni-
trones
Aiming at understanding the complex machinery of bio-
logical processes involving carbohydrates at molecular
level, glycobiology is posing a pressing need to synthetic
organic chemists for new methods leading to natural and
artificial glycosides in a meaningful scale, pure form, and
well defined structure.1 While the access to complex O-
oligosaccharides and O-glycoconjugates is at present pro-
vided by various sophisticated chemical and enzymatic
methods of O-glycosidation in solution as well as in solid
phase,2 problems still exist to prepare carbon linked isos-
teres because of the few available anomeric carbon-car-
bon bond forming reactions endowed with both chemical
efficiency and stereocontrol.3 In fact, methods which are
successfully employed with simple model systems show
some limitations when applied to the construction of com-
plicated carbohydrate-based architecture. This problem
can be circumvented by the use of C-functionalized carbo-
hydrate derivatives bearing an - or -linked highly reac-
tive carbon functionality at the anomeric center. More
complex molecular residues can be installed via reactions
of the functional group with suitable substrates. Following
this simple concept, we have employed formyl C-glyco-
sides 3 (Scheme 1) as convenient synthetic building
blocks via Wittig-type coupling reactions of the formyl
group4 and demonstrated their utility for the synthesis of
C-oligosaccharide5 and various C-glycoconjugates.6 In
addition to their high reactivity and stability, these ano-
meric sugar aldehydes proved to fulfill another substantial
prerequisite for their advantageous use in synthesis, i.e.
their ready access in multigram scale. A convenient, gen-
eral method for their preparation was demonstrated7 via
addition of 2-lithiothiazole to sugar lactones 1, followed
by deoxygenation of the resulting ketol 2 and aldehyde
liberation via the thiazole-to-formyl unmasking protocol8
(Scheme 1). Quite recently, we have extended the poten-
transform to CHO
N
N
Li
O
O
O
S
two steps
remove
S
OH
CHO
O
2
3
1
Scheme 1
Having decided to prepare nitrile oxides via oxidation of
oximes, Paton and co-workers considered10 the synthesis
of glycosyl oximes as a key process in their approach.
Since sugar aldehydes were presumed to be inconvenient
precursors, the oximes were prepared in good yield (76–
90%) by a 16 hour reduction of 2,6-anhydro-1-deoxy-1-
nitroalditols (glycosyl nitromethane derivatives) with a
stannate(II) complex generated in situ from SnCl2
PhSH Et3N. Instead, we have observed that pyranose and
furanose oximes can be obtained from formyl C-glyco-
sides 3 in a more convenient manner, high yields just by 1
hour treatment of these sugar aldehydes at room tempera-
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1701,1706,ftx,en;Z05602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1702
A. Dondoni, P. P. Giovannini
PAPER
Table Transformation of Anomeric Sugar Aldehydes 3 to Oximes
4, Furoxans 6, Nitrones 7
ture with hydroxylamine hydrochloride and sodium car-
bonate (Scheme 2). Under these conditions, various
-
linked sugar aldehydes 3a–f incorporating glycopyrano-
syl (manno, gluco, galacto, 2-azidogalacto) and glyco-
furanosyl residues (manno, ribo), which were prepared as
Aldehyde, 3
Oxime, 4
Furoxan, 6
Nitrone, 7
(% yield)a
(% yield)a
(% yield)a
9
described7 afforded the corresponding oximes 4a–f in
BnO
O
CHO
4a (78)
4b (85)
6a (60)
6b (80)
7a (95)
7b (88)
high isolated yield11 (Table). Hence, this method appears
to be more practical than the Paton procedure since it
avoids the in situ preparation of a tin reagent and gives
similar if not better yields. However, it has to be pointed
out that glycosylnitromethanes are more straightforward-
ly accessible substrates from aldoses than sugar alde-
hydes. Nevertheless, this disadvantage is compensated by
the structural diversity, the variable substitution and pro-
tective group pattern in which the sugar aldehydes are
available. On the other hand, nitromethyl derivatives of
sugars can be only prepared as O-acetyl derivatives in a
single anomeric form and those derived from furanoses
are obtained as mixtures of furanoid and pyranoid forms.12
Although it has been already demonstrated10 that glycosyl
oximes are precursors to nitrile oxides via an oxidative
process, we tested this transformation with our own com-
pounds using the classical N-bromosuccinimide-based
method of Grundman proceeding through the formation
of an hydroximic acid bromide intermediate.13 For all
oximes 4a–f reported in Table, treatment with N-bromo-
succimimide (NBS), then with triethylamine, there was
evidence of nitrile oxide formation as shown by a strong
IR absorption band at around 2300 cm–1 typical of the
CNO group stretching.14 Slow dimerization of nitrile ox-
ides 5 took place at room temperature leading to the furox-
ans 6 in very good yield (Table). The compounds 5
survived for a time sufficient to give the cycloaddition re-
action with suitable dipolarophiles. Typically, generating
the nitrile oxide 5b from the glucopyranosyl oxime 4b in
the presence of dimethyl acetylenedicarboxylate (Scheme
2) afforded the corresponding C-glycosylated isoxazole
8b in good isolated yield (75%).
R
R
BnO
3a, R = OBn
BnO
CHO
O
OBn
BnO
OBn
3b
BnO
BnO
CHO
O
4c (85)
4d (88)
6c (80)
6d (60)
7c (80)b
7d (75)
OBn
OBn
3c
BnO
BnO
CHO
O
OBn
N3
3d
O
O
4e (90)
4f (85)
6e (75)
6f (75)
7e (72)b
7f (90)
CHO
O
O
O
3e
BnO
CHO
O
BnO OBn
3f
a All yields refer to isolated products after chromatography.
b Ref.6a
Scheme 2
Synthesis 2002, No. 12, 1701–1706 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Formyl C-Glycosides as Precursors to Glycosyl Nitrile Oxides and Nitrones
1703
1H NMR: = 8.50 (s, 1 H, OH), 7.45–7.13 (m, 20 H, 4 Ph), 7.00 (d,
1 H, J1,2 = 4.5 Hz, H-1), 4.92, 4.57 (2 d, 2 H, J = 10.5 Hz, PhCH2),
4.89, 4.70 (2 d, 2 H, J = 11.5 Hz, PhCH2), 4.60 (dd, 1 H, J2,3 = 0.8
Hz, H-2), 4.39 (dd, 1 H, J3,4 = 3.0 Hz, H-3), 3.94 (dd, 1 H,
We have already reported the transformation of anomeric
and non anomeric sugar aldehydes to the corresponding
nitrones.6a,15 In particular, aldehydes 3c, 3e were
transformed6a into N-benzyl nitrones 7c, 7e (Table). Nev-
ertheless we sought the opportunity for providing some
more examples of this functionalization employing the al-
dehydes 3a,b,d,f. Nitrones, unlike nitrile oxides, are sta-
ble compounds. They can be used both as partners in 1,3-
dipolar cycloaddition reactions16 and as quite reactive
C=N substrates toward various nucleophiles.17 In particu-
lar, we have employed glycosyl nitrones for the synthesis
of C-glycosyl amino acids.6a Hence, treatment of com-
pounds 3a,b,d,f. with N-benzylhydroxylamine as
described6a,15 afforded the corresponding N-benzyl ni-
trones 7a,b,d,f in excellent yields (Table). NOE experi-
ments supported the Z-configuration for all these
compounds since they showed a substantial enhancement
in the difference spectra between CH=N and CH2Ph sig-
nals.18
J4,5 = J5,6 = 9.5 Hz, H-5), 3.80 (dd, 1 H, J6,7a = 2.0, J7a,7b = 11.0 Hz,
H-7a), 3.76 (dd, 1 H, J6,7b = 5.5 Hz, H-7b), 3.70 (dd, 1 H, H-4), 3.55
(ddd, 1 H, H-6).
Anal. Calcd for C35H37NO6 (567.67): C, 74.05; H, 6.57; N, 2.47.
Found: C, 74.41; H, 6.60; N, 2.47.
(E)-4a
Colorless syrup; [ ]D +1.2 (c 0.9, CHCl3).
1H NMR: = 7.70 (s, 1 H, OH), 7.55 (d, 1 H, J1,2 = 6.3 Hz, H-1),
7.45–7.15 (m, 20 H, 4 Ph), 4.98, 4.71 (2 d, 2 H, J = 11.8 Hz,
PhCH2), 4.92, 4.58 (2 d, 2 H, J = 10.5 Hz, PhCH2), 4.77, 4.72 (2 d,
2 H, J = 12.0 Hz, PhCH2), 4.67, 4.58 (2 d, 2 H, J = 11.8 Hz,
PhCH2), 4.05 (dd, 1 H, J2,3 = 1.0 Hz, H-2), 4.00 (dd, 1 H, J4,5
5,6 = 9.5 Hz, H-5), 3.96 (dd, 1 H, J3,4 = 2.8 Hz, H-3), 3.82–3.72 (m,
2 H, H-7a, H-7b), 3.69 (dd, 1 H, H-4), 3.55 (ddd, 1 H, J6,7a = 2.5,
6,7b = 4.8 Hz, H-6).
=
J
J
Anal. Calcd for C35H37NO6 (567.67): C, 74.05; H, 6.57; N, 2.47.
Found: C, 74.20; H, 6.58, N, 2.48.
In conclusion, the synthetic utility of anomeric sugar alde-
hydes has been confirmed by their efficient transforma-
tion into highly reactive derivatives such as nitrile oxides
and nitrones, which in turn can be manipulated for the
construction of more complex C-glycoconjugates.
Oxime 4b
Prepared by following the general procedure I using the aldehyde
3b.
Purified by flash chromatography using cyclohexane–EtOAc, 2:1;
White solid; mp 140–142 °C (cyclohexane–EtOAc); [ ]D +6.4 (c
0.9, CHCl3).
1H NMR: = 7.50–7.12 (m, 21 H, 4 Ph, H-1), 4.95, 4.90 (2 d, 2 H,
J = 11.0 Hz, PhCH2), 4.84, 4.56 (2 d, 2 H, J = 11.0 Hz, PhCH2),
4.77, 4.65 (2 d, 2 H, J = 10.5 Hz, PhCH2), 4.63, 4.54 (2 d, 2 H,
J = 12.5 Hz, PhCH2), 3.97 (dd, 1 H, J1,2 = 7.0, J2,3 = 9.5 Hz, H-2),
3.80–3.64 (m, 4 H, H-5, H-6, H-7a, H-7b), 3.56 (dd, 1 H, J3,4 = 9,0
Hz, H-3), 3.52 (ddd, 1 H, J5,6 = 9.5, J6,7a = J6,7b = 3.0 Hz, H-6).
CH2Cl2 was freshly distilled from calcium hydride. MgSO4 and hy-
droxylamine hydrochloride were used as reagent grade (Aldrich).
NBS was crystallized from H2O, dried at 40 °C in vacuo just before
use. N-benzylhydroxylamine,6a and aldehydes 3a–f were synthe-
sized as described. Reactions were monitored by TLC on silica gel
60 F254 with detection by charring with sulfuric acid. Flash column
chromatography was performed on silica gel 60 (230–400 mesh).
Melting points were determined on a Büchi 5110 apparatus. Optical
rotations were measured using a Perkin Elmer Model 214 polarim-
eter at 20 2 °C in the stated solvent; [ ]D values are given in 10–1
degcm2g–1. NMR spectra were recorded for CDCl3 solution at r.t.
unless otherwise specified, using a Varian 300 Unity instrument.
MALDI-TOF mass spectra were acquired using 2,5-dihydroxyben-
zoic acid as the matrix.
Anal. Calcd for C35H37NO6 (567.67): C, 74.05; H, 6.57; N, 2.47.
Found: C, 74.26; H, 6.55, N, 2.48.
Oxime 4c
Prepared by following the general procedure I using the aldehyde
3c.
Purified by flash chromatography using cyclohexane–EtOAc, 3:1;
colorless syrup; [ ]D –0.2 (c 1.7, CHCl3); [ ]D +23.5 (c 1.0, MeOH).
Oximes 4a–f; General Procedure I
To a stirred soln of aldehyde (1.0 mmol) in THF (7.0 mL), was add-
ed a soln of hydroxylamine hydrochloride (0.21 g, 3.0 mmol) in
H2O (6.0 mL). The mixture was cooled (ice-bath) and an aq soln of
Na2CO3 (1.0 mL, 1.0 M) was added dropwise. After the addition
was complete, the reaction mixture was warmed up to r.t., stirred for
additional 1 h, then diluted with H2O (20 mL), and extracted with
EtOAc (3 15 mL). The combined organic portions were dried
(Na2SO4) and concentrated. The crude oximes were purified by
flash chromatography.
1H NMR: = 7.50–7.20 (m, 21 H, 4 Ph, H-1), 4.97, 4.64 (2 d, 2 H,
J = 11.5 Hz, PhCH2), 4.86, 4.66 (2 d, 2 H, J = 10.8 Hz, PhCH2),
4.79, 4.74 (2 d, 2 H, J = 11.2 Hz, PhCH2), 4.50, 4.42 (2 d, 2 H,
J = 12.0 Hz, PhCH2), 4.02 (dd, 1 H, J4,5 = 2.5, J5,6 = 0.5 Hz, H-5),
4.01–3.90 (m, 2 H, H-2, H-3), 3.70–3.52 (m, 4 H, H-4, H-6, H-7a,
H-7b).
Anal. Calcd for C35H37NO6 (567.67): C, 74.05; H, 6.57; N, 2.47.
Found: C, 73.88; H, 6.55, N, 2.47.
Oxime 4d
Oxime 4a
Prepared by following the general procedure I using the aldehyde
3d.
Prepared by following the general procedure I, using the aldehyde
3a.
Purified by flash chromatography using cyclohexane–EtOAc, 5:1;
colorless syrup; [ ]D +11.5 (c 0.6, CHCl3).
1H NMR: = 7.50–7.20 (m, 16 H, 3 Ph, H-1), 4.90, 4.60 (2 d, 2 H,
J = 11.5 Hz, PhCH2), 4.78, 4.70 (2 d, 2 H, J = 11.5 Hz, PhCH2),
4.50, 4.42 (2 d, 2 H, J = 12.0 Hz, PhCH2), 4.01 (dd, 1 H, J4,5 = 2.8,
Crude was purified by flash chromatography using cyclohexane–
Et2O, 1:1. Pure samples of each isomer were obtained by flash chro-
matography (cyclohexane–Et2O, 3:1).
(Z)-4a
White solid; mp 141–142 °C (cyclohexane–EtOAc); [ ]D +49.7 (c
0.8, CHCl3).
J5,6 = 0.5 Hz, H-5), 3.98 (dd, 1 H, J2,3 = J3,4 = 10.0 Hz, H-3), 3.75
(dd, 1 H, J1,2 = 6.5 Hz, H-2), 3.64–3.54 (m, 3 H, H-6, H-7a, H-7b),
3.52 (dd, 1 H, H-4).
Synthesis 2002, No. 12, 1701–1706 ISSN 0039-7881 © Thieme Stuttgart · New York

1704
A. Dondoni, P. P. Giovannini
PAPER
Anal. Calcd for C28H30N4O5 (502.56): C, 66.92; H, 6.02; N, 11.15.
Found: C, 67.00; H, 5.97; N, 11.17.
1H NMR (selected data): = 5.01 (d, 1 H, J1,2 = 0.5 Hz, H-1), 4.83,
4.73 (2 d, 2 H, J = 11.8 Hz, PhCH2), 4.68, 4.38 (2 d, 2 H, J = 11.2
Hz, PhCH2), 4.16 (dd, 1 H, J2,3 = 2.5 Hz, H-2), 4.03 (dd, 1 H,
J3 ,4 = J4 ,5 = 9.5 Hz, H-4 ), 3.94 (dd, 1 H, J3,4 = J4,5 = 9.5 Hz, H-4),
3.56 (dd, 1 H, H-3).
Oxime 4e
Prepared by following the general procedure I using the aldehyde
3e.
MALDI–TOF: m/z = 1154.3 (M + Na), 1170.7 (M + K).
Purified the crude oxime by flash chromatography using cyclohex-
ane–EtOAc, 1:1. Pure samples of each isomer were obtained by
flash chromatography (cyclohexane–EtOAc, 4:1).
Anal. Calcd for C70H70N2O12 (1131.31): C, 74.32; H, 6.24; N, 2.48.
Found: C, 74.54; H, 6.23; N, 2.47.
Furoxan 6b
(Z)-4e
Prepared by following the general procedure II using the oxime 4b.
White solid; mp 131–132 °C (cyclohexane–EtOAc); [ ]D +128.3 (c
1.4, CHCl3).
Purified by flash chromatography (cyclohexane–EtOAc, 8:1); col-
orless syrup; [ ]D –11.7 (c 1.2, CHCl3).
1H NMR: = 8.60 (s, 1 H, OH), 6.89 (d, 1 H, J1,2 = 4.0 Hz, H-1),
5.07 (dd, 1 H, J2,3 = 4.0, J3,4 = 6.0 Hz, H-3), 4.81 (dd, 1 H, J4,5 = 3.5
Hz, H-4), 4.66 (dd, 1 H, H-2), 4.46 (ddd, 1 H, J5,6 = 7.2, J6,7a = 6.0,
J6,7b = 5.0 Hz, H-6), 4.14 (dd, 1 H, J7a,7b = 8,5 Hz, H-7a), 4.09 (dd,
1 H, H-7b), 3.59 (dd, 1 H, H-5), 1.48 (s, 6 H, 2 CH3), 1.40, 1.35 (2
s, 6 H, 2 CH3).
1H NMR (selected data): = 4.96, 4.88 (2 d, 2 H, J = 11.0 Hz,
PhCH2), 4.92, 4.90 (2 d, 2 H, J = 11.8 Hz, PhCH2), 4.68, 4.36 (2 d,
2 H, J = 11.2 Hz, PhCH2), 4.63, 4.32 (2 d, 2 H, J = 11.0 Hz,
PhCH2), 3.69 (dd, 1 H, J = 1.8, 4.5 Hz), 3.66 (dd, 1 H, J = 1.8, 5.0
Hz), 3.62–3.53 (m, 2 H).
MALDI–TOF: m/z = 1154.0 (M + Na), 1170.6 (M + K)
Anal. Calcd for C13H21NO6 (287.31): C, 54.35; H, 7.37; N, 4.88.
Found: C, 54.42; H, 7.43; N, 4.91.
Anal. Calcd for C70H70N2O12 (1131.31): C, 74.32; H, 6.24; N, 2.48.
Found: C, 74.48; H, 6.25; N, 2.48.
(E)-4e
White solid; mp 112–113 °C (cyclohexane–EtOAc); [ ]D +42.4 (c
0.9, CHCl3).
Furoxan 6c
Prepared by following the general procedure II using the oxime 4c.
1H NMR: = 7.90 (s, 1 H, OH), 7.52 (d, 1 H, J1,2 = 7.2 Hz, H-1),
4.85 (dd, 1 H, J3,4 = 6.0, J4,5 = 3.2 Hz, H-4), 4.81 (dd, 1 H, J2,3 = 3.5
Hz, H-3), 4.45 (ddd, 1 H, J5,6 = 7.7, J6,7a = 6.0, J6,7b = 4.8 Hz, H-6),
4.15 (dd, 1 H, H-2), 4.15–4.06 (m, 2 H, H-7a, H-7b), 3.60 (dd, 1 H,
H-5), 1.52, 1.47, 1.40,1.35 (4 s, 12 H, 4 CH3).
Purified by flash chromatography (cyclohexane–EtOAc, 4:1); col-
orless syrup; [ ]D +27.5 (c 0.7, CHCl3).
1H NMR (selected data): = 4.42, 4.37 (2 d, 2 H, J = 12.0 Hz,
PhCH2), 4.42, 4.36 (2 d, 2 H, J = 12.0 Hz, PhCH2), 4.30 (dd, 1 H,
J1,2 = J2,3 = 9.5 Hz, H-2), 3.92 (dd, 1 H, J3,4 = 2.5, J4.5 = 0.5 Hz, H-
Anal. Calcd for C13H21NO6 (287.31): C, 54.35; H, 7.37; N, 4.88.
Found: C, 54.50; H, 7.39; N, 4.89.
4), 3.87 (dd, 1 H, J3 ,4 = 2.5, J4 ,5 = 0.5 Hz, H-4 ), 3.40–3.30 (m, 2
H, H-3, H-3 ).
MALDI–TOF: m/z = 1154.6 (M + Na), 1170.5 (M + K).
Oxime 4f
Anal. Calcd for C70H70N2O12 (1131.31): C, 74.32; H, 6.24; N, 2.48.
Found: C, 74.51; H, 6.24; N, 2.49.
Prepared by following the general procedure I using the aldehyde
3f.
Purified by flash chromatography using cyclohexane–EtOAc, 3:1;
colorless syrup.
Furoxan 6d
Prepared by following the general procedure II using the oxime 4d.
Purified by flash chromatography (cyclohexane–EtOAc, 5:1); col-
orless syrup; [ ]D –0.4 (c 0.8, CHCl3); [ ]D +4.2 (c 1.2, EtOAc).
1H NMR (selected data): = 3.90 (dd, 1 H, J3,4 = 2.5, J4,5 = 0.5 Hz,
H-4), 3.82 (dd, 1 H, J3 ,4 = 0.5, J4 ,5 = 2.3 Hz, H-4 ), 3.27 (dd, 1 H,
J2,3 = 9.5 Hz, H-3), 3.19 (dd, 1 H, J2 ,3 = 10.0 Hz, H-3'), 3.57 3.45
(m, 6 H, H-5, H-5 , H-6a, H-6b, H-6a , H-6b ).
(Z)-4f
1H NMR (selected data): = 6.85 (d, 1 H, J1,2 = 5.0 Hz, H-1), 5.32
(dd, 1 H, J2,3 = 1.8 Hz, H-2), 3.76 (dd, 1 H, J5,6a = 2.5 Hz, H-6a).
(E)-4f
1H NMR (C6D6, selected data): = 7.51 (d, 1 H, J1,2 = 7.0 Hz, H-1),
4.94 (dd, 1 H, J2,3 = 5.0 Hz, H-2), 4.39 (dd, 1 H, J5,6a = 4.0,
J6a,6b = 10.5 Hz, H-6a), 3.30 (dd, 1 H, J5,6b = 3.5 Hz, H-6b).
MALDI–TOF: m/z = 1024.6 (M + Na), 1040.6 (M + K).
Anal. Calcd for C56H56N8O10 (1001.09): C, 67.19; H, 5.64; N, 11.19.
Found: C, 67.38; H, 5.62; N, 11.21.
MALDI TOF: m/z = 471.0 (M + Na), 487.1 (M + K).
Anal. Calcd for C27H29NO5 (447.52): C, 72.46; H, 6.53; N, 3.13.
Found: C, 72.67; H, 6.54; N, 3.12.
Furoxan 6e
Prepared by following the general procedure II using the oxime 4e.
Furoxans 6a f; General Procedure II
Purified by flash chromatography (CH2Cl2–EtOAc, 10:1); colorless
syrup; [ ]D +52.8 (c 2.4, CHCl3).
To a stirred soln of oxime (1.0 mmol) in DMF (17.0 mL), was added
NBS (0.2 g, 1.1 mmol). After 30 min, the mixture was cooled (ice-
bath), a soln of Et3N in DMF (1.1 mL, 1.0 M) was added dropwise
within 5 min. The reaction mixture was then stirred for 1 h at r.t.,
concentrated, and the crude furoxan purified by flash chromatogra-
phy.
1H NMR: = 5.16 (dd, 1 H, J1,2 = 3.8, J2,3 = 6.0 Hz, H-2), 4.95 (dd,
1 H, J1 ,2 = 3.8, J2 ,3 = 6.0 Hz, H-2 ), 4.91 (d, 1 H, H-1 ), 4.90 (dd, 1
H, J3 ,4 = 3.5 Hz, H-3 ) 4.86 (dd, 1 H, J3,4 = 3.9 Hz, H-3), 4.64 (d, 1
H, H-1), 4.57 (ddd, 1 H, J4 ,5 = 7.8, J5 ,6a = 5.5, J5 ,6b = 4.5 Hz, H-
5 ), 4.50 (ddd, 1 H, J4,5 = 6.2, J5,6a = 6.5, J5,6b = 5.0 Hz, H-5), 4.20–
4.10 (m, 4 H, H-6a, H-6b, H-6a , H-6b ), 3.76 (dd, 1 H, H-4), 3.61
(dd, 1 H, H-4 ), 1.50 (s, 6 H, 2 CH3), 1.49, 1.47 (2 s, 6 H, 2 CH3),
1.36 (s, 6 H, 2 CH3), 1.34, 1.31 (2 s, 6 H, 2 CH3).
Furoxan 6a
Prepared by following the general procedure II using the oxime 4a.
Flash chromatography (cyclohexane–EtOAc, 3:1); colorless syrup;
[ ]D +7.7 (c 1.1, CHCl3).
MALDI–TOF: m/z = 594.1 (M + Na), 610.0 (M + K).
Synthesis 2002, No. 12, 1701–1706 ISSN 0039-7881 © Thieme Stuttgart · New York

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Formyl C-Glycosides as Precursors to Glycosyl Nitrile Oxides and Nitrones
1705
Anal. Calcd for C26H38N2O12 (570.59): C, 54.73; H, 6.71; N, 4.91.
Found: C, 54.91; H, 6.73; N, 4.90.
1H NMR: = 7.50–7.25 (m, 20 H, 4 Ph), 6.67 (d, 1 H, J1,2 = 7.2 Hz,
H-1), 4.95 (s, 2 H, PhCH2), 4.87, 4.57 (2 d, 2 H, J = 11.5 Hz,
PhCH2), 4.75, 4.70 (2 d, 2 H, J = 11.5 Hz, PhCH2), 4.64 (dd, 1 H,
J2,3 = 10.0 Hz, H-2), 4.47, 4.42 (2 d, 2 H, J = 12.0 Hz, PhCH2), 4.00
(dd, 1 H, J4,5 = 2.5, J5,6 = 0.8 Hz, H-5), 3.82 (dd, 1 H, J3,4 = 10.0 Hz,
H-3), 3.65 (ddd, 1 H, J6,7a = 5.5, J6,7b = 7.5 Hz, H-6), 4.60 (dd, 1 H,
H-4), 3.54 (dd, 1 H, J7a,7b = 7.5 Hz, H-7a), 3.51 (dd, 1 H, H-7b).
Furoxan 6f
Prepared by following the general procedure II using the oxime 4f.
Purified by flash chromatography (cyclohexane–EtOAc, 5:1); col-
orless syrup; [ ]D –14.8 (c 1.7, CHCl3).
Anal. Calcd for C35H36N4O5 (592.68): C, 70.93; H, 6.12; N, 9.45.
Found: C, 70.95; H, 6.12; N, 9.48.
1H NMR (selected data) : = 5.20 (d, 1 H, J1,2 = 5.8 Hz, H-1), 5.16
(d, 1 H, J1 ,2 = 6.2 Hz, H-1 ), 4.34–4.24 (m, 2 H, H-4, H-4 ), 4.60
(dd, 1 H, J2 ,3 = J3 ,4 = 4.8 Hz, H-3 ), 4.20 (dd, 1 H, J2,3 = J3,4 = 5.3
Hz, H-3), 3.60–3.56 (m, 2 H, H-5a, H-5b), 3.53 (dd, 1 H, J4 ,5a = 4.0,
J5a ,5b = 11.0 Hz, H-5a ), 3.47 (dd, 1 H, J4 ,5b = 3.8 Hz, H-5b ).
Nitrone 7f
Prepared by following the general procedure III using the aldehyde
3f.
MALDI–TOF: m/z = 914.0 (M + Na), 931.0 (M + K).
White solid, mp 106–107 °C (MeOH); [ ]D +179.5 (c 0.8, CHCl3).
Anal. Calcd for C54H54N2O10 (891.01): C, 72.79; H, 6.11; N, 3.14.
Found: 72.65; H, 6.10; N, 3.15.
1H NMR: = 7.50–7.20 (m, 20 H, 4 Ph), 6.82 (d, 1 H, J1,2 = 5.3 Hz,
H-1), 5.25 (dd, 1 H, J2,3 = 0.8 Hz, H-2), 4.94, 4.75 (2 d, 2 H,
J = 12.0 Hz, PhCH2), 4.70 (s, 2 H, PhCH2), 4.52, 4.24 (2 d, 2 H,
J = 12.8 Hz, PhCH2), 4.51, 4.44 (2 d, 2 H, J = 11.8 Hz, PhCH2),
4.28 (ddd, 1 H, J4,5 = 9.0, J5,6a = 2.3, J5,6b = 2.8 Hz, H-5), 4.13 (dd,
1 H, J3,4 = 4.8 Hz, H-3), 3.92 (dd, 1 H, H-4), 3.77 (dd, 1 H,
J6a,6b = 10.7 Hz, H-6a), 3.56 (dd, 1 H, H-6b).
Nitrones 7a,b,d,f; General Procedure III
To a soln of aldehyde (1.0 mmol) in CH2Cl2 (15.0 mL), N-benzyl-
hydroxylamine (0.13 g, 1.0 mmol), anhyd MgSO4 (0.12 g, 1.0
mmol) were added. The mixture was stirred at r.t. for 5 h, then fil-
tered, and the solvent was evaporated. The crude nitrones 7a and 7d
were purified by flash chromatography, whereas nitrones 7b and 7f
were purified by crystallization.
Anal. Calcd for C34H35NO5 (537.65): C, 75.95; H, 6.56; N, 2.61.
Found: C, 75.66; H, 6.58; N, 2.60.
Nitrone 7a
3-(2,3,4,6-Tetra-O-benzyl- -d-glucopyranosyl)-4,5-dicarboxy-
methyl-isoxazole (8b)
Prepared by following the general procedure III using the aldehyde
3a.
To a stirred soln of oxime 4 b (0.57 g, 1.0 mmol), dimethyl acety-
lenedicarboxylate (0.71 g, 5.0 mmol) in DMF (17.0 mL) was added
NBS (0.2 g, 1.1 mmol). After 30 min, the mixture was cooled (ice-
bath), a soln of Et3N in DMF (1.1 mL 1.0 M) was added dropwise
within 5 min. The reactionmixture was stirred 1 h at r.t., concentrat-
ed, and the residue was purified by flash chromatography (cyclo-
hexane–EtOAc, 6:1) to afford 8b as a colorless syrup; [ ]D –0.1 (c
1.3, CHCl3); [ ]365 +27.5 (c 1.1, EtOAc).
1H NMR: = 7.40–7.05 (m, 20 H, 4 Ph), 4.98, 4.93 (2 d, 2 H,
J = 10.5 Hz, PhCH2), 4.90, 4.64 (2 d, 2 H, J = 10.8 Hz, PhCH2),
4.74, 4.50 (2 d, 2 H, J = 11.0 Hz, PhCH2), 4.73 (d, 1 H, J1,2 = 9.8
Hz, H-1), 4.57, 4.50 (2 d, 2 H, J = 12.0 Hz, PhCH2), 4.08 (dd, 1 H,
Purified by flash chromatography (cyclohexane–EtOAc, 1:1);
white solid; mp 136–138 °C (cyclohexane–EtOAc); [ ]D +55.6 (c
1.0, CHCl3).
1H NMR: = 7.45–7.12 (m, 25 H, 5 Ph), 6.85 (d, 1 H, J1,2 = 4.8 Hz,
H-1), 4.89, 4.52 (2d, 2 H, J = 10.8 Hz, PhCH2), 4.82, 4.45 (2 d, 2 H,
J = 11.8 Hz, PhCH2), 4.80, 4.74 (2 d, 2 H, J = 13.0 Hz, PhCH2),
4.75, 4.64 (2 d, 2 H, J = 11.8 Hz, PhCH2), 4.62, 4.55 (2 d, 2 H,
J = 12.5 Hz, PhCH2), 4.61 (m, 1 H, H-2), 4.08 (s, 1 H, H-3), 3.90
(dd, 1 H, J4,5 = J5,6 = 9.5 Hz, H-5), 3.78 –3.64 (m, 3 H, H-4, H-7a,
H-7b), 3.54 (ddd, 1 H, J6,7a = 2.0, J6,7b = 5.5 Hz, H-6).
Anal. Calcd for C42H43NO6 (657.79): C, 76.69; H, 6.59; N, 2.13.
Found: C, 76.99; H, 6.40; N, 2.13.
J2,3 = 9.0 Hz, H-2), 4.02 (s, 3 H, CH3), 3.83 (dd, 1 H, J3,4 = 9.0 Hz,
H-3), 3.76 (s, 3 H, CH3), 3.74 (dd, 1 H, J4,5 = 9.5 Hz, H-4), 3.72 (m,
2 H, H-6a, H-6b), 3.60 (ddd, 1 H, J5,6a = J5,6b = 3.0 Hz, H-5).
Nitrone 7b
MALDI–TOF: m/z = 730.4 (M + Na), 746.5 (M + K).
Prepared by following the general procedure III using the aldehyde
3b.
Anal. Calcd for C41H41NO10 (707.76): C, 69.58; H, 5.84; N, 1.98.
Found: C, 69.77; H, 5.82; N, 1.97.
White solid; mp 158–159 °C (cyclohexane –EtOAc); [ ]D +23.5 (c
0.5, CHCl3).
1H NMR: = 7.40–7.08 (m, 25 H, 5 Ph), 6.53 (d, 1 H, J1,2 = 7.2 Hz,
H-1), 4.89, 4.84 (2 d, 2 H, J = 11.0 Hz, PhCH2), 4.86, 4.78 (2 d, 2
H, J = 14.0 Hz, PhCH2), 4.81, 4.51 (2 d, 2H, J = 10.0 Hz, PhCH2)
4.79 (dd, 1 H, J2,3 = 8.0 Hz, H-2), 4.69, 4.46 (2 d, 2 H, J = 11.2 Hz,
PhCH2), 4.62, 4.47 (2 d, 2 H, J = 12.5 Hz, PhCH2), 4.38 (dd, 1 H,
J3,4 = , J4,5 = 8.7 Hz, H-4), 3.74–3.66 (m, 2 H, H-7a, H-7b), 3.53
(ddd, 1 H, J6,7a = J6,7b = 2.5 Hz, H-6), 3.49 (dd, 1 H, H-3).
Acknowledgement
We thank Mr. P. Formaglio (University of Ferrara, Italy) for NMR
measurements. This research was financially supported by the Uni-
versity of Ferrara.
References
Anal. Calcd for C42H43NO6 (592.68): C, 76.69; H, 6.59; N, 2.13.
Found: C, 76.90; H, 6.45; N, 2.11.
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Prepared by following the general procedure III using the aldehyde
3d.
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Purified by flash chromatography (cyclohexane–EtOAc, 3:1); col-
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Synthesis 2002, No. 12, 1701–1706 ISSN 0039-7881 © Thieme Stuttgart · New York

1706
A. Dondoni, P. P. Giovannini
PAPER
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Synthesis 2002, No. 12, 1701–1706 ISSN 0039-7881 © Thieme Stuttgart · New York