Solid-phase de novo synthesis of a (±)-2-deoxy-glycoside

Article abstract of DOI:10.1016/j.carres.2010.01.017

The solid-phase synthesis of methyl 2-deoxy-3-O-benzyl-d,l-arabino-hexopyranoside was achieved in a six-step sequence via a de novo strategy based on the hetero-Diels-Alder reaction of a vinyl ether supported on an azalactone-functionalized polystyrene re

Full text of DOI:10.1016/j.carres.2010.01.017

Carbohydrate Research 345 (2010) 844–849
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Solid-phase de novo synthesis of a ( )-2-deoxy-glycoside
*
Céline Lucchesi, Amélie Arboré, Sagrario Pascual, Laurent Fontaine, Christian Maignan, Gilles Dujardin
UCO2M, UMR 6011 CNRS, Université du Maine, Faculté des Sciences, Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The solid-phase synthesis of methyl 2-deoxy-3-O-benzyl-
D,
L
-arabino-hexopyranoside was achieved in a
Received 7 December 2009
Received in revised form 21 January 2010
Accepted 25 January 2010
Available online 1 February 2010
six-step sequence via a de novo strategy based on the hetero-Diels–Alder reaction of a vinyl ether sup-
ported on an azalactone-functionalized polystyrene resin, followed by the functional modification of
the heteroadduct and the final release of the methyl glycoside by acidic solvolysis.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-Deoxy-glycoside
Methodology
Solid-phase synthesis
De novo synthesis
Due to the occurrence of 2-deoxy-glycosides as subunits of
numerous natural products of biological significance, the synthesis
of 2-deoxy-glycosides has become a domain of importance in the
field of carbohydrate chemistry.1 De novo approaches starting from
non-carbohydrate precursors have been successfully employed in
the two last decades for this purpose and are of specific interest,
especially when they allow efficient asymmetric control, such as
methods based on inverse electron demand [4+2] heterocycloaddi-
tion,2 functional modifications of acylfuran-derived pyranones,3
2,3-epoxy-aldehyde allylboration,4 or tungsten-based alkynol
cycloisomerization.5 In the continuous development of carbohy-
drate and oligosaccharide chemistry, solid-phase synthesis has ap-
peared as a very useful technique.6 However, to the best of our
knowledge, no examples of the solid-supported de novo synthesis
of 2-deoxy-glycosides has been reported to date.
Our group has been interested for a long time in the application
of inverse electron demand [4+2] heterocycloadditions to the
asymmetric synthesis of C-, N- and O-glycosides2,7 and in the
development of solid-supported heterocycloaddition processes8
and the use of innovative solid-supports.9 We logically turned
our attention to the applicability on solid-support of the [4+2]-
based de novo approach to 2-deoxy-glycosides, which typically in-
volves the following sequence: (i) cycloaddition of a vinyl ether
with a 4-oxasubstituted oxadiene; (ii) reduction at C-6; (iii) stereo-
controlled hydroboration–oxydation; (iv) acidic solvolysis (Scheme
1). For this purpose, we focused this study on the use of an immo-
bilized dienophile, considering that such a strategy would offer
optimal introduction of diversity at the O-3, O-4 and O-6 positions
of the 2-deoxy-hexose by allowing easy orthogonal protections,
regiocontrolled glycosidations and functional group modifications.
It should be noted that such a solid-supported-dienophile [4+2]
strategy10 had been already applied to the solid phase asymmetric
synthesis of an impressive library of dihydropyrancarboxamides by
Schreiber’s group11 in 2001, but seemed to be never applied to date
in pyranoside or oligosaccharide solid-phase synthesis.
The key parameter to consider in developing the solid support
of the [4+2]-based de novo approach to 2-deoxy-glycosides is the
robustness of the internal linker to the multi-step sequence. In
2003, our group described the synthesis of a solid-supported ad-
duct 1 (Scheme 2) with an internal ester linkage.8c A heteroadduct
such as 1 resulted from the Eu(fod)3-catalyzed heterocycloaddition
between an appropriate 1-oxadiene and a solid-supported vinyl
ether, immobilized on commercial carboxy polystyrene resin by
anchorage of 1,4-butanediol mono vinyl ether under Mitsunobu
conditions. In connection with the present project, to use this so-
lid-supported adduct 1 as a 2-deoxy-glycoside precursor, we
needed first to perform the reduction of the conjugated methyl es-
ter in the presence of the internal ester linkage. Not so surprisingly,
all our attempts to perform such a regioselective reduction were
unsuccessful. We had to reconsider the choice of the support
and/or of the bifunctional vinyl ether precursor to provide a hete-
roadduct (2) possessing a linker that would be stable under the
reducing conditions of the sequence. We report here the results
of this study, leading to a first access to a 2-deoxy-glycoside in
racemic form, and our efforts for improving the yields of the
transformations.
Apart from 1,4-butanediol mono vinyl ether, we selected 3-ami-
nopropyl vinyl ether as another available vinyl ether precursor.
However, our different attempts to acylate 3-aminopropyl vinyl
ether on carboxy polystyrene resin under conditions that respect
the vinyl ether functionality (IBCF, NMM, DCM, rt) led only to weak
* Corresponding author.
E-mail address: gilles.dujardin@univ-lemans.fr (G. Dujardin).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.01.017

C. Lucchesi et al. / Carbohydrate Research 345 (2010) 844–849
845
OPg
O
(ii) Reduction
OPg
OPg
O
(iv) Acidic
cleavage
OPg
O
(iii) Hydroboration-
oxidation
HO
HO
RO2C
OX
(i)
O
O
O
RO2C
O
OH
OH
Scheme 1. The solid-phase [4+2] route to 2-deoxy-glycosides.
OBn
OPg
OPg
?
OH
OH
O
CO2Me
O
O
O
O
CO2Me
O
2
O
O
n
n
X
X
Y
Y
1
2
Scheme 2. The critical choice of the internal linker X–Y.
rates of amidation of the solid-supported carboxylic acid sites
(typically <20%). Alternatively, the immobilization of the O-vinyl-
3-amino-1-propanol was tested on a new acylating resin, the
azlactone-PS-resin 3 (Scheme 3). This acylation is based on the
ring-opening reaction of the supported azlactone functionality
vinyl ethers with arylidene and alkylidene pyruvates,11a those
conditions only led here to the degradation of the latter or both
reactants (Table 1, entries 2–3). The use of tin chloride18 was also
revealed to be incompatible for the reaction of vinyl ether 6 with
diene 7b (Table 1, entry 4). In contrast, good results were obtained
when the cycloaddition was performed in the presence of Siever’s
catalyst (Eu(fod)3) in dichloromethane at reflux (Table 1, entries
6–7). With 20 mol % of this catalyst, the heteroadduct 8 was pro-
duced in high yield (80%) with a good cis stereoselectivity (>13/
1). From this study, we considered Siever’s catalyst Eu(fod)3 as
the optimal candidate for the Lewis acid-catalyzed heterocycload-
dition of the solid-supported vinyl ether 2. We also showed that
reducing conditions using Super hydride™ were efficient to cleanly
transform adduct 8a into the allylic alcohol 9a, without alteration
of the bis-amide internal linker.
We thus investigated the de novo synthesis of an O-glycoside
derivative (Scheme 4) on solid-support. Solid-supported vinyl
ether 4 and oxadiene 7a were thus submitted to the Eu(fod)3-cat-
alyzed conditions previously determined, in dichloromethane at
reflux. The conversion of 4 into 10 was exemplified by IR spectros-
copy (C@O ester, 1731 cmÀ1). The immobilized heteroadduct 10
was then reduced to the allylic alcohol 11 with an excess of LiEt3BH
in THF, as confirmed by the disappearance of the C@O ester bond in
the IR spectrum. Hydroboration of the solid-supported unprotected
dihydropyran 11 was then performed with an excess of BH3ÁMe2S
complex in THF at room temperature. For the subsequent oxidation
of the organoborane intermediates, we selected Kabalka’s proce-
dure,19 using an excess of Me3NO in THF at reflux. After acidic
treatment of the expected tetrahydropyranediol 12 in methanol
at 40 °C, the ( )-methyl glycoside 13 was finally obtained in 10%
with an amine, which provides an N-acyl-a-aminoamide chain
without any by-product release.12 Azlactone supports have been
previously used for immobilization of proteins,13 enzymes,14 and
as nucleophile scavengers.15 The azlactone-PS-resin 3 was pre-
pared by suspension polymerization of styrene, divinylbenzene
and N-(p-vinylbenzyl)-4,4-dimethylazlactone (VBM), under previ-
ously optimized conditions.8 Simple treatment of the resin 3 with
O-vinyl-3-amino-1-propanol in THF at room temperature pro-
duced the supported vinyl ether 4 (Scheme 3). The efficiency of this
acylating procedure was qualitatively attested by HRMAS 1H NMR
(see Supplementary data) and infrared spectroscopy. It was also
confirmed by high-yield preparation under the same conditions
of the model vinyl ether 6 starting from 2-phenyl-4,4-dimethylaz-
lactone 5.
We had first to define the optimal conditions to perform the key
heterocycloaddition, and especially the choice of an appropriate
Lewis acid that would efficiently catalyze the reaction and that
would be compatible with the polyfunctionality of both reactants.
This study was first performed under solution-phase conditions
with the model vinyl ether 6 and the benzyloxy-substituted and
activated oxadiene 7 (Table 1). As previously reported with other
solid-supported vinyl ethers,7 a total absence of reactivity between
6
and heterodiene 7a was observed under simple thermal
conditions (Table 1, entry 1). The chiral copper(II) catalyst
[(PhBOX)Cu(OTf)2], developed by the Evans16 and Jorgensen17
groups, proved to be inefficient when applied to the reaction be-
tween oxadiene 7a and dienophile 6 in THF or diethyl ether.
Although this chiral catalyst was successfully used by Schreiber’s
group for enantioselective heterocycloadditions of solid-supported
overall yield (6 steps from 1) in a 4/1 ratio of the two a/b anomers.
This first de novo synthesis of a 2-deoxy-glycoside on solid-sup-
port (in the racemic series) displays the same stereochemical fea-
tures as in solution-phase: the relative configuration of the C-3,
C-4, C-5 stereogenic centers thus created is stereocontrolled by
syn addition of the borane from the opposite face of the benzyloxy
group.
Other supports delivering unreducible linkers between the
polymer matrix and the vinyl ether moiety were also investigated.
We thus tested the possibility of linking the vinyl ether to the solid
support via an alkyl–aryl ether linkage that would be inert under
the conditions used in the whole solid-phase sequence (Scheme
5). We thus anchored 1,4-butanediol mono vinyl ether to a com-
mercial ‘phenol resin’ under Mitsunobu conditions. A similar se-
H2N
O
O
H
N
O
R
O
(3 equiv.)
R
N
H
O
N
THF, rt
O
3 : R =
4 : R =
6 : R = Ph (92 % yield)
(1.55 mmol/g)
5 : R = Ph
Scheme 3. Preparation of the vinyl ethers 4 and 6.

846
C. Lucchesi et al. / Carbohydrate Research 345 (2010) 844–849
Table 1
Heterocycloaddition study between model vinyl ether 6 and heterodienes 7a–b
7a: Pg = Bn OPg
7b: Pg = t-Bu
OPg
O
O
CO2Me
Conditions
O
R'
O
O
O
H
N
H
N
Ph
Ph
N
H
N
H
O
O
8 : R' = CO2Me
9 : R' = CH2OH
6
(Pg = Bn)
LiEt3BH (4 equiv.), THF,
18 h, rt, > 90% yield
Entry
Catalyst (mol %)
None
[(PhBOX)Cu(OTf)2], 10
[(PhBOX)Cu(OTf)2], 20
SnCl4, 10
Yb(fod)3, 10
Eu(fod)3, 10
Eu(fod)3, 20
7
Solvent, T, time
Conversion
<5%
% Yieldc
cis/transd
1
2
3
4
5
6
7
7a
7a
7a
7b
7a
7a
7a
Toluene, reflux, 72 h
THF, 0 °C, 18 h
THF, rt, 18 h
CH2Cl2, 0 °C, 18 h
CH2Cl2, reflux, 18 h
CH2Cl2, reflux, 18 h
CH2Cl2, reflux, 18 h
—
—
—
—
32
45
80
a
<5%
<5%
<5%
b
a
>95%
>95%
>95%
79/21
79/21
93/7
a
b
c
Degradation of 6.
Degradation of 6 and 7a.
Isolated adduct after column chromatography.
d
cis/trans ratio determined by 1H NMR of the crude product.
OBn
7a
Eu(fod)3
O
H
O
O
R
O
O
N
N
H
N
CH2Cl2
72 h, reflux
H
N
H
O
O
4
10 : R = CO2Me
11 : R = CH2OH
LiEt3BH
THF, 18 h, rt
HCl.MeOH
THF
OBn
OBn
1. BH3.Me2S
THF, 18 h, rt
OH
OH
18 h, 40 ºC
OH
OH
2. Me3NO
THF, 1 h,
reflux
O
O
O
O
MeO
H
N
N
13
H
12
O
10 % overall yield / (6 steps)
Scheme 4. De novo synthesis of methyl 2-deoxy-glycoside 13 using azlactonic solid-support.
quence was then applied to the solid-supported vinyl ether 14,
therefore leading to the target O-methyl glycoside 13, obtained
partially in a debenzylated form (18) but without real improve-
ment of the overall yield. Comparison of the results (Schemes 4
and 5) suggests that the putative sensitivity of the bis-amide linker
to some reducing conditions would not be responsible for the lim-
itation of the overall efficiency of the solid-phase synthesis.
In summary, we have synthesized the methyl 2-deoxy-3-O-ben-
each of the six steps) could be due to some limitation in the last
steps of the solid-phase synthesis (hydroboration–oxidation20
and acidic cleavage). However, this work validates the HDA-based
de novo route to 2-deoxy-glysosides for further developments on
solid-support.
1. Experimental
1.1. General
zyl-D,L-arabino-hexopyranoside 13 in a six-step sequence via a de
novo strategy based on the hetero-Diels–Alder reaction of a vinyl
ether supported on polystyrene resin. The global stereoselectivity
of key-heterocycloaddition step is not affected by the solid-phase
conditions as shown by the synthesis of model adducts. Consider-
ing the successful solution-phase synthesis of the allylic alcohol 9a
(Table 1), the limited overall yield (nearly 70% average yield for
Fine chemicals were purchased from commercial sources and
were used without further purification. Dichloromethane was
distilled over CaCl2 before use. Dry THF was freshly prepared by
distillation over sodium and benzophenone. All reactions on so-
lid-support were performed with an orbital shaking apparatus.

C. Lucchesi et al. / Carbohydrate Research 345 (2010) 844–849
Phenol resin (1.5 mmol/g)
847
HO
OBn
O
O
Eu(fod)3
CH2Cl2
7 d , reflux
OBn
O
DIAD, PPh3, THF
rt, 48 h
O
+
R
O
O
Ps
CO2Me
O
7a
14
15 : R = CO2Me
16 : R = CH2OH
LiAlH4
THF, 18 h, rt
HCl /MeOH,
OBn
OBn
OH
THF
1. BH3.Me2S
THF, 18 h, rt
OH
+
OH
OH
OH
18 h, 40 ºC
2. Me3NO
1 h, reflux
O
O
O
MeO
O
MeO
OH
OH
O
13
18
17
5 % overall yield
/ (6 steps)
8% overall yield
/ (6 steps)
Scheme 5. De novo synthesis of methyl 2-deoxy-glycoside 13 using phenolic solid-support.
Flash column chromatographies were performed on silica gel
(230–400 mesh) with distilled solvents. Analytical thin layer
chromatography (TLC, Silica Gel 60, F254) was performed in the
specified developing solvents and visualized under UV or by heat-
ing after treatment with vanilin/H2SO4 in 95% EtOH. 1H NMR
spectra were taken on a 400 MHz spectrometer using TMS as inter-
nal reference. 13C NMR spectra were obtained on a 100 MHz
spectrometer with the residual CHCl3 signal as internal reference.
High resolution mass spectra were determined on a TOF mass
spectrometer.
1.2.2. N-(2-(3-(Vinyloxy)propylcarbamoyl)propan-2-yl)benzam-
ide 6
Compound 5 (3.2 g, 17 mmol) and the commercially available
3-aminopropyl vinyl ether (1.9 g, 18.7 mmol) were dissolved in
THF (30 mL). The reaction mixture was stirred under argon at room
temperature for 30 min. After THF evaporation under reduced
pressure, the residue was dissolved in dichloromethane and the or-
ganic layer was washed with water. The combined aqueous layers
were extracted with dichloromethane. The combined organic lay-
ers were dried (MgSO4) and dichloromethane was evaporated un-
der reduced pressure. The obtained solid was purified by column
chromatography (silica gel, 1:4 cyclohexane–EtOAc). Compound
6 was obtained as a white solid (4.6 g, 92%). Rf = 0.57 (1:4 cyclohex-
ane–EtOAc); mp 104 °C; 1H NMR (400 MHz, CDCl3) d 1.69 (s, 6H),
1.90 (quint, J = 6.0 Hz, 2H), 3.43 (dt, J = 5.6, 6.1 Hz, 2H), 3.77 (t,
J = 5.8 Hz, 2H), 4.00 (dd, J = 2.1, 6.9 Hz, 1H), 4.17 (dd, J = 2.2,
14.2 Hz, 1H), 6.39 (dd, 1H, J = 6.9, 14.4 Hz, 1H), 7.45 (m, 3H), 7.78
(dd, J = 1.5, 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 25.1, 28.5,
37.8, 57.4, 66.4, 87.0, 127.4, 128.5, 131.6, 134.7, 151.5, 167.0,
174.8; IR (ATR) 3273, 1643, 1537, 1198 cmÀ1. Anal. Calcd for
C16H22N2O3: C, 66.21; H, 7.59; N, 9.66. Found: C, 66.34; H, 7.67;
N, 9.74.
1.2. Model study
1.2.1. 4,4-Dimethyl-2-phenyloxazol-5(4H)-one 5
Methylalanine (13.28 g, 0.129 mol) was dissolved in water
(27 mL) at 0 °C. To this solution were added, dropwise and alterna-
tively, benzoyl chloride (15 mL, 0.129 mol) and the same volume of
10 M aqueous NaOH (15 mL, 10.32 g, 0.258 mol). The reaction mix-
ture was then stirred at room temperature for 3 h. Concentrated
HCl was added. After filtration and trituration of the so-formed
precipitate in diethyl ether, the intermediate N-benzoylmethylala-
nine was isolated as a white solid (20.85 g, 0.101 mol, 78%). Mp
202 °C; 1H NMR (200 MHz, MeOD) d 1.63 (s, 6H), 7.67 (m, 5H);
13C NMR (50 MHz, MeOD) d 25.5, 57.5, 128.5, 129.5, 132.7, 135.7,
169.9, 178.1; IR (ATR) 3348, 1713, 1613, 1537 cmÀ1. Anal. Calcd
for C11H13NO3: C, 63.77; H, 6.28; N, 6.76. Found: C, 63.84; H,
6.54; N, 6.79. A 100 mL reactor was equipped with a mechanical
stirring, a condenser and argon inlet. N-benzoylmethylalanine
(15.01 g, 72.5 mmol) was suspended in acetonitrile (72 mL) under
mechanical stirring (300 rpm). Ethyl chloroformate (7 mL,
72.5 mmol) was added and the reaction mixture was stirred at
room temperature for 30 min. Triethylamine (20 mL, 142.3 mmol)
was then added dropwise at 10 °C. The reaction mixture was stir-
red for 2 h at room temperature and 1 h at 45 °C. After filtration
of triethylamine salts and acetonitrile evaporation, the residue
was extracted two times with pentane (2 Â 40 mL). After pentane
evaporation, compound 5 was obtained as a yellow oil (10.41 g,
76%). Mp 200 °C; 1H NMR (200 MHz, CDCl3) d 1.54 (s, 6H), 7.75
(m, 5H); 13C NMR (50 MHz, CDCl3) d 24.8, 66.0, 126.0, 127.9,
128.9, 132.7, 159.7, 181.2; IR (ATR) 1817, 1651 cmÀ1. Anal. Calcd
for C11H11NO2: C, 69.84; H, 5.82; N, 7.41. Found: C, 69.61; H,
6.01; N, 7.48.
1.2.3. Methyl 2-(3-benzamidopropoxy)-4-(benzyloxy)-3,4-dihy-
dro-2H-pyran-6-carboxylate 8
To a solution of vinyl ether 6 in dichloromethane was added the
diene 7a (1.2 equiv) and then Sievers’ catalyst Eu(fod)3 (0.1–
0.2 equiv) dissolved in dichloromethane, under argon. The reaction
mixture was heated in dichloromethane at reflux until complete
conversion. After evaporation of dichloromethane under reduced
pressure, the orange oily crude product was purified by column
chromatography (silica gel, 1:4 cyclohexane–EtOAc) to afford the
expected compound 8 as a yellow oil. 80% yield. cis/trans ra-
tio = 93:7. Rf = 0.38 (1:4 cyclohexane–EtOAc). 1H NMR (400 MHz,
CDCl3) d cis adduct: 1.67 (s, 3H), 1.71 (s, 3H), 1.92 (m, 2H), 2.03
(ddd, J = 13.8, 6.8 Hz, 1H); 2.18 (ddd, J = 13.8, 6.7, 2.4 Hz, 1H),
3.26 (m, 2H), 3.52 (m, 2H), 3.78 (s, 3H), 4.18 (ddd, J = 6.8, 6.7,
3.3 Hz, 1H), 4.58 (s, 2H), 5.05 (dd, J = 6.8, 2.4 Hz, 1H), 6.10 (d,
J = 3.3 Hz, 1H), 7.04 (t, 1H), 7.36 (m, 9H), 7.77 (dd, J = 8.7, 1.4 Hz,
2H). trans adduct: 6,15 (d, J = 4,4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 24.4, 25.2, 28.6, 33.0, 36.8, 52.5, 57.2, 66.9, 67.2, 70.4,
99.1, 111.2, 127.0 to 128.5, 131.4, 135.0, 137.7, 141.8, 163.2,

848
C. Lucchesi et al. / Carbohydrate Research 345 (2010) 844–849
166.4, 175.2; IR (ATR) 1728, 1651 cmÀ1. Anal. Calcd: C, 65.88; H,
6.67; N, 5.49. Found: C, 64.39; H, 6.74; N, 5.24.
(MgSO4) and concentrated. The resin was successively washed
with THF, MeOH, Et2O and petroleum ether. It was dried under re-
duced pressure for 24 h. The crude compound was purified by col-
umn chromatography (silica gel, 100% EtOAc) to afford the methyl
1.3. Solid-phase synthesis of the methyl 2-deoxy-3-O-benzyl-
D,L
-arabino-hexopyranoside 13 on azlactone resin
glycoside 13 as an oil (2.6 mg, 10% over 6 steps, purity >90%).
ratio = 4:1. Rf = 0.55 (100% EtOAc).
a/b
Major diastereoisomer
a:
1H NMR (400 MHz, CDCl3) d 1.61
1.3.1. Azlactone resin-supported 3-(vinyloxy)propanamide 4
To a suspension of azlactone resin 38 (500 mg, 0.24 mmol/g,
0.12 mmol) in CH2Cl2 under argon was added 3-aminopropyl vinyl
(ddd, J = 13.0, 11.4, 3.6 Hz, 1H, H-2), 2.01 (br s, 1H, OH), 2.29
(ddd, J = 13.0, 4.8, 1.0 Hz, 1H, H-2), 2.51 (br s, 1H, OH), 3.33 (s,
3H, CH3O), 3.39–3.83 (m, 3H, H-3, H-4 and H-5), 3.75 (m, 2H, H-
6), 4.49 (d, J = 11.6 Hz, 1H, CH2Ph), 4.67 (d, J = 11.6 Hz, 1H, CH2Ph),
4.83 (dd, J = 3.6, 1.0 Hz, 1H, H-1), 7.28–7.38 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 34.6 (C-2), 54.7 (CH3O), 62.9 (C-6), 71.1 and
71.2 (C-3 and C-5), 71.5 (C-6), 77.2 (C-4), 98.7 (C-1), 127.7, 128.5,
130.9, 138.2 (C-Ar). Characteristic signal of the minor diastereoiso-
mer: 1H NMR (400 MHz, CDCl3) d 3.50 (s, 3H, CH3O); 4.44 (dd,
J = 10.0, 2.0 Hz, 1H, H-1); 13C NMR (100 MHz, CDCl3) d 100.5 (C-
1). HRMS (CIÀ)[MÀH]+ (C14H19O5): Calcd: 267.1232; Found:
267.1246.
ether (40 lL, 0.36 mmol). The reaction mixture was stirred under
orbital stirring (320 rpm) at room temperature for 18 h. The white
resin was filtered and washed successively with CH2Cl2 and Et2O 4
times and finally with petroleum ether. The white resin 4 was
dried under reduced pressure for 24 h (515 mg). 1H HRMAS NMR
(400 MHz, CDCl3) d (characteristic peaks): 1.90 (–OCH2CH2–),
3.40–3.45 (–CONHCH2–), 3.75–3,80 (–OCH2CH2–), 4.00–4.05
(vinylic H, b-trans), 4.20–4,25 (–vinylic H, b-cis), 6.40–6.50 (vinylic
H, a
); IR (ATR) 3374, 1650, 1630 cmÀ1; Anal. Calcd for quantitative
N-acylation: N, 0.68. Found: N, 0.83.
1.4. Solid-phase synthesis of methyl 2-deoxy-3-O-benzyl-D,L-
1.3.2. Azlactone resin-supported 2-alkoxy-4-(benzyloxy)-3,4-
arabino-hexopyranoside 13 on phenol resin
dihydro-2H-pyran-6-carboxy-lic acid methyl ester 10
To
a suspension of supported vinyl ether 4 (496 mg,
0.115 mmol theor.) in dichloromethane (6 mL) were added methyl
(E)-(benzyloxymethylene)pyruvate 7a (156 mg, 0.48 mmol) and
Eu(fod)3 (30 mg, 0.024 mmol). The suspension was stirred under
orbital stirring (320 rpm) while heated to reflux for 4 days. The re-
sin was filtered and successively washed with CH2Cl2 and Et2O
(four times) then with petroleum ether. The orange resin 10 was
dried under reduced pressure for 24 h (548 mg). IR (ATR) 3342,
1.4.1. Phenol resin-supported 4-(vinyloxy)butyl ether 14
To a suspension of commercial phenol resin (2 g, 1.5 mmol/g,
3 mmol) in dry THF (40 mL) under argon was added triphenylphos-
phine (1.97 g, 7.5 mmol), 4-hydroxybutyl vinyl ether (1.85 mL,
15 mmol) and diisopropyl azodicarboxylate (DIAD) (1.5 mL,
7.5 mmol). The reaction mixture was stirred under orbital stirring
at room temperature for 48 h. The resin was filtered and washed
successively with THF and Et2O three times and then CH2Cl2 and
petroleum ether three times. The pink resin 14 was dried under re-
duced pressure for 24 h (2.20 g). IR (KBr) 3021, 2911, 2844, 1632,
1602 cmÀ1. Owing to the capacity of the phenol resin employed,
the mass evolution (10%) seemed to indicate an incomplete
conversion.
1731, 1650 (large) cmÀ1
.
1.3.3. Azlactone resin-supported 2-alkoxy-4-(benzyloxy)-6-
(hydroxymethyl)-3,4-dihydro-2H-pyran 11
To a suspension of supported adduct 10 (498 mg; 0,104 mmol
theor.) in dry THF (6 mL), cooled to 0 °C, was added dropwise a
solution of LiEt3BH 1 M in THF (1 mL, 1 mmol). Orbital stirring
(320 rpm) was set for 18 h at room temperature. Then a saturated
KHCO3 solution (2 mL) was added. The resin was filtered and suc-
cessively washed with water, CH2Cl2 and Et2O (three times) them
petroleum ether. The yellow resin 11 was dried under reduced
1.4.2. Phenol resin-supported 2-alkoxy-4-(benzyloxy)-3,4-dihy-
dro-2H-pyran-6-carboxylic acid methyl ester 15
To a suspension of supported vinyl ether 14 (500 mg, 0.68 mmol
theor.) in dichloromethane (12 mL) were added methyl (E)-(ben-
zyloxymethylene)pyruvate 7a (440 mg, 2.0 mmol) and the catalyst
Eu(fod)3 (105 mg, 0.10 mmol). The suspension was stirred under
orbital stirring while heated to reflux for 7 days. The resin was fil-
tered and successively washed with CH2Cl2 and Et2O (four times)
then with petroleum ether. The red resin 15 was dried under re-
pressure for 24 h (483 mg). IR (ATR) 3360, 1651 cmÀ1
.
1.3.4. Azlactone resin-supported 2-alkoxy-4-(benzyloxy)-5-
hydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran 12
To a suspension of supported allylic alcohol 11 (450 mg,
0.097 mmol theor.) in dry THF (5 mL), cooled to 0 °C, was added
dropwise a solution of BH3ÁMe2S 2 M in THF (0.20 mL, 0.40 mmol).
The resin was stirred under orbital stirring (320 rpm) for 18 h at
room temperature. Trimethylamine N-oxide (111 mg, 1 mmol)
was added to the suspension, which was then heated to reflux
for 1 h. The resin was filtered and successively washed with THF,
CH2Cl2, Et2O (three times) and petroleum ether. The yellow resin
12 was dried under reduced pressure for 24 h (459 mg). IR (ATR)
duced pressure for 24 h (544 mg). IR (KBr) 1733, 1635, 1601 cmÀ1
.
1.4.3. Phenol resin-supported 2-alkoxy-4-(benzyloxy)-6-(hydr-
oxymethyl)-3,4-dihydro-2H-pyran 16
To a suspension of supported adduct 15 (510 mg; 0,64 mmol
theor.) in dry THF (4 mL), cooled to 0 °C, was added dropwise a
solution of LiAlH4 1 M in THF (1 mL, 1 mmol). Orbital stirring
was set for 1 h at room temperature and the reaction medium
was cooled again to 0 °C for another dropwise addition of a solu-
tion of LiAlH4 1 M in THF (1 mL, 1 mmol) and allowed to stirring
at room temperature for 15 h. Then the mixture was cooled to
0 °C and a saturated Na2SO4 solution (0.5 mL) was added. After
additional stirring at room temperature for 1 h, water (2 mL) was
added and the mixture was filtered. The resulting resin was succes-
sively washed with (i) water and THF, two times alternatively, (ii)
methanol and THF, four times alternatively, (iii) Et2O then petro-
leum ether. During washing with methanol, uplayer salts were re-
moved. The orange resin 16 was dried under reduced pressure for
3400, 1651 cmÀ1
.
1.3.5. Methyl 2-deoxy-3-O-benzyl-D,L-arabino-hexopyranoside
1321
To a suspension of resin 12 (421 mg, 0.089 mmol theor.) in THF
(5 mL), was added a solution of HCl(g) in methanol (3 mL). Orbital
stirring (320 rpm) was set for 24 h at 30 °C. The medium was
hydrolysed with 20 mL of 1/4-saturated KHCO3 aqueous solution.
The reaction mixture was filtered, the beads were washed with
THF and the filtrate volume was reduced under reduced pressure
and extracted with dichloromethane. The organic layer was dried
24 h (590 mg). IR (ATR) 3536, 1643, 1604 cmÀ1
.

C. Lucchesi et al. / Carbohydrate Research 345 (2010) 844–849
849
4010; (d) Zhuang, W.; Thorhauge, J.; Jorgensen, K. A. Chem. Commun. 2000,
459–460; (e) Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jorgensen, K. A. J. Org.
Chem. 2000, 58, 4487–4490.
1.4.4. Phenol resin-supported 2-alkoxy-4-(benzyloxy)-5-hydr-
oxy-6-(hydroxymethyl)-tetrahydro-2H-pyran 17
To a suspension of supported allylic alcohol 16 (275 mg,
0.30 mmol) in dry THF (4 mL), cooled to 0 °C, was added dropwise
a solution of BH3ÁMe2S 2 M in THF (0.60 mL, 1.2 mmol). The resin
was stirred under orbital stirring for 15 h at room temperature. Tri-
methylamine N-oxide (333 mg, 3.0 mmol) was added to the sus-
pension, which was then heated to reflux while for 5 h. The resin
was filtered and successively washed with water and THF (three
times alternatively), then Et2O and petroleum ether. The yellow re-
sin 17 was dried under reduced pressure for 24 h (280 mg). IR
3. (a) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 2771–2774; (b) Guo, H.
B.; O’Doherty, G. A. Org. Lett. 2005, 7, 3921–3924; (c) Guppi, S. R.; Zhou, M. Q.;
O’Doherty, G. A. Org. Lett. 2006, 8, 293–296; (d) Zhou, M. Q.; O’Doherty, G. A.
Org. Lett. 2006, 8, 4339–4342; (e) Zhou, M. Q.; O’Doherty, G. A. J. Org. Chem.
2007, 72, 2485–2493; (f) Zhou, M. Q.; O’Doherty, G. A. Org. Lett. 2008, 10, 2283–
2286; (g) Yu, X. M.; O’Doherty, G. A. Org. Lett. 2008, 10, 4529–4532; (h) Shan, M.
D.; Xing, Y. L.; O’Doherty, G. A. J. Org. Chem. 2009, 74, 5961–5966.
4. Roush, W. R.; Staub, J. A.; Van Nieuwenkze, M. S. J. Org. Chem. 1991, 56, 4487–
4490.
5. (a) McDonald, F. E.; Reddy, K. S.; Diaz, Y. J. Am. Chem. Soc. 2000, 122, 4304–
4309; (b) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001, 40, 3653–
3655.
6. Review: Seeberger, P.; Haase, W. C. Chem. Rev. 2000, 100, 4349–4394.
7. Gaulon, C.; Dhal, R.; Chapin, T.; Maisonneuve, V.; Dujardin, G. J. Org. Chem.
2004, 69, 4192–4202.
8. (a) Leconte, S.; Dujardin, G.; Brown, E. Eur. J. Org. Chem. 2000, 639–643; (b)
Dujardin, G.; Leconte, S.; Coutable, L.; Brown, E. Tetrahedron Lett. 2001, 42,
8849–8852; (c) Arboré, A.; Dujardin, G.; Maignan, C. Eur. J. Org. Chem. 2003,
4118–4120.
9. Lucchesi, C.; Pascual, S.; Jouanneaux, A.; Dujardin, G.; Fontaine, L. J. Polym. Sci.,
Part A: Polym. Chem. 2007, 45, 3677–3686.
10. Reviews: (a) Yli-Kauhaluoma, J. Tetrahedron 2001, 57, 7053–7071; (b) Feliu, L.;
Vera-Luque, P.; Albericio, F.; Alvarez, M. J. Comb. Chem. 2007, 9, 521–565.
11. (a) Stavenger, R. A.; Schreiber, S. L. Angew. Chem., Int. Ed. 2001, 40, 3417–3421;
(b) Kurosu, M.; Porter, J. R.; Foley, M. A. Tetrahedron Lett. 2004, 45, 145–148.
12. Heilmann, S. M.; Rasmussen, J. K.; Krepski, L. R. J. Polym. Sci., Part A: Polym.
Chem. 2001, 39, 3655–3677.
(ATR) 3475, 1601 cmÀ1
.
1.4.5. 2-Deoxy-3-O-benzyl-1-O-methyl-
D
,
L
-arabino-hexopyran-
oside 1321 and 2-deoxy-1-O-methyl-
D,L-arabino-hexopyranoside
18
To a suspension of resin 17 (230 mg, 0.245 mmol theor.) in THF
(5 mL), was added a 3% solution of HCl(g) in methanol (2 mL). Orbi-
tal stirring was set for 15 h at 40 °C. Beads were filtered and
washed with (i) THF and MeOH and (ii) THF and Et2O. The resulting
solution was treated with aqueous saturated K2CO3, reduced under
reduced pressure and then extracted with dichloromethane. The
organic layer was dried (MgSO4) and concentrated. The crude com-
pound was purified by column chromatography (silica gel, 85:15
CH2Cl2/acetone) to afford the methyl glycoside 13 as an oil
13. Fontaine, L.; Lemele, T.; Brosse, J.-C.; Sennyey, G.; Senet, J.-P.; Wattiez, D.
Macromol. Chem. Phys. 2002, 203, 1377–1384.
14. (a) Heilmann, S. M.; Drtina, G. J.; Haddad, L. C.; Rasmussen, J. K.; Gaddam, B. N.;
Liu, J. J.; Fitzsimons, R. T.; Fansler, D. D.; Vyvyan, J. R.; Yang, Y. N.; Beauchamp,
T. J. J. Mol. Catal. B: Enzym. 2004, 30, 33–42; (b) Drtina, G. J.; Haddad, L. C.;
Rasmussen, J. K.; Gaddam, B. N.; Williams, M. G.; Moeller, S. J.; Fitzsimons, R. T.;
Fansler, D. D.; Buhl, T. L.; Yang, Y. N.; Weller, V. A.; Lee, J. M.; Beauchamp, T. J.;
Heilmann, S. M. React. Funct. Polym. 2005, 64, 13–24.
(5 mg, 8% over six steps, purity >90%).
(EtOAc), 0.20 (85:15 CH2Cl2/acetone). The debenzylated methyl
-glycoside 18 was separately obtained in a second fraction
a/b ratio = 5:1. Rf = 0.55
D,L
(2.5 mg, 5% yield).
15. (a) Tripp, J. A.; Stein, J. A.; Svec, F.; Fréchet, J. M. Org. Lett. 2000, 2, 195–198; (b)
Tripp, J. A.; Svec, F.; Fréchet, J. M. J. Comb. Chem. 2001, 3, 216–223; (c)
Guyomard, A.; Fournier, D.; Pascual, S.; Fontaine, L.; Bardeau, J.-F. Eur. Polym. J.
2004, 40, 2343–2348; (d) Fournier, D.; Pascual, S.; Montembault, V.;
Haddleton, D. M.; Fontaine, L. J. Comb. Chem. 2006, 8, 522–530; (e) Lucchesi,
C.; Pascual, S.; Dujardin, G.; Fontaine, L. React. Funct. Polym. 2008, 68, 97–102.
16. Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635–1649.
17. Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 2000, 65,
4487–4497.
18. Martel, A.; Leconte, S.; Dujardin, G.; Brown, E.; Maisonneuve, V.; Retoux, R. Eur.
J. Org. Chem. 2002, 514–520.
19. Kabalka, G. W.; Hedgecock, H. C. J. J. Org. Chem. 1975, 40, 1776–1779.
20. For a rare example of hydroboration–oxidation on solid support, see: Reiser, U.;
Jauch, J. Synlett 2001, 90–92.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.01.017.
References
1. Reviews: (a) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385–8417;
(b) Kirschning, A.; Jesberger, M.; Schoning, K. U. Synthesis 2001, 507–540; (c)
Hou, D.; Lowary, T. L. Carbohydr. Res. 2009, 344, 1911–1940.
2. (a) Schmidt, R. R.; Maier, M. Tetrahedron Lett. 1985, 26, 2065–2068; (b) Schmidt,
R. R.; Frick, W.; Haag-Zeino, B.; Apparao, S. Tetrahedron Lett. 1987, 28, 4045–
4048; (c) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett. 1996, 37, 4007–
21. Yadav, J. S.; Rao, K. V.; Prasad, A. R. Synthesis 2006, 3888–3894.