Synthesis of protected 2-amino-2-deoxy-D-xylothionolactam derivatives and some aspects of their reactivity

Article abstract of DOI:10.1016/S0008-6215(03)00239-8

The synthesis of polyfunctionalized δ-lactams as key intermediates of glycomimetics in the 2-acetamido-2-deoxy sugar series is presented. Starting from a chiral γ-amino vinylic ester synthesized from Garner's aldehyde and after regioselective reduction, 1

Full text of DOI:10.1016/S0008-6215(03)00239-8

Carbohydrate Research 338 (2003) 1591ꢁ1601
/
www.elsevier.com/locate/carres
Note
Synthesis of protected 2-amino-2-deoxy-D-xylothionolactam
derivatives and some aspects of their reactivity
Laurent Devel,a,1 Louis Hamon,b Hubert Becker,a Annie Thellend,a Anne Vidal-Crosa,*
a Structure et Fonction de Mole´cules Bioactives, Universite´ Pierre et Marie Curie, Tour 44-45, 3e`me e´tage, 4 place Jussieu, F-75252 Paris, France
b Laboratoire de Synthe`se asyme´trique, Universite´ Pierre et Marie Curie, Baˆtiment F, 2e`me e´tage, 8 rue Cuvier, F-75252 Paris, France
Received 27 January 2003; received in revised form 14 April 2003; accepted 13 May 2003
Abstract
The synthesis of polyfunctionalized d-lactams as key intermediates of glycomimetics in the 2-acetamido-2-deoxy sugar series is
presented. Starting from a chiral g-amino vinylic ester synthesized from Garner’s aldehyde and after regioselective reduction, 1-
azido-3-(N-tert-butyloxycarbonyl-2,2-dimethyloxazolidin-4-yl)-2-propene was obtained. Next, a cis-dihydroxylation reaction
provided the protected
D-xylitol and L-arabinitol azides. A simple protection-deprotection sequence, followed by an oxidation
and a reductive cyclization, led to protected 2-amino-d-lactams bearing a tert-butyloxycarbonyl group on the amine functionality.
To explore the reactivity of such compounds, activation of the lactam into the corresponding thionolactam was performed. The
resulting 2-amino-D-xylothionolactam derivative, a versatile intermediate, allowed access to a first generation of protected 2-amino-
D-xylosamidoxime derivatives which are of interest as precursors of N-acetylhexosaminidase and N-acetylglucosaminyltransferase
inhibitors. In this series of compounds, epimerization at C-2 was observed. AM1 calculations performed on these analogs showed
that they adopted a B2,5 conformation and that the axial epimer was favored in the protected series whereas the equatorial epimer
was preferred in the unprotected series.
# 2003 Elsevier Ltd. All rights reserved.
Keywords: Glycomimetics; N-Acetamido-sugar amidoxime; Xylose and arabinose analogs
1. Introduction
derivatives such as 3,10 and neutral8b,11 4 or positively
charged12 5 transition state analogues (Scheme 1).
More recently, imidazole derivatives13 like 6 have
proved to be good mechanistic probes by bringing out
information concerning the direction of protonation in
the active site.7a,14
Concerning glycosyltransferases inhibitors, various
structures have recently emerged15 and compounds
such as 2 and 3 have been used as basic scaffolds to
generate selective and efficient inhibitors.
Due to their implication in a number of biological and
pathological processes,1 glycosidases and glycosyltrans-
ferases have raised increasing interest.2,3 Recent emer-
gence of glycosyltransferase three dimensional
structures4 stressed mechanistic similarities between
both types of enzymes and strengthened the hypothesis
that they shared a common oxocarbenium ion-like
transition state.3a,4a,4c,5,6
The quest for glycosidase inhibitors has provided a
wide variety of structures7 such as piperidinols like 1-
deoxynojirimycin 18and isofagomine 2,9 or pyrrolidinol
Compared to the wide variety of structures in the
glucose, mannose, galactose and even fucose series,
fewer examples of glycomimetics bearing an acetamido
function at C-2 position have been described.16 Yet,
such derivatives could be of interest considering the key
role of enzymes such as N-acetylhexosaminidases17a or
N-acetylglucosaminyltransferases.17b d-Lactams have
already proved their potentiality in the glucose, galac-
tose and mannose series, giving access to piperidi-
nol,8,11b imidazole14 or glycoamidoxime12 derivatives.
* Corresponding author. Tel.: ꢀ
144-277650.
E-mail address: vidalc@ccr.jussieu.fr (A. Vidal-Cros).
/
33-144-275159; fax: ꢀ33-
/
1
Present address: De´partement d’Inge´nierie et d’Etude des
Prote´ines, CEA-Direction des Sciences du Vivant, Centre de
Etudes de Saclay, F-91191 Gif/Yvette Cedex, France.
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00239-8

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L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ1601
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which was then reacted with sodium azide to give the
allylic azide 9 in 76% yield. A subsequent cis-dihydrox-
ylation reaction was carried out using osmium tetroxide
in catalytic amount.25 Diastereoisomers 10a (major) and
10b were obtained in a low diastereoisomeric excess (de
10%). The reaction was then conducted in presence of
chiral ligands using mixtures such as Admix-a and
Admix-b.26 In the presence of hydroquinidine 1,4-
phtalazinediyl diether (DHQD)2PHAL, the diol diater-
eoisomer 10b was isolated with a 80% diastereoisomeric
excess. In return, with hydroquinine 1,4-phtalazinediyl
diether (DHQ)2PHAL, no enhancement in favor of 10a
was observed as the diastereoisomeric excess of 10%
Scheme 1.
remained unchanged. To explain this result, a matchꢁ
/
mismatch effect27 in favor of 10b may be considered.
Thus the dihydroxylation was conducted without a
chiral ligand.
The use of this functionality remains little explored in
the case of 2-acetamido analogs as evidenced by a
paucity of reports in the literature.18 In the present
work, we report the synthesis of polyfunctionalized 2-
acetamido-2-deoxy-d-lactams in their protected form as
precursors of glycomimetics in the N-acetyl series. From
The relative configuration of the newly formed
stereogenic centers in 10a and 10b was attributed after
their cyclization into the bicyclic compounds 11a and
11b upon addition of sodium hydride (Scheme 3). In this
rigidified system, the relative configurations of the three
contiguous asymmetric centers could be established by
Garner’s synthon,19,20 the synthesis of
D-xylonolactams
is described as well as the stability of such derivatives
toward epimerization.
measuring the H-2ꢁ
/
H-3 and H-3ꢁH-4 coupling con-
/
stants (J2, 3 and J3, 4 1.5 Hz for 11a and J2, 3 6 Hz and J3,
9 Hz, for 11b).
2. Results and discussion
4
The xylitol derivative 10a, which has the correct
configuration for the construction of the D-xylonolac-
The unsaturated ester 7, obtained by homologation of
Garner’s aldehyde, was reduced to the allylic alcohol 8
(Scheme 2).
The reduction of a g-aminovinylic ester such as 7 has
been previously described in the literature22 by using
diisobutylaluminum hydride (DIBAL-H) in dichloro-
tam skeleton, was further transformed into the corre-
sponding di-O-benzyl derivative 12a (Scheme 4). In
order to prevent the aforementioned cyclization reac-
tion, benzyl bromide was added prior to the addition of
methane at ꢂ70 8C. When these conditions were
/
applied, a mixture of starting material, saturated
aldehyde and allylic alcohol was obtained in a 55%
yield. Nevertheless, the allylic alcohol 8 was obtained
with an excellent yield (93%) by performing the reaction
at 0 8C in tetrahydrofuran23 avoiding the conjugated
reduction. One-step methods24 to introduce the azido
function proved to be unfruitful. Therefore, the alcohol
function was activated as the corresponding mesylate
Scheme 3.
Scheme 2.

L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ
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1593
Scheme 4.
sodium hydride. Next, the oxazolidine ring was sub-
jected to acid-catalysed opening,28 thus unmasking the
primary hydroxyl function.
The two diastereoisomers 16a and 16a? were nicely
separated by crystallization. As they did not diffract
properly, the structure of 16a? was further confirmed by
Several reaction conditions were tested for the oxida-
tion of 13a, including treatment with pyridinium
dichromate (PDC)29 or ruthenium tetraoxide.30 The
highest yield was obtained by using the 2,2,6,6-tetra-
methyl-1-piperidinyloxy radical (TEMPO reagent)31 in
catalytic amount. The resulting carboxylic acid was
directly esterified with freshly prepared diazomethane to
give the azido ester 14a in a good yield (75%).
Regioselective reduction of the azide function was
achieved by hydrogenation in the presence of Lindlar’s
catalyst,32 leading to 15a in 85% yield.
Activation of d-lactam carbonyl functions into their
corresponding thionocarbonyl derivatives has been pre-
viously achieved for glycomimetics by transforming the
amido functionality into thioamide. This method has
notably been employed to synthesize various glycoami-
dines and glycoamidoximes.12,33 To have access to the
protected 2-acetamido-xylothionolactam 17a (see
Scheme 7), we chose to maintain the carbamate and
introduce the acetamido group at a later stage of the
synthesis. Lactam 15a was first treated with the Law-
esson’s reagent34 in the presence of pyridine at reflux in
toluene. Under these conditions, transformation of the
lactam into the thionolactam did not give the expected
product 16a35 but was accompanied by epimerization at
C-2, leading to the thionolactam derivative 16a? as the
only product. The epimerization reaction was partially
avoided by carrying out the reaction at room tempera-
ture and in the absence of base. The expected thiono-
lactam 16a was thus obtained as the major product (81%
yield) with a small proportion of the C-2 epimer 16a?
(Scheme 5).
the preparation of its enantiomer 16b from the
L-
arabino diol 10b following a parallel reaction sequence
(Scheme 6). When the thionylation reaction was applied
to the
L-arabino derivative 15b, the epimerization
reaction was not observed, and the corresponding
thionolactam 16b was isolated in 56% yield.
Thionolactam 16b was crystallized, and its structure
was resolved by single-crystal X-ray diffraction analysis.
The relative configuration of the three contiguous
centers was confirmed from this structure (Fig. 1).
Attempts to cleave the carbamate group in 16a using
TFA followed by acetylation of the resulting amine led
to a complex mixture, from which the expected N-
acetylxylothionolactam derivative 17a could not be
isolated. Considering furthermore the observed epimeric
instability of 16a, it appeared necessary to find milder
conditions to convert the carbamate group into the
acetamido group. Compound 17a could be obtained
after treatment of 16a with TBDMSOTf in the presence
of 2,6-lutidine following the method reported by Ohfune
and coworkers36 and further reaction with a fluoride-ion
donor in presence of methanol and acetic anhydride
(Scheme 7).
The moderate yield (43%) of this reaction was
balanced by the ease to isolate the product directly by
precipitation and recrystallization. However the N-
acetylxylothionolactam (17a) turned out to be unstable
and partial epimerization took place. Thus, pure 17a
was engaged rapidly in the next step and was converted
into amidoxime 18a in basic medium upon reaction with
hydroxylamine. To limit the epimerization at the C-2
leading to 18a?, the best conditions were the use of
Scheme 5.

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L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ1601
/
Scheme 6.
cesium carbonate as a base in dimethylformamide. In
that case, a 4:1 ratio in favor of the expected N-
acetylxylosamidoxime derivative 18a was obtained.
As partial epimerization at C-2 limits the access to the
desired
D-xylo series, calculations using AM1 method
were achieved on the lactam and thionolactam deriva-
tives. From the results obtained (data not shown), the
epimerization can be rationalized by two main factors.
First, steric hindrance due to bulky protecting groups
and second, an increase of the a-proton acidity for the
thionolactam derivatives. Indeed, the concurrent pre-
sence of bulky protecting groups on the amine and the
hydroxyl functions shifts the equilibrium toward the
axial epimer. By contrast, when the hydroxyl groups are
unprotected, the equatorial epimer always displayed a
higher stability whatever the C-2 nitrogen substituent
may be. The greater stability (6.2 kcal/mol) for the
equatorial epimer was also attributed to a favorable
hydrogen bonding between the C-3 hydroxyl group and
the carbonyl of the carbamate or the acetamido group.
A conformational effect was ruled out as the preferred
conformation was found to be a boat conformation
(B2,5) for both the protected and unprotected com-
pounds. As expected, the thionolactam derivatives were
Fig. 1. ORTEP view of 16b.
Scheme 7.

L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ
/1601
1595
more susceptible to epimerization and the presence of
the 2-acetamido group had an additional effect on the
enhancement of the a-proton acidity. This result was in
agreement with our experimental observations, as 17a
was rather unstable and proned to epimerization.
4.2. 3-(N-tert-Butyloxycarbonyl-2,2-dimethyloxazolidin-
4-yl)-prop-2-en-1-ol (8)
In a three-necked flask, the unsaturated ester 7 (11.3 g,
37.7 mmol) was dissolved in dry THF (100 mL). The
reaction mixture was cooled to 0 8C and DIBAL-H (89
mL, 89 mmol, 1 M soln in THF) was added dropwise.
After 1.5 h at 0 8C, the mixture was poured in cold
MeOH (100 mL). After a few min, a saturated soln of
sodium potassium tartrate (100 mL), water (150 mL)
and EtOAc (150 mL) were successively added and
stirred overnight. The aq layer was then extracted with
3. Conclusion
A synthetic route allowing access to polyfunctionalized
lactam glycomimetics was developed. An example of
activation of the pseudo-anomeric position in 2-amino
series was also described allowing access to O-protected
N-acetylxylosamidoximes.
The main problem we had to face was the epimeric
instability at the C-2 position. It clearly appears that the
nature of protecting groups on the amino group and on
the two hydroxyl functions drastically influence this side
reaction. Tuning the nature of these protecting groups
might therefore limit this epimerization reaction. Work
is in progress to explore such a difference in reactivity.
EtOAc (3ꢃ100 mL), and the organic phase washed
/
with brine (250 mL), dried (MgSO4) and concentrated.
The pale-yellow oil was purified by chromatography
(3:7 EtOAcꢁ
93%). Rf 0.30 (3:7 EtOAcꢁ
/
cyclohexane) to give 8 as colorless oil (9 g,
cyclohexane); [a]D25
/
ꢂ
/
13.58 (c
1
0.35, CHCl3); H NMR (400 MHz, CDCl3): d major
rotamer 5.75 (m, 1 H, H-2), 5.66 (dd, 1 H, J3, 4 6.6 Hz,
J2, 3 15.2 Hz, H-3), 4.28 (m, 1 H, H-4), 4.13 (m, 2 H, H-
1), 4.02 (dd, 1 H, J4, 5 6.5 Hz, J5, 5? 8.8 Hz, H-5), 3.72
(dd, 1 H, J4, 5? 1.5 Hz, J
8.8 Hz, H-5?), 2.10 (br s, 1
5, 5?
H, OH), 1.56, 1.49 (2ꢃ s, 6 H, C(CH3)2), 1.46 (s, 9 H,
/
C(CH3)3); minor rotamer 5.75 (m, 1 H, H-2). 5.66 (dd, 1
H, J3, 4 6.6 Hz, J2, 3 15.2 Hz, H-3), 4.40 (m, 1 H, H-4),
4.13 (m, 2 H, H-1), 4.02 (dd, 1 H, J4, 5 6.5 Hz, J5, 5? 8.8
Hz, H-5 ), 3.72 (dd, 1 H, J4, 5 1.5 Hz, J5, 5? 8.8 Hz, H-5?),
4. Experimental
2.44 (br s, 1 H, OH), 1.59, 1.49 (2ꢃ s, 6 H, C(CH3)2),
/
1.41 (s, 9 H, C(CH3)3); 13C NMR (100 MHz, CDCl3): d
major rotamer 150.68 (CO), 129.74 (C-2), 128.32 (C-3),
92.14 (C(CH3)2), 78.88 (C(CH3)3), 66.63 (C-5), 61.17
(C-1), 57.22 (C-4), 26.93 (C(CH3)3), 25.07, 22.11
(C(CH3)2); minor rotamer 150.40 (COBoc), 129.74 (C-
2), 128.68 (C-3), 92.43 (C(CH3)2), 78.13 (C(CH3)3),
66.63 (C-5), 61.17 (C-1), 57.22 (C-4), 26.93 (C(CH3)3),
27.67, 23.29 (C(CH3)2); Anal. Calcd for C13H23NO4: C,
60.68; H, 9.01; N, 5.44. Found: C, 60.53; H, 9.17; N,
5.47.
4.1. General methods
Tetrahydrofuran and diethyl ether were distilled from
˚
sodium benzophenone and kept over 4 A molecular
sieves. Dimethyl sulfoxide, triethylamine, dichloro-
methane and toluene were distilled from CaH2. Dry
N,N-dimethylformamide and other reagents were com-
mercially available from Fluka, Aldrich or Acros.
Anhydrous reactions were performed under argon
atmosphere, and all glassware was flame-dried under a
stream of nitrogen prior to use. The course of the
reactions was monitored by thin-layer chromatography
with E. Merck 60F-250 precoated silica gel (0.2 mm) on
glass. Chromatography was performed with E. Merck
4.3. 1-Azido-3-(N-tert-butyloxycarbonyl-2,2-
dimethyloxazolidin-4-yl)-2-propen (9)
To a soln of alcohol 8 (5 g, 11.46 mmol) in CH2Cl2 (40
mL) was added triethylamine (3.3 mL, 23.9 mmol). The
mixture was cooled to 0 8C and methanesulfonyl chlo-
ride (1.9 mL, 23.9 mmol) was added dropwise. After 15
min, water (15 mL) was added. The aq phase was
Kieselgel-60, 0.040ꢁ
0.063 mm (flash). 1H and 13C NMR
/
spectra were recorded on Brucker DMX-500, ARX-400,
AC-250, AC-200. Chemical shifts are reported in ppm
with residual chloroform, methanol or water as internal
reference. Optical rotations were measured at 21 8C on a
extracted with CH2Cl2 (3ꢃ10 mL). The organic phase
/
Perkinꢁ
/
Elmer 241C polarimeter with sodium (589 nm)
was washed with brine (20 mL), dried (MgSO4) and
concentrated. The yellow oil was taken up in DMF (40
mL) and sodium azide (1.9 g, 30 mmol) was added
rapidly. After stirring 1.5 h at rt, water (40 mL) and
EtOAc (40 mL) were added. After extracting the aq
lamp. Melting points were determined on a Reichert
Heizbank (Kofler) apparatus, and are uncorrected.
Mass spectra were recorded on a NERMAG R30-10
in the CI ionization mode, and ammonia was used as
ionizing gas. Microanalysis was obtained from the
University Pierre et Marie Curie and from CNRS
(Vernaison) laboratories.
phase with EtOAc (3ꢃ30 mL), washing the organic
/
layer with brine (100 mL), and drying (MgSO4), the
solvent was evaporated. The yellow oil was purified by

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L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ1601
/
chromatography (95:5 EtOAcꢁ
pure azide 9 (2.45 g, 76%). Rf 0.30 (95:5 EtOAcꢁ
cyclohexane); [a]D25
26.78 (c 0.88, CHCl3); IR (thin
film): n 2103 (N3), 1690 (CO) cmꢂ1 1H NMR (400
/
cyclohexane) to lead to
Anal. Calcd for C13H24N4O5: C, 49.36; H, 7.65; N,
17.71. Found: C, 49.49; H, 7.77; N, 17.57.
/
ꢂ
/
Compound 10b (1.79 g, 31%); Rf 0.35 (3:7 EtOAcꢁ
/
1
;
cyclohexane); Mp 92 8C; H NMR (400 MHz, CDCl3):
MHz, CDCl3): d major rotamer 5.68 (m, 2 H, H-2, H-3),
4.33 (m, 1 H, H-4), 4.02 (dd, 1 H, J4, 5 6 Hz, J5, 5? 9 Hz,
d ppm 4.58 (br s, 1 H, OH), 4.06 (dd, 1 H, J4, 5 9 Hz , J5,
5? 9 Hz, H-5 ), 3.91 (dd, 1 H, J4, 5? 5 Hz, J5, 5? 9 Hz, H-5?),
3.75 (dd, 1 H, J4, 5? 5 Hz, J4, 5 9 Hz, H-4 ), 3.61 (m, 1 H,
H-2), 3.48 (dd, 1 H, J1, 2 8 Hz, J1, 1? 12 Hz, H-1), 3.28
H-5), 3.74 (m, 2 H, H-1, H-5?), 1.53, 1.41 (2ꢃ s, 6 H,
/
C(CH3)2), 1.37 (s, 9 H, C(CH3)3); minor rotamer 5.77
(m, 2 H, H-2, H-3), 4.46 (m, 1 H, H-4), 4.02 (dd, 1 H, J4,
(dd, 1 H, J2, 3 9 Hz, J3, 4 9 Hz, H-3), 3.21 (dd, 1 H, J1?, 2
Hz, J1, 1? 12 Hz, H-1?), 2.29 (br s, 1 H, OH), 1.49ꢁ1.44,
(2ꢃ
s, 15 H, (C(CH3)3), (C(CH3)2)); 13C NMR (100
5
6 Hz, J5, 5? 9 Hz, H-5), 3.74 (m, 2 H, H-1, H-5?), 1.55,
/
5
1.44 (2ꢃ
/
s, 6 H, C(CH3)2), 1.38 (s, 9 H, C(CH3)3); 13C
/
NMR (100 MHz, CDCl3): d major rotamer 152.11
(CO), 134.38, 125.21 (C-2, C-3), 93.99 (C(CH3)2), 80.69
(C(CH3)3), 68.51 (C-5), 58.83 (C-4), 52.40 (C-1), 29.00
(C(CH3)3), 26.98, 23.89 (C(CH3)2); minor rotamer
152.11 (COBoc), 134.98, 125.21 (C-2, C-3), 94.44
(C(CH3)2), 80.14 (C(CH3)3), 68.51 (C-5), 58.83 (C-4),
52.40 (C-1), 29.00 (C(CH3)3), 27.77, 25.06 (C(CH3)2);
CIMS: m/z 300 [MNH4]ꢀ, 283 [MH]ꢀ; Anal. Calcd for
C13H22N4O3: C, 55.30; H, 7.85; N, 19.84. Found: C,
55.55; H, 7.92; N, 19.68.
MHz, CDCl3): d 155.06 (COBoc), 94.52 (C(CH3)2),
82.43 (C(CH3)3), 72.60 (C-3), 69.12 (C-2), 66.15 (C-5),
59.41 (C-4), 53.02 (C-1), 28.70 (C(CH3)3), 28.03, 24.37
(C(CH3)2); Anal. Calcd for C13H24N4O5: C, 49.36; H,
7.65; N, 17.71. Found: C, 49.38; H, 7.82; N, 17.70.
4.5. 2-Amino-5-azido-2,4-N,O-carbonyl-2,5-dideoxy-
1,2-isopropylidene-D-xylitol (11a) and 4-amino-1-azido-
2,4-N,O-carbonyl-1,4-dideoxy-4,5-isopropylidene-L-
arabinitol (11b)
4.4. 2-Amino-5-azido-2-(N-tert-butyloxycarbonyl)-2,5-
To a soln of diastereoisomers 10a and 10b (1:9, 0.074 g,
0.23 mmol) in DMF (1 mL) was added NaH (60%
dispersion in oil, 0.025 g, 0.62 mmol) by small portions.
The mixture was stirred at rt for 2 h and a soln of 0.1 M
HCl (1 mL) was added. The reaction mixture was
dideoxy-1,2-N,O-isopropylidene-
amino-1-azido-4-(N-tert-butyloxycarbonyl)-1,4-dideoxy-
4,5-N,O-isopropylidene- -arabinitol (10b)
D-xylitol (10a) and 4-
L
To a soln of tert-butanol (21 mL), water (2 mL),
morpholine N-oxide (2.8 g, 23.8 mmol) and OsO4
(0.21 mmol, 2.5% in tert-butanol) in THF, a soln of
azide 9 (6.1 g, 21.6 mmol) in THF (50 mL) was added
and stirred for 24 h at rt. A soln of NaSH (50 mL) and
fluorisil (15 g) were added and the mixture was stirred
for 2 h. After filtration over celite and several washings
with EtOAc, the aq phase was extracted with EtOAc
extracted with EtOAc (3ꢃ2 mL) and the organic layer
was washed with brine (2 mL), dried (MgSO4) and
concentrated. The orange oil was purified by chromato-
/
graphy (2:3 EtOAcꢁ
isolated as a 2:3 mixture (0.021 g, 38%).
Compound 11a Rf 0.30 (2:3 EtOAcꢁ
cyclohexane); 1H
/cyclohexane) and 11a and 11b was
/
NMR (400 MHz, CDCl3, D2O exchange): d 4.35 (ddd, 1
H, J3, 4 1.5 Hz, J4, 5 6 Hz, J4, 5? 6 Hz, H-4), 4.14 (dd, 1 H,
J2, 3 1.5 Hz, J3, 4 1.5 Hz, H-3), 4.11 (dd, 1 H, J1, 2 6 Hz,
(3ꢃ
(100 mL) and dried (MgSO4). After concentration, the
yellow oil was purified by chromatography (3:7 EtOAcꢁ
/30 mL). The organic layer was washed with brine
J
1, 1? 9 Hz, H-1), 4.04 (d, 1 H, J1, 1? 9 Hz, H-1?), 3.85 (dd,
1 H, J2, 3 1.5 Hz, J1, 2 6 Hz, H-2), 3.68 (m, 2 H, H-5, H-
5?), 1.61, 1.57 (2ꢃ s, 6 H, (C(CH3)2)).
Compound 11b Rf 0.30 (2:3 EtOAcꢁ
/
cyclohexane) yielding a white solid (5.14 g, 75%) as a
mixture of 10a and 10b (55:45). The two diastereoi-
somers could be separated by adding warm pentane, 10b
was filtered off and 10a cristallized out at room
temperature.
/
/
cyclohexane); 1H
NMR (400 MHz, CDCl3, D2O exchange): d 4.49 (ddd, 1
H, J1, 2 4 Hz, J1?, 2 6 Hz, J2, 3 6 Hz, H-2), 4.35 (dd, 1 H,
J4, 5 6 Hz, J5, 5? 8.5 Hz, H-5), 4.03 (dd, 1 H, J2, 3 6 Hz, J3,
4 9 Hz, H-3), 3.84 (ddd, 1 H, J3, 4 9 Hz, J4, 5 6 Hz, J4, 5? 9
Hz, H-4), 3.77 (dd, 1 H, J1, 2 4 Hz, J1, 1? 13 Hz, H-1),
Compound 10a (2.33 g, 39%); Rf 0.35 (3:7 EtOAcꢁ
/
cyclohexane); mp 116 8C; [a]D25
ꢂ63.38 (c 1, CHCl3); IR
/
(thin film): n 3303 (OH), 2106 (N3), 1653 (CO) cmꢂ1; 1H
NMR (400 MHz, CDCl3): d 4.88 (br s, 1 H, OH), 4.14
(m, 1 H, H-2), 3.93 (m, 1 H, H-1), 3.80 (m, 1 H, H-1?),
3.61 (m, 2 H, H-3, H-4), 3.44 ( dd, 1 H, J4, 5 8 Hz, J5, 5?
12 Hz, H-5), 3.25 (dd, 1 H, J4, 5? 5 Hz, J5, 5?12 Hz, H-5?),
3.68ꢁ
/
3.63 (m, 2 H, H-5, H-1?), 1.63, 1.57 (2ꢃ s, 6 H,
/
(C(CH3)2)); CIMS: m/z 260 [MNH4]ꢀ, 243 [MH]ꢀ.
4.6. 2-Amino-5-azido-3,4-di-O-benzyl-2-(N-tert-
butyloxycarbonyl)-2,5-dideoxy-1,2-N,O-isopropylidene-
2.75 (br s, 1 H, OH), 1.53, 1.48, 1.45, 1.43 (4ꢃ
/
s, 15 H,
D
-xylitol (12a) and 4-amino-1-azido-2,3-di-O-benzyl-4-
(N-tert-butyloxycarbonyl)-1,4-dideoxy-4,5-N,O-
isopropylidene- -arabinitol (12b)
(C(CH3)3), (C(CH3)2); 13C NMR (100 MHz, CDCl3): d
156.17 (CO), 94.84 (C(CH3)2), 82.55 (C(CH3)3), 74.60
(C-3), 71.24 (C-2), 65.18 (C-5), 60.10 (C-4), 54.52 (C-1),
28.72, 24.61 (C(CH3)3), 27.49, 27.28 (C(CH3)2); CIMS:
L
Benzylbromide (2.6 mL, 22.12 mmol) was added to a
soln of 10a or 10b (1.4 g, 4.42 mmol) in DMF (9
m/z 317 [MH] ꢀ, 278 [MNH4ꢂ56] ꢀ, 261 [MHꢂ
/
/
56]ꢀ;

L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ
/1601
1597
mL).The reaction mixture was cooled to 0 8C and NaH
(0.44 g, 11 mmol, 60% dispersion in oil) was added by
small portions. After 3 h, water (10 mL) and EtOAc (20
mL) were added. The aq phase was extracted with
63.88 (C-5), 59.50 (C-4), 51.30 (C-1), 28.86 (C(CH3)3),
26.35, 23.26 (C(CH3)2).
4.7. 2-Amino-5-azido-3,4-di-O-benzyl-2-(N-tert-
butyloxycarbonyl)-2,5-dideoxy-
amino-1-azido-2,3-di-O-benzyl-4-(N-tert-
butyloxycarbonyl)-1,4-dideoxy-4- -arabinitol (13b)
D-xylitol (13a) and 4-
EtOAc (3ꢃ20 mL) and the organic phase was washed
with brine (20 mL) and dried (MgSO4). After evapora-
tion of solvent, the crude product was purified by
/
L
chromatography (5:95 EtOAcꢁ
pale yellow oil (2.06 g, 94%).
Compound 12a Rf 0.50 (5:95 EtOAcꢁ
[a]2D5
25.48 (c 1, CHCl3); IR (thin film): n 2103 (N3),
1691 (CO), 715 (Ph) cmꢂ1 1H NMR (400 MHz,
CDCl3): d major rotamer 7.40ꢁ7.31 (m, 10 H, 2ꢃ
Ph), 4.69 (m, 4 H, 2ꢃ CH2Ph), 4.34 (m, 2 H, H-1, H-
2), 3.95 (m, 1 H, H-1?), 3.81 (m, 2 H, H-3, H-4), 3.40 (m,
2 H, H-5, H-5?), 1.72, 1.62 (2ꢃ s, 6 H, C(CH3)2), 1.53 (s,
9 H, C(CH3)3)); minor rotamer 7.40ꢁ7.31 (m, 10 H, 2ꢃ
Ph), 4.69 (m, 4 H, 2ꢃ CH2Ph), 4.34 (m, 1 H, H-1), 4.14
/
cyclohexane) to yield a
To a soln of 12a or 12b (2.9 g, 5.84 mmol) in MeOH (20
mL) was added DOWEX resin 50W (Hꢀ) (5 g). The
mixture was stirred at rt for 48 h and filtered. The resin
was abundantly washed with MeOH and CH2Cl2. After
solvent evaporation, the oil was purified by chromato-
/
cyclohexane);
ꢂ
/
;
/
/
graphy (3:7 EtOAcꢁ
alcohol was isolated as a colorless oil (2.0 g, 75%).
Compound 13a (75%) Rf 0.35 (3:7 EtOAcꢁcyclohex-
ane); [a]2D5
21.38 (c 1, CHCl3); IR (thin film): n 2103
(N3), 1702 (CO) cmꢂ1; 1H NMR (400 MHz, CDCl3): d
7.29ꢁ7.18 (m, 10 H, 2ꢃ Ph), 4.91 (d, 1 H, J2, NH 10 Hz,
NH), 4.68, 4.61, 4.56, 4.49 (4ꢃ d, 4 H, Jgem 11 Hz, 2ꢃ
/
cyclohexane) and the primary
/
/
/
ꢂ
/
/
/
/
/
/
(m, 1 H, H-2), 3.95 (m, 1 H, H-1?), 3.40 (m, 2 H, H-5, H-
5?), 1.53 (s, 6 H, C(CH3)2), 1.45 (s, 9 H, C(CH3)3); 13C
NMR (100 MHz, CDCl3): d major rotamer 153.52
/
/
CH2Ph), 3.80 (d, 1 H, J3, 4 7 Hz, H-3), 3.73 (m, 1 H, H-
2), 3.63 (ddd, 1 H, J4, 5 3 Hz, J4, 5? 5.5 Hz, J3, 4 7 Hz, H-
4), 3.52 (dd, 1 H, J1, 2 7.5 Hz, J1, 1? 11 Hz, H-1), 3.42 (dd,
1 H, J4, 5 3 Hz, J5, 5? 13 Hz, H-5), 3.39 (m, 1 H, H-1?),
3.27 (dd, 1 H, J5, 5? 13 Hz, J4, 5? 5.5 Hz, H-5?), 2.62 (br s,
1 H, OH), 1.34 (s, 9 H, (C(CH3)3); 13C NMR (100 MHz,
CDCl3): d 156.46 (CO), 138.20, 128.96, 128.91, 128.75,
(CO), 138.56, 138.26, 128.81, 128.65, 128.25 (2ꢃ
94.38 (C(CH3)2), 80.85 (C(CH3)3), 77.84 , 77.63 (C-3, C-
4), 74.26, 73.77 (2ꢃ CH2Ph), 64.99 (C-1), 57.73 (C-2),
/
Ph) ,
/
52.22 (C-5), 28.78 (C(CH3)3), 27.69, 24.51 (C(CH3)2)
minor rotamer 152.84 (CO), 138.56, 138.26, 128.81,
128.65, 128.25 (2ꢃ
/
Ph), 94.84 (C(CH3)2), 80.63
128.55, 128.41, 128.33 (2ꢃ
(C-4), 77.45 (C-3), 75.45, 73.70 (2ꢃ
1), 52.34 (C-2), 51.53 (C-5), 28.76 (C(CH3)3); CIMS: m/
z 474 [MNH4]ꢀ, 457 [MH]ꢀ, 429 [MHꢂ28]ꢀ, 418
[MNH4ꢂ
56]ꢀ, 401 [MHꢂ56]ꢀ; Anal. Calcd for
/
Ph), 80.38 (C(CH3)3,), 80.00
(C(CH3)3), 78.08, 77.41 (C-3, C-4), 74.26, 73.77 (2ꢃ
/
/
CH2Ph), 63.52 (C-
CH2Ph), 64.99 (C-1), 59.79 (C-2), 52.22 (C-5), 28.78
(C(CH3)3), 27.10, 22.89 (C(CH3)2); CIMS: m/z 514
/
[MNH4]ꢀ, 497 [MH]ꢀ, 469 [MHꢂ
/
28]ꢀ, 458
/
/
[MNH4ꢂ
/
56]ꢀ , 441 [MHꢂ
/
56]ꢀ; Anal. Calcd for
C24H32N4O5: C, 63.14; H, 7.06; N, 12.27. Found: C,
63.16; H, 7.26; N, 12.00.
C27H36N4O5: C, 65.30; H, 7.31; N, 11.28. Found: C,
65.46; H, 7.48; N, 11.08.
Compound 13b Rf 0.30 (3:7 EtOAcꢁ
NMR (400 MHz, CDCl3): d 7.44ꢁ7.32 (m, 10 H, 2ꢃ
Ph) 5.43 (d, 1 H, J2, NH 7 Hz, NH), 4.76ꢁ4.68 (m, 4 H,
2ꢃ CH2Ph), 3.91 (m, 1 H, H-3), 3.78 (m, 3 H, H-2, H-4,
/
cyclohexane); 1H
Compound 12b Rf 0.50 (5:95 EtOAcꢁ
1H NMR (400 MHz, CDCl3): d major rotamer 7.36ꢁ
7.28 (m, 10 H, 2ꢃ Ph), 4.72ꢁ4.46 (m, 4 H, 2ꢃ
/
cyclohexane);
/
/
/
/
/
/
/
/
CH2Ph), 4.21 (m, 1 H, H-5?), 4.17 (m, 1 H, H-3), 3.95
(m, 1 H, H-4), 3.84 (dd, 1 H, J4, 5 7 Hz, J5, 5? 8.5 Hz, H-
5), 3.52 (m, 1 H, H-4), 3.29 (m, 2 H, H-1, H-1?), 1.64,
H-5), 3.66 (m, 1 H, H-5?), 3.50 (m, 2 H, H-1, H-1?), 3.04
(br s, 1 H, OH), 1.49 (s, 9 H, C(CH3)3); 13C NMR (100
MHz, CDCl3): d 156.69 (CO), 137.95, 137.80, 128.99,
1.57 (2ꢃ
minor rotamer 7.36ꢁ
(m, 4 H, 2ꢃ CH2Ph), 4.21 (m, 1 H, H-5?), 3.99 (m, 1 H,
/
s, 6 H, (C(CH3)2), 1.49 (s, 9 H, (C(CH3)3);
128.77, 128.70, 128.55 (2ꢃ
/
CH2Ph), 80.06 (C(CH3)3),
CH2Ph),
63.06 (C-5), 52.63 (C-4), 51.72 (C-1), 28.77 (C(CH3)3).
/
7.28 (m, 10 H, 2ꢃ Ph), 4.72ꢁ4.46
/
/
78.96 (C-2), 77.89 (C-3), 73.95, 73.84 (2ꢃ
/
/
H-4), 3.84 (dd, 1 H, J4, 5 7 Hz, J5, 5? 8.5 Hz, H-5), 3.64
(m, 1 H, H-4), 3.38 (m, 1 H, H-2), 3.20 (m, 2 H, H-1, H-
4.8. 2-Amino-5-azido-3,4-di-O-benzyl-2-(N-tert-
butyloxycarbonyl)-2,5-dideoxy-D-methylxylonate (14a)
and 4-amino-1-azido-4-(N-tert-butyloxycarbonyl)-2,3-di-
O-benzyl-1,4-dideoxy-L-methylarabinonate (14b)
1?), 1.61, 1.53 (2ꢃ s, 6 H, (C(CH3)2), 1.53 (s, 9 H,
/
(C(CH3)3); 13C NMR (100 MHz, CDCl3): d major
rotamer 153.36 (CO), 138.44, 138.09, 128.75, 128.61,
128.57, 128.21 (2ꢃ
/
Ph), 93.97 (C(CH3)2), 80.79
(C(CH3)3), 79.82 (C-2), 78.75 (C-3), 75.43, 73.81 (2ꢃ
/
To a soln of alcohol 13a or 13b (1.8 g, 3.94 mmol) in
acetone (20 mL), were added successively TEMPO (60
mg, 0.4 mmol), potassium bromide (50 mg, 0.4 mmol)
and a 5% soln of NaHCO3 (10 mL). The reaction
mixture was cooled to 0 8C and sodium hypochlorite
(9.7 mL, 157.6 mmol) was added dropwise. After 40
CH2Ph), 63.88 (C-5), 59.50 (C-4), 52.18 (C-1), 28.86
(C(CH3)3), 26.92, 25.28 (C(CH3)2); minor rotamer
153.36 (CO), 138.44, 138.09, 128.75, 128.61, 128.57,
128.21 (2ꢃ
79.82 (C-2), 77.00 (C-3), 75.43 , 73.81 (2ꢃ
/
Ph), 93.97 (C(CH3)2), 80.79 (C(CH3)3),
CH2Ph),
/

1598
L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ1601
/
min, the temperature was raised to rt and EtOAc ( 20
mL) was added. The aq phase was acidified to pH 2 by
Compound 15a Rf 0.3 (EtOAc); Mp 148 8C; [a]H25g
158 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.35ꢁ
7.31 (m, 10 H, 2ꢃ Ph), 6.45 (br s, 1 H, NH), 5.29 (d, 1
H, J2, NH 7 Hz, NH), 4.78, 4.74 (2ꢃ d, 2 H, Jgem 11.7
Hz, CH2Ph), 4.60 (s, 2 H, CH2Ph), 4.21 (dd, 1 H, J2, NH
7 Hz, J2, 3 7 Hz, H-2), 3.82 (m, 2 H, H-3, H-4), 3.55 (d, 1
ꢂ
/
/
using a 6 M HCl soln and extracted with EtOAc (3ꢃ
/
20
/
mL). The organic layer was washed with brine (40 mL),
dried (MgSO4) and concentrated. The orange oil was
taken up with MeOH (20 mL) and an excess of CH2N2
in Et2O was added. After stirring overnight, the reaction
mixture was concentrated and the crude product was
/
H, J5, 5? 13 Hz, H-5), 3.36 (dd, 1 H, J5, 5? 13 Hz, J4, 5?
5
Hz, H-5?), 1.47 (s, 9 H, C(CH3)3); 13C NMR (100 MHz,
CDCl3): d 170.38 (C-1), 156.01 (CO), 138.22, 137.81,
purified by chromatography (1:9 EtOAcꢁ
to yield a colorless oil (1.42 g, 75%).
Compound 14a Rf 0.7 (3:7 EtOAcꢁ
/
cyclohexane)
128.98, 128.79, 128.45, 128.33, 128.21, 128.09 (2ꢃ
80.17 (C(CH3)3), 79.57 (C-3), 75.28 (C-4), 73.16, 71.96
(2ꢃ CH2Ph), 54.61 (C-2), 42.25 (C-5), 28.62 (C(CH3)3);
CIMS: m/z 427 [MH]ꢀ, 371 [MHꢂ56]ꢀ; Anal. Calcd
/
Ph),
/
cyclohexane); [a]D25
1
ꢂ19.78 (c 1, CHCl3); H NMR (400 MHz, CDCl3): d
/
/
7.28ꢁ7.11 (m, 10 H, 2ꢃ Ph), 5.20 (d, 1 H, J2, NH 10 Hz,
/
/
/
NH), 4.56 (m, 3 H, CH2Ph), 4.40 (d, 1 H, Jgem 11.5 Hz,
CH2Ph), 4.37 (dd, 1 H, J2, 3 7.5 Hz, J2, NH 10 Hz, H-2),
4.08 (dd, 1 H, J3, 4 2 Hz, J2, 3 7.5 Hz, H-3), 3.64 (ddd, 1
H, J3, 4 2 Hz, J4, 5 3 Hz, J4, 5? 6 Hz, H-4), 3.56 (s, 3 H,
OCH3), 3.47 (dd, 1 H, J5, 5? 14 Hz, J4, 5 3 Hz, H-5), 3.30
(dd, 1 H, J5, 5? 14 Hz, J4, 5? 6 Hz, H-5?), 1.37 (s, 9 H,
C(CH3)3); 13C NMR (100 MHz, CDCl3): d 171.80 (C-
1), 156.21 (CO), 138.03, 137.87, 128.85, 128.59, 128.41,
for C24H30N2O5: C, 67.59; H, 7.09; N, 6.57. Found: C,
67.54; H, 7.06; N, 6.61.
Compound 15b Rf 0.5 (4:1 EtOAcꢁ
/
cyclohexane); Mp
68 (c 1, CHCl3) and [a]H25g
228 (c 1,
7.17 (m,
Ph) 6.15 (br s, 1 H, NH), 5.34 (d, 1 H, J2, NH
7 Hz, NH), 4.57ꢁ4.40 (m, 5 H, 2ꢃ CH2Ph, H-2), 4.24
89 8C; [a]2D5
ꢂ
/
ꢂ
/
1
CHCl3); H NMR (400 MHz, CDCl3): d 7.37ꢁ
/
10 H, 2ꢃ
/
/
/
(dd, 1 H, J2, 3 3 Hz, J3, 4 3 Hz, H-3), 3.66 (m, 1 H, H-4),
3.49 (ddd, 1 H, J5, 5? 13 Hz, J4, 5 2 Hz, J5, NH 2.5 Hz, H-
5), 3.22 (ddd, 1 H, J5, 5? 13 Hz, J4, 5? 5 Hz, J5?, NH 2.5 Hz,
H-5?), 1.39 (s, 9 H, C(CH3)3); 13C NMR (100 MHz,
CDCl3): d 170.38 (C-1), 155.89 (CO), 137.84, 137.46,
128.33 (2ꢃ
3), 75.09, 73.87 (2ꢃ
(OCH3), 51.43 (C-5), 28.66 (C(CH3)3); CIMS: m/z 502
[MNH4]ꢀ, 485 [MH]ꢀ; 457 [MHꢂ28]ꢀ, 446 [MNH4ꢂ
56]ꢀ, 429 [MHꢂ56]ꢀ.
Compound 14b Rf 0.6 (3:7 EtOAcꢁ
NMR (400 MHz, CDCl3): d 7.41ꢁ7.28 (m, 10 H, 2ꢃ
Ph), 5.77 (d, 1 H, J4, NH 8.5 Hz, NH), 4.76 (dd, 1 H, J3, 4
4.5 Hz, J4, NH 8.5 Hz, H-4), 4.71, 4.69, 4.59, 4.56 (4ꢃ d,
/
Ph), 80.77 (C(CH3)3), 79.88 (C-4), 79.05 (C-
/
CH2Ph), 54.34 (C-2), 52.88
/
/
/
128.66, 128.16, 128.08, 127.99, 127.91 (2ꢃ Ph), 79.76
/
1
/
cyclohexane); H
(C(CH3)3), 75.56 (C-2), 73.48 (CH2Ph), 71.86 (C-4),
71.19 (CH2Ph), 51.97 (C-3) , 43.11 (C-5), 28.54
(C(CH3)3); Anal. Calcd for C24H30N2O5: C, 67.59; H,
7.09; N, 6.57. Found: C, 67.07; H, 7.18; N, 6.56.
/
/
/
4 H, Jgem 11.7 Hz, CH2Ph ), 3.92 (dd, 1 H, J2, 3 4.5 Hz,
J3, 4 4.5 Hz, H-3), 3.75 (s, 3 H, OCH3), 3.70 (m, 1 H, H-
4.10. 2,5-Diamino-3,4-di-O-benzyl-2-N-tert-
butyloxycarbonyl-2,5-dideoxy-D-xylothiono-1,5-lactam
2), 3.52 (m, 2 H, H-1, H-1?), 1.44 (s, 9 H, C(CH3)3); 13
C
NMR (100 MHz, CDCl3): d 171.80 (C-5), 156.69 (CO),
137.95, 137.80, 128.99, 128.77, 128.70, 128.55 (2ꢃ Ph),
80.06 (C(CH3)3), 78.96 (C-2), 77.89 (C-3), 73.95, 73.84
(2ꢃ CH2Ph), 63.06 (C-4), 52.63 (OCH3), 51.72 (C-1),
(16a) and 2,5-diamino-3,4-di-O-benzyl-2-N-tert-
butyloxycarbonyl-2,5-dideoxy-D-arabinothiono-1,5-
lactam (16a?)
/
/
28.77 (C(CH3)3).
To a soln of lactam 15a (1.23 g, 2.88 mmol) in dry THF
(30 mL) was added the Lawesson’s reagent (0.7 g, 1.73
mmol). After stirring at rt for 1 h, the mixture was
concentrated, dissolved in CH2Cl2 (3 mL) and purified
4.9. 2,5-Diamino-3,4-di-O-benzyl-2N-tert-
butyloxycarbonyl-2,5-dideoxy-D-xylono-1,5-lactam (15a)
or 2,5-diamino-3,4-di-O-benzyl-2N-tert-
butyloxycarbonyl-2,5-dideoxy-
L
(15b)
by chromatography (0.1:0.9:9 Et3Nꢁ
/
EtOAcꢁcyclohex-
/
-arabinol-1,5-lactam
ane). After recrystallization from Et2O, 16a and 16a?
were isolated as a white solid (1.03 g, 81%) in a ratio 9:1.
The two epimers were separated by a second recristalli-
zation from hot Et2O.
To a soln of ester 14a (0.83 g, 1.71 mmol) in MeOH (20
mL) was added Pd/Ca(CO3)2 (0.25 g, 25% weight). After
degassing, the mixture was stirred under a hydrogen
atmosphere during 12 h. The reaction mixture was
filtered and washed thoroughly with MeOH. The
solvent was evaporated and 15a was isolated as a white
solid (0.619 g, 85%). The solid was recristallized from
Et2O and pure 15a isolated quantitatively. For 15b, the
procedure as described above was applied except that
Compound 16a Rf 0.25 (0.1:2.9:7 Et3Nꢁ
cyclohexane); Mp 127 8C; [a]D25
348 (c 1, CHCl3); H
NMR (400 MHz, CDCl3): d 8.49 (br s, 1 H, NH), 7.31ꢁ
7.21 (m, 10 H, 2ꢃ Ph), 5.38 (d, 1 H, J2, NH 8 Hz, NH),
4.61, 4.55, 4.48, 4.45 (4ꢃ d, 4 H, Jgem 11.7 Hz, 2ꢃ
/
EtOAcꢁ
/
1
ꢂ
/
/
/
/
/
CH2Ph), 4.40 (dd, 1 H, J2, NH 8 Hz, J2, 3 8 Hz, H-2), 3.84
(m, 1 H, H-3), 3.55 (m, 1 H, H-4), 3.50 (m, 1 H, H-5),
3.38 (ddd, 1 H, J5, 5? 14 Hz, J4, 5? 4 Hz, J5?, NH 4 Hz, H-
5?), 1.39 (s, 9 H, C(CH3)3); 13C NMR (100 MHz,
CDCl3): d 201.89 (C-1), 156.43 (CO), 138.62, 138.23,
15b was recristallized from 1:1 etherꢁ
/
pentane giving a
white solid (0.575 g, 79%).

L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ
/1601
1599
129.29, 129.11, 128.69, 128.65, 128.59 (2ꢃ
(C(CH3)3) 80.56 (C-3), 75.80 (C-4), 73.39, 72.17 (2ꢃ
CH2Ph), 59.65 (C-2), 45.90 (C-5), 28.92 (C(CH3)3);
/
Ph), 80.70
2), 44.52 (C-5), 23.06 (COCH3); CIMS: m/z 402
[MNH4]ꢀ, 385 [MH]ꢀ, 294 [MNH4ꢂ108]ꢀ, 277
[MHꢂ
108]ꢀ.
/
/
/
CIMS: m/z 460 [MNH4]ꢀ, 443 [MH]ꢀ, 387 [MHꢂ
/
56]ꢀ; Anal. Calcd for C24H30N2O4S: C, 65.13; H,
6.83; N, 6.33. Found: C, 65.04; H, 6.86; N, 6.43.
4.13. 2,5-Diamino-3,4-di-O-benzyl-2-N-acetamido-2,5-
dideoxy- -xylosamidoxime (18a) and 2,5-diamino-3,4-di-
D
Compound 16a? Rf 0.35 (0.1:2.9:7 Et3Nꢁ
cyclohexane); Mp 143 8C; [a]D25
58 (c 1, CHCl3); H
NMR (400 MHz, CDCl3): d 7.93 (br s, 1 H, NH) , 7.28ꢁ
7.19 (m, 10 H, 2ꢃ Ph), 5.61 (d, 1 H, J2, NH 6 Hz, NH),
4.59ꢁ4.44 (m, 5 H, 2ꢃ CH2Ph, H-2), 4.16 (dd, 1 H, J2, 3
3 Hz, J3, 4 3 Hz, H-3), 3.79 (m, 1 H, H-4), 3.56 (ddd, 1 H,
5, 5? 14 Hz, J5, NH 3 Hz, J4, 5 4.5 Hz, H-5), 3.28 (ddd, 1
/
EtOAcꢁ
/
O-benzyl-2N-acetamido-2,5-dideoxy-
arabinosamidoxime (18a?)
D-
1
ꢀ
/
/
/
A soln of 17a (0.231 g, 0.6 mmol), hydroxylamine
hydrochloride (0.083 g, 1.2 mmol) and cesium carbonate
(0.391 g, 1.2 mmol) in DMF was stirred at rt for 48 h.
The mixture was then concentrated under diminished
pressure and filtered. The solid was thoroughly washed
with MeOH and the filtrate was concentrated. The
crude product was purified by chromatography (9:1
/
/
J
H, J5, 5? 14 Hz, J5?, NH 3 Hz, J4, 5? 3 Hz, H-5?) 1.39 (s, 9
H, (C(CH3)3); 13C NMR (100 MHz, CDCl3): d
202.61(C-1), 156.07(CO), 138.45, 138.17, 129.25,
128.71, 128.58 (2ꢃ Ph), 80.30 (C(CH3)3), 76.29( C-3),
/
CH2Cl2ꢁ
isolated (0.078 g, 34%) in a 4:1 ratio.
Compound 18a Rf 0.38 (9:1 CH2Cl2ꢁ
NMR (200 MHz, CD2Cl2): d 7.25ꢁ7.18 (m, 10 H, 2ꢃ
Ph), 6.72 (d, 1 H, J2, NH 9 Hz, NH), 4.92 (dd, 1 H, J2, NH
9 Hz, J2, 4.5 Hz, H-2 ), 4.64ꢁ4.47 (m, 4 H, 2ꢃ
/
EtOH) and a mixture of 18a and 18a? was
74.13(CH2Ph), 72.98 (C-4), 72.03 (CH2Ph), 56.62 (C-2),
45.75(C-5), 28.89 (C(CH3)3); Anal. Calcd for
C24H30N2O4S: C, 65.13; H, 6.83; N, 6.33. Found: C,
64.98; H, 7.02; N, 6.19.
/
MeOH); 1H
/
/
/
/
3
4.11. 2,5-Diamino-3,4-di-O-benzyl-2-N-tert-
butyloxycarbonyl-2,5-dideoxy-L-arabinothiono-1,5-
lactam (16b)
CH2Ph), 3.82 (m, 1 H, H-4), 3.76 (m, 1 H, H-3), 3.49
(dd, 1 H, J5, 5? 13 Hz, J4, 5 7 Hz, H-5), 3.36 (dd, 1 H, J5, 5?
13 Hz, J4, 5? 3 Hz, H-5?), 1.84 (s, 3 H, COCH3); 13C
NMR (50 MHz, CD2Cl2): d 170.40 (COCH3), 152.08
(C-1), 138.67, 138.47, 129.31, 129.15, 128.99, 128.77,
Same physical characteristics as (16a?) (0.79 g, 56%).
[a]2D5
78 (c 1, CHCl3). Resolution of the RX structure
was performed at the Centre de Resolution de Struc-
ꢂ
/
128.65, 128.56 (2ꢃ
72.33 (2ꢃ CH2Ph), 47.90 (C-2), 42.22 (C-5), 23.78
(COCH3).
Compound 18a? Rf 0.35 (9:1 CH2Cl2ꢁ
NMR (200 MHz, CD2Cl2): d 7.25ꢁ7.18 (m, 10 H, 2ꢃ
Ph), 6.42 (d, 1 H, J2, NH 8 Hz, NH), 5.15 (dd, 1 H, J2, NH
8 Hz, J2, 3.5 Hz, H-2 ), 4.64ꢁ4.47 (m, 4 H, 2ꢃ
/
Ph), 77.53 (C-3), 75.79 (C-4), 73.00,
/
tures, UPMC, Paris.
/
MeOH); 1H
4.12. 2,5-Diamino-3,4-di-O-benzyl-2-N-acetamido-2,5-
dideoxy-D-xylo-1,5-thionolactam (17a) and 2,5-diamino-
/
/
3,4-di-O-benzyl-2-N-acetamido-2,5-dideoxy-
arabinothiono-1,5-lactam (17a?)
D-
/
/
3
CH2Ph), 4.11 (m, 1 H, H-3), 3.76 (m, 1 H, H-4), 3.46
(dd, 1 H, J5, 5? 13 Hz, J4, 5 2.5 Hz, H-5), 3.29 (d, 1 H, J5,
To a soln of 16a (0.77 g, 1.74 mmol) in anhyd CH2Cl2 (5
mL) were successively added 2,6-lutidine (0.5 mL, 4.35
mmol) and TBDMSOTf (0.88 mL, 3.83 mmol). After
stirring for 2 h at rt, MeOH (3 mL) was added, followed
by acetic anhydride (1.6 mL, 17.4 mmol) and tetra-
butylammonium fluoride (1.9 mL, 1.9 mmol). The soln
was stirred for 1 h and a white precipitate appeared. The
mixture was filtered and the solid recristallized from
EtOAc leading to 17a as a white solid (0.290 g, 43%).
13 Hz, H-5?), 1.93 (s, 3 H, COCH3); 13C NMR (50
MHz, CD2Cl2): d 170.87 (COCH3), 151.84 (C-1),
138.67, 138.47, 129.31, 129.15, 128.99, 128.77, 128.65,
5?
128.56 (2ꢃ
(2ꢃ CH2Ph), 46.75 (C-2), 42.22 (C-5), 23.56 (COCH3);
CIMS: m/z (mixture of the two epimers): 384 [MH],ꢀ
368 [MHꢂ
16]ꢀ, 276 [MHꢂ108].ꢀ
/
Ph), 76.33 (C-3), 73.71 (C-4), 72.73, 71.92
/
/
/
Compound 17a Rf 0.6 (9:1 CH2Cl2ꢁ
NMR (400 MHz, CDCl3): d 8.19 (br s, 1 H, NH)
7.39ꢁ7.34 (m, 10 H, 2ꢃ Ph), 6.28 (d, 1 H, J2, NH 8 Hz,
NHAc), 4.88 (dd, 1 H, J2, 3 5.5 Hz, J2, NH 8 Hz, H-2),
4.65, 4.57, 4.48, 4.42 (4ꢃ d, 4 H, Jgem 11.7 Hz, CH2Ph),
/
MeOH); 1H
4.14. Energy minimization calculations
/
/
The structure of lactams and thionolactams was opti-
mized using AM1 parametrization AMPAL version
2.14. This program runs on RISK 6000 computers at
the CCR Jussieu. All optimizations were carried out
using the BFGS procedure. As all species have an even
number of electrons, the default RHF calculations were
performed. Since the 2.14 version is limited to 59 atoms,
the isopropyl group was used instead of the tert-butyl
group on the 2-amino functionality, in such a way that
/
3.84 (m, 1 H, H-4), 3.64 (m, 1 H, H-3), 3.57 (d, 1 H, J5, 5?
13.2 Hz, H-5), 3.40 (dd, 1 H, J5, 5? 13.2 Hz, J5?, NH 3.5
Hz, H-5?), 1.92 (s, 3 H, COCH3); 13C NMR (100 MHz,
Me2SO d6): d 200.02 (C-1), 169.34 (COCH3), 138.56,
138.34, 128.59, 128.51, 128.07, 127.87 (2ꢃ
/
Ph), 80.71
(C-4), 76.08 (C-3), 71.99 , 70.34 (2ꢃ CH2Ph), 58.85 (C-
/

1600
L. Devel et al. / Carbohydrate Research 338 (2003) 1591ꢁ1601
/
6. Tvaroska, I.; Andre´, I.; Carver, J. P. J. Am. Chem. Soc.
2000, 122, 8762.
the steric interactions of the methyl groups could mimic
those of a tert-butyl group.
7. (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int.
Ed. 1999, 38, 750;
(b) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M.
Chem. Rev. 2002, 102, 515.
5. Supplementary material
8. (a) Paulsen, H.; Sangster, I.; Heyns, K. Chem. Ber. 1967,
100, 802;
Crystallographic data for the structural analysis has
been deposited with the Cambridge Crystallographic
Data Centre, CCDC No. 207472. Copies of this
information may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge, CB2
(b) Inouye, S.; Tsuruoka, T.; Ito, T.; Niida, T. Tetrahe-
dron 1968, 23, 2125.
9. (a) Ichikawa, Y.; Igarashi, Y. Tetrahedron Lett. 1995, 36,
4585;
(b) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J.
Am. Chem. Soc. 1998, 120, 3007;
1EZ, UK (Fax: ꢀ44-1223-336-033; e-mail: depos-
/
it@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk.
(c) Bols, M. Acc. Chem. Res. 1998, 31, 1;
(d) Nishimura, Y.; Shitara, E.; Adachi, H.; Toyoshima,
M.; Nakajima, M.; Okami, Y.; Takeuchi, T. J. Org. Chem.
2000, 65, 2.
Acknowledgements
10. (a) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem.
Res. 1993, 26, 182;
We thank Carine Duhayon (Centre de Re´solution de
Structures, UPMC, Paris) for the resolution of the RX
structure; the Ministe`re de la Recherche et de l’En-
seignement for financing L. DEVEL and the Progamme
Physique et Chimie du Vivant (Centre National de la
Recherche Scientifique) for financial support.
(b) Wang, Y. F.; Takaoka, Y.; Wong, C.-H. Angew.
Chem., Int. Ed. 1994, 33, 1242;
(c) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siudak,
G.; Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 8146;
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T.; Kanie, O.; Wong, C.-H. J. Org. Chem. 1999, 64, 5280.
11. (a) Fleet, G. W. J.; Carpenter, N. C.; Petursson, S.;
Ramsden, N. G. Tetrahedron Lett. 1990, 31, 409;
(b) Hoos, R.; Naughton, A. B.; Vasella, A. Helv. Chim.
Acta 1993, 76, 1802;
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