An expeditious synthesis of N-acetylneuraminic acid α-C-glycosyl derivatives ("α-C-glycosides") from the anomeric acetates

Article abstract of DOI:10.1002/ejoc.200700181

The reductive metallation of the readily available peracetylated derivatives of methyl N-acetylneuraminate 3a and 3b by samarium diiodide without any additive generates the corresponding anomeric samarium(III) organometallics. These intermediates react ef

Full text of DOI:10.1002/ejoc.200700181

FULL PAPER
DOI: 10.1002/ejoc.200700181
An Expeditious Synthesis of N-Acetylneuraminic Acid α-C-Glycosyl
Derivatives (“α-C-Glycosides”) from the Anomeric Acetates
Adeline Malapelle,[a] Anna Coslovi,[a][‡] Gilles Doisneau,[a] and Jean-Marie Beau*[a]
Keywords: Carbohydrates / C-Glycosides / Reductive metallation / Samarium / Sialic acid
The reductive metallation of the readily available peracetyl-
ated derivatives of methyl N-acetylneuraminate 3a and 3b
by samarium diiodide without any additive generates the
corresponding anomeric samarium(III) organometallics.
These intermediates react efficiently with carbonyl com-
pounds under Barbier conditions, providing a fast synthesis
of C-ketosides. The α- and β-acetates are equally effective,
and excellent yields are obtained for coupling with cyclic
ketones. The procedure has been conveniently applied to the
synthesis of a C-ketoside of N-acetylneuraminic acid with an
attached linker, ready to use as a building block in the elabo-
ration of multivalent biological probes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
(e.g., C-disaccharides) rely heavily on reductive samariation
of appropriate anomeric substituents of Neu5Ac. This was
described by Linhardt and co-workers on the anomeric pyr-
idyl sulfone of Neu5Ac derivative 2 (Figure 1),[10] as an ex-
tension of our work on neutral aldoses[11] and 2-acetamido-
2-deoxy sugars.[12]
Introduction
N-Acetylneuraminic acid (Neu5Ac) is the major member
of the sialic acid family, a class of about fifty 2-keto-3-de-
oxy-nonulosonic acids that are important constituents of
oligosaccharides, glycoconjugates, and polysaccharides.[1–3]
Neu5Ac is commonly found as the α-ketosidically linked
terminal sugar on cell surface glycoconjugates. As a result
of this exposed position within glycoconjugates, it is in-
volved in numerous biological phenomena,[2,3] and this sig-
nificant role in physiological processes and diseases has
stimulated synthetic efforts towards the construction of nat-
ural and structurally modified Neu5Ac.[4,5] Molecular
probes containing this important α-linked structural motif,
elaborated for biological research, are, however, vulnerable
to cleavage. In vivo, the α-glycosidic bond of this terminal
residue is cleaved by neuraminidases, while in vitro it is sen-
sitive to very mild acidic conditions. The replacement of the
interglycosidic oxygen atom with a carbon atom provides
carbon-linked analogues that are stable towards degrada-
tion.
Figure 1. Structure of Neu5Ac derivatives.
It was later reported that the anomeric chloride or the
phenyl sulfone could also be used in this procedure without
the need for activation by HMPA.[13] We also showed that
the stable and crystalline 2-pyridyl sulfide of N-acetyl neur-
aminic acid derivative 1 is an excellent precursor of the an-
omeric organometallic species in a samarium-Reformatsky
procedure.[14] These results were anticipated, since re-
duction of an anomeric substituent on this substrate, α to
both an ester and an oxygen atom (Reformatsky-type reac-
tion), is much easier than the same procedure on a func-
tional group α to an oxygen atom alone. Here we report an
even simpler synthesis based on reductive samariation, in
the absence of any additive, of the anomeric acetates 3.[15]
These compounds, easily prepared from Neu5Ac through
high yielding-reactions, are storable intermediates fre-
quently used as starting derivatives in the chemistry of
Neu5Ac.
In spite of the many available methods for the synthesis
of C-glycosides,[6,7] only a few are applicable to the synthe-
sis of simple C-glycosides of Neu5Ac or related ulosonic
acids.[8] Apart from an interesting de novo approach from
-gluconolactone,[9] routes to more complex C-glycosides
[a] Laboratoire de Synthèse de Biomolécules, Institut de Chimie
Moléculaire et des Matériaux associé au CNRS, Université
Paris Sud 11,
91405 Orsay Cedex, France
Fax: +33-6985-3715
E-mail: jmbeau@icmo.u-psud.fr
[‡] Current address: Department of Biochemistry, Biophysics and
Macromolecular Chemistry, University of Trieste,
Via L. Giorgieri 1, 34127 Trieste, Italy
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The possibility of this approach was inferred from Inana- of cesium acetate in acetonitrile at room temperature[22]
ga’s reports on the samarium diiodide-induced α-deoxygen- gave the desired α derivative 3a (74% yield from Neu5Ac).
ation of ester[16] and acetylated carbohydrate lactones
The β-anomer 3b was purified by flash column
(Scheme 1).[17] This procedure was further developed by En- chromatography on silica gel (white, crystalline solid in 74%
holm and co-workers in α-deoxygenation-carbonyl addition yield) from a 1:4 α/β mixture obtained by standard treat-
reactions of benzoylated lactones.[18] In work closely related ment (acetic anhydride in dry pyridine at room temperature
to this, Hanessian and Girard have also achieved efficient overnight) of the methyl ester 4.
and easy anomeric deoxygenation of O-acetylated 2-uloson-
The anomeric configurations of 3a and 3b were readily
ates (Neu5Ac and KDO) with SmI2.[19] For the success of assigned by their NMR spectroscopic data and comparison
all these reactions, however, additives that enhance the re- with known spectroscopic data.
ducing ability of SmI2 were needed: HMPA[16–18] or ethyl-
ene glycol.[19] In the latter reaction, which needed two hours
for completion, the presence of the ethylene glycol was cru-
cial, playing the roles both of a proton source and of an
Separate Reductive Samariation of 3a and 3b
The α-acetate 3a and the β-acetate 3b were each individu-
ally subjected to reductive samariation at room temperature
in the presence of several carbonyl compounds – aldehydes
or ketones – in the absence of any additive. These reactions
were performed under Barbier conditions to provide the de-
sired C-sialosides. On addition of a freshly prepared solu-
tion of samarium diiodide in THF[23] (0.1 ) to a THF
solution of either 3a or 3b (0.33 ) and the carbonyl com-
pound (2 equiv.), decoloration of the blue SmI2 was noted.
This required only 20 min with 3a, while the time needed
for the complete reduction of the axial anomer 3b was
longer, but still less than 2 h. Standard treatment and purifi-
cation over silica gel furnished the C-sialodides in good to
moderate yields depending on the carbonyl partner
(Table 1). All these experiments were performed at room
temperature in the absence of any additive. It was essential
to use a very freshly prepared SmI2/THF solution (from sa-
extra ligand for coordination to the samarium atom.
Scheme 1.
Results and Discussion
To evaluate the individual behavior of each anomeric marium metal and diiodoethane),[23] and the reported re-
acetate – 3a and 3b – in the reductive process better, they sults were obtained with solutions never more than 2 days
were first prepared and tested separately. They were easily old. Experimentally, we found that the best coupling results
obtained by previously described procedures (Scheme 2). were obtained with a SmI2/THF solution prepared on the
The α isomer 3a was selectively prepared via the anomeric same day. The reasons behind this particular behavior are
chloride 5. Overnight treatment of Neu5Ac with an acidic not yet known, though this very precise procedure suggests
methanolic solution provided a quantitative yield of the that an unidentified more active samarium species is present
methyl ester 4,[20] which was converted into the chloride 5 in a fresh solution and disappears with time.
by treatment for 24 h in a 1:1 mixture of acetic acid and
The new products were isolated and fully characterized.
acetyl chloride, saturated at 0 °C with hydrogen chloride.[21] The times needed for the reduction of the acetates were
Overnight treatment of the crude chloride 5 with 1.5 equiv. much longer than those required for the reductive samaria-
Scheme 2. Preparation of Neu5Ac peracetates 3a and 3b. a) MeOH, Dowex H+, room temperature, 24 h; b) HCl, AcOH/AcCl (1:1), room
temperature; c) CsOAc (1.5 equiv.), MeCN, room temperature; 74% from Neu5Ac; d) Ac2O, pyridine, room temperature, overnight (3a/
3b ≈ 1:4 α/β mixture); flash column chromatography on silica gel; 74% of 3b from Neu5Ac.
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Table 1. SmI2-promoted couplings between acetates 3a or 3b and carbonyl compounds.
[a] Yields of the purified compounds after silica gel chromatography. [b] The reduction product 3c (40–44%) was also formed.
tions of the anomeric 2-pyridyl sulfide 1[14] or the 2-pyridyl 3a and 33% yield from 3b, Table 1, Entries 9 and 10), were
sulfone 2[10] (20 min for 3a, 2 h for 3b, compared to less much less efficient, however. The reduction of the carbonyl
than 1 min for 1 or 2). Despite this longer reaction time, partners became the main reaction pathway and the forma-
the yields of products were good and no degradation prod- tion of the reduction product 3c from 3a/3b is believed to
uct (e.g., deacylation products) of the starting material was result from the protonation of the organometallic interme-
ever observed.
diate during the workup procedure. This samarium-Re-
The coupling reaction with cyclopentanone gave the C- formatsky procedure is necessarily conducted under Barbier
sialyl derivative 6 in yields of 97% (from 3a) or 82% (from conditions for successful coupling reactions. Under these
3b) (Table 1, Entries 1 and 2). As expected, and in agree- conditions, the reduction of the carbonyl partner may be-
ment with previously published results, treatment with a come competitive, consequently affecting the efficiency of
symmetric ketone furnished the C-sialoside as a single dia- the coupling process. In the examples given in Table 1, cy-
stereomer with an equatorial orientation of the newly clic ketones and cyclohexanecarbaldehyde gave good results
formed C–C bond (see below). Treatment with 4-tert-butyl- (they were not reduced), but when the carbonyl group of a
cyclohexanone gave the coupling product 7, again in a high substrate became more sensitive to reduction by SmI2 (as
yield and as a single diastereomer (yields of 91% from 3a with n-octanal, Entries 9 and 10), or when the coupling rate
and 83% from 3b, Table 1, Entries 3 and 4). The bulky tert- was too slow (as with pentan-3-one, less “electrophilic” for
butyl group induced total discrimination of the two faces steric reasons; Entries 7 and 8), the coupling yields de-
of the cyclic ketone. Use of cyclohexanecarbaldehyde as the creased. These lower efficiencies, in relation to the same re-
carbonyl partner provided a mixture of two diastereomers actions performed with anomeric 2-pyridyl sulfide 1,[14] il-
8 (selectivity of 1.25:1) in 87% and 83% yields (Table 1, lustrate the limitations of using acetates 3a and 3b as “C-
Entries 5 and 6). Both diastereomers displayed a standard sialyl donors”. In relation to this, the axial isomer 3b was
1
5C2-chair conformation as determined by H NMR analy- systematically less efficient in the coupling procedure than
sis: J3ax,4, J4,5, and J5,6 values of 10.2, 11.8, and 10.5 Hz, the equatorial isomer 3a, probably as a consequence of its
respectively, for one isomer and J3ax,4, J4,5, and J5,6 values slower reduction rate by SmI2.
of 12, 10.5, and 10.5 Hz, respectively, for the other. The
Empirical rules were first used to deduce the α configura-
couplings of the anomeric acetates with pentan-3-one and tions of the C-sialyl derivatives, with regard to Hasegawa’s
1
n-octanal, providing 9 (44% yield from 3a and 26% yield observations on the H NMR spectra of α- and β-O-glyco-
from 3b, Table 1, Entries 7 and 8) and 10 (39% yield from side derivatives. We found that the values for δ(4-H), J7,8
,
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and ∆δH9a–9b (numbering is given in formulae 6–10, Table 1) with toluene and filtered through a pad of silica), the 3a/3b
were in agreement with an equatorial orientation of the new mixture was subjected to the standard reductive samari-
C–C bond. For example, the δ(4-H) values determined for ation conditions in the presence of carbonyl compounds
products 6, 8a, and 8b (after chromatographic separation (Table 3). The same carbonyl compounds (4-tert-butylcy-
of the two isomers of 8) were 4.74, 4.75, and 4.83 ppm, clohexanone and cyclohexanecarbaldehyde) provided re-
respectively. The J7,8 values for the same products were 7.4, sults essentially identical to those obtained above with the
8.1, and 7.8 Hz, respectively, and the ∆δH9a–9b values were separate anomers in a 2 hour reaction, the reduction time
between 0.22 and 0.36 ppm. Experimental evidence for this needed to complete the reaction with the β anomer 3b
stereochemical assignment at C2 of the C-sialosides was ob- (Table 3, Entries 1 and 2). Cyclohexanone (Entry 3), 4-sub-
tained from the values of the 3JC1,H3ax and 3JC1,H3eq hetero- stituted cyclohexanones 16 and 18 (Entries 5 and 6), and
nuclear coupling constants in the corresponding depro- cyclobutanone (Entry 7) were also good substrates, provid-
tected C-ketosides 11, 12a, and 12b (Table 2) obtained by a ing the C-glycosides 14, 17, 19, and 20, respectively, in
standard deacetylation procedure (MeONa/MeOH).
yields of 79–88% (Table 3). Reactions with 16 and 18 were,
however, not selective, providing a 1:1 mixture of dia-
stereomers 17 and 19 that were not separated. For each of
these products (giving a single spot on TLC), 1H NMR
spectra of the two diastereomers were very similar, and only
the values of δCOOMe and δOAc were significantly different.
Reaction in the presence of 1.4 equiv. of cyclohexane-1,4-
dione provided the monocondensation product in 30% iso-
lated yield (Entry 4, Table 3). In sharp contrast with cyclo-
hexanecarbaldehyde, and as noted above with the separate
anomers and n-octanal, low coupling yields were obtained
with the 3-(tert-butyldimethylsilyloxy)propanal 21 or the
galactose-derived aldehyde 23,[24] giving 22 and the C-disac-
charide 24 in 26% and 30% yields, respectively, as 1:1 mix-
tures of two diastereomers.
1
Table 2. Values for the heteronuclear H,13C coupling constants
and formulas of the compounds.
Aldehyde 21 was too reactive towards the reduction by
SmI2 and produced the pinacol byproduct 25 in 53% yield
together with the reduction product 3c (17% yield). Simi-
larly, the sugar-derived aldehyde 23 also furnished the pina-
col product 26 (30%), the reduction product 3c (21%), and
some starting acetates 3a/3b (14%).
This new coupling process was applied to the rapid con-
struction of a C-ketoside that could be used as a stable unit
easy to integrate into various dendrimeric or polymeric
structures. As discussed above, the use of a symmetric 4-
substituted cyclohexanone should provide a high coupling
yield without adding a new stereogenic center. The coupling
reactions with already functionalized 4-hydroxycyclohexa-
none were unfortunately not selective (Entries 5 and 6,
Table 3). This prompted us to elaborate a functional spacer
after the coupling reaction by use of the commercially avail-
able 4-dioxolanocyclohexanone (27; Scheme 3).
Reductive samariation of the acetates 3a and 3b in the
presence of 4-dioxolanocyclohexanone (27, 2 equiv.) fur-
nished 28 as a single stereomer in an isolated 85% yield.
This high-yielding reaction was carried out on a gram scale
with respect to the sialyl substrate. Straightforward depro-
tection of 28 with a HCl/THF solution (5%) at room tem-
perature, followed by acetylation, furnished ketone 15 in an
only moderate yield (54%, Scheme 4). Stereoselective re-
These values indicate a trans-diaxial orientation of the
C-1/C-2 and the C-3/H-3ax bonds and a gauche relationship
between the C-1/C-2 and the C-3/H-3eq bonds, which
clearly demonstrates that reductive samariation in the pres-
ence either of a ketone (e.g., 6) or of an aldehyde (e.g., 8)
selectively furnished the α-C-ketosides. In addition, oxi-
dation of the mixture of the two isomers 8a and 8b, with
PCC in dichloromethane in the presence of molecular
sieves, furnished a single ketone 13 in a 50% yield. This
shows that the two isomers 8a and 8b differ only in the
configuration at the exocyclic asymmetric center. These ste-
reochemical conclusions were extended to all the other
coupling products.
Reductive Samariation of the Mixture of Anomeric
Acetates 3a and 3b
Following these preliminary results on separate anomers ductive opening of the dioxolane ring in 28 was ineffective
3a and 3b, we then considered the use of the more practical with either the Et3SiH/TMSOTf or the NaBH3CN/
crude synthetic mixture of 3a and 3b obtained by peracety- BF3·Et2O systems, but treatment with TMSOTf (1.2 equiv.)
lation of methyl ester 4 with Ac2O in pyridine (Scheme 2), and BH3·Me2S (1.2 equiv.) in dichloromethane at 0 °C for
which contained 3a and 3b in a 1 to 4 ratio. Without any 10 min provided alcohol 29 in 83% yield as a 6:1 mixture
other purification (the reaction mixture was co-evaporated of diastereomers. This selectivity was improved to 20:1 in
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Table 3. SmI2-promoted coupling of acetates 3a and 3b with carbonyl compounds.
[a] Yields for the purified compounds after silica gel chromatography. [b] With 1.4 equiv. of cyclohexane-1,4-dione. [c] Pinacol 25 (53%)
and reduction product 3c (17%) were also formed. [d] Acetates 3a and 3b (14%) were recovered; pinacol 26 (30%) and reduction product
3c (21%) were also formed.
Scheme 3. Coupling reaction with 4-dioxolanocyclohexanone 27.
favor of the equatorial isomer by use of the same reagents
at –78 °C for 4 h, providing a single compound 29 in 91% mide and silver oxide in toluene failed, but the desired al-
yield after flash column chromatography. lylated product 30 was obtained in 62% yield by use of
O-Allylation of the primary alcohol 29 with allyl bro-
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Scheme 4. Selective synthesis of the C-sialoside building block 32.
Scheme 5. Postulated mechanism for the formation of the samarium enolate from 3a and 3b.
2 equiv. of the easily prepared allyl trichloroacetimidate in and induce an easy electron transfer from the samarium
dichloromethane/cyclohexane (1:2) in the presence of tri- atom to one of the carbonyls. This first electron transfer
fluoromethanesulfonic acid (0.5 equiv.). The deprotected produces an anomeric radical (33a or 33b), which is further
building block 32 was obtained in a two-step sequence reduced to an anomeric organosamarium species (34a or
through deacetylation to 31 (88% yield) with potassium 34b), that may rearrange to a samarium enolate 35. The
carbonate (0.4 equiv.) in methanol followed by saponifica- same reasoning would also apply to the corresponding an-
tion of the methyl ester in aqueous NaOH (1 ; 95% yield omeric 2-pyridyl sulfide 2.[14,15]
of 32).
In these coupling reactions, the anomeric configuration
of the starting acetate in the Neu5Ac derivatives did not
Conclusions
have any influence on the distribution of the reaction prod-
We have shown that both α- and β-acetates of peracety-
ucts. In addition, we would not originally have expected a lated Neu5Ac (3a and 3b) are useful precursors of C-ketos-
facile reduction of acetates 3 without the use of additives to ides through reductive samariation at room temperature un-
enhance the reducing power of SmI2. The reaction proceeds der Barbier conditions in the presence of carbonyl com-
through two successive electron transfers and we suggest pounds. The crude mixture of acetates can equally well be
here that the formation of a chelate structure as in 3a·Sm used for this selective transformation. This procedure pro-
and 3b·Sm (Scheme 5) could be crucial for the initial elec- vides rapid access to α-C-ketosides of NeuAc from easily
tron transfer. The carbonyl oxygens of both the anomeric available starting materials, and is remarkably efficient for
acetate and the methyl ester, together with the endocyclic couplings with cyclic ketones. We have applied this pro-
O-6 oxygen atom, may behave as a tridentate ligand for the cedure to the preparation of a C-sialyl derivative, which will
samarium atom. This chelation scheme would increase the be used as a stable motif to be integrated into different
reducing ability of SmI2, as do most chelating agents,[25] multivalent structures.
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NH), 5.35 (d, J7,8 = 5.2 Hz, 1 H, 7-H), 5.22 (ddd, J4,3ax = 11.5, J4,5
= 10.6, J4,3eq = 5.1 Hz, 1 H, 4-H), 5.08–5.00 (m, 1 H, 8-H), 4.49
(dd, J9a,9b = 12.5, J9a,8 = 2.8 Hz, 1 H, 9a-H), 4.18–4.00 (m, 3 H,
6-H, 5-H, 9b-H), 3.76 (s, 3 H, CO2CH3), 2.51 (dd, J3eq,3ax = 13.4,
J3eq,4 = 5.1 Hz, 1 H, 3eq-H), 2.12, 2.04, 2.01 (3ϫs, 15 H, 5ϫOAc),
1.86 (s, 3 H, NAc) ppm. MS (ESI): m/z = 556.2 [M + Na]+.
Experimental Section
General: All air-sensitive reactions were carried out under argon.
The glassware was oven-dried at 120 °C and cooled in a dessicator.
Solvents were purified by distillation just prior to use or dried by
standard methods. THF was distilled from sodium and benzophe-
none. Toluene and acetonitrile were distilled from calcium hydride.
Dichloromethane was distilled from phosphorus pentoxide. Meth-
anol and DMF were dried on 3 Å and 4 Å molecular sieves, respec-
tively. Pyridine and triethylamine were dried with KOH. Thin layer
chromatography analysis was performed on Merck 60F254 sheets
with detection by UV and by charring with 5% ethanolic H2SO4.
Silica gel SDS 60 ACC 35–70 µm was used for flash column
chromatography. NMR spectra were recorded at room temperature
with Bruker AC 250, AM 250, AM 360, and AM 400 spectrome-
ters. Spin multiplicities are given with the following abbreviations:
s (singlet), d (doublet), t (triplet), m (multiplet). Chemical shifts are
quoted in ppm (δ scale) and are referenced to residual 1H in the
NMR solvents. The deuterated solvents used were specified for
each product: CDCl3, D2O, CD3OD. 1H NMR spectra of C-glyco-
syl analogues of N-acetylneuraminic acid were assigned by stan-
dard methods with the aid of a combination of single frequency
decoupling, TOCSY, and COSY experiments. The 13C NMR spec-
tra were assigned by standard methods with the aid of a combina-
tion of single frequency decoupling, HSQC, and HMBC experi-
ments. Low- and high-resolution mass spectra [MS(ESI), HRMS]
were recorded on a MAT 95S Electrospray Mass Spectrometer. Op-
tical rotations were measured at 28 °C with a Perkin–Elmer 341
polarimeter. Melting points were determined in capillary tubes with
a Büchi B-545 apparatus. Elemental analyses were obtained from
the “Service de Microanalyses” at the I.C.S.N.-C.N.R.S (Gif-sur-
Yvette, France).
Methyl 5-Acetamido-2-chloro-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-
glycero-β- -galacto-2-nonulopyranosonate (5): A solution of methyl 5-
D
acetamido-3,5-dideoxy--glycero--galacto-2-nonulopyranosate (4)
(2.0 g, 6.2 mmol) in a mixture of AcCl/AcOH (40 mL, 1:1, v/v) was
saturated at 0 °C with anhydrous HCl. The resulting mixture was
stirred at room temperature for a day and was then concentrated.
Chloride
5 was obtained quantitatively as a foam (3.13 g,
6.2 mmol) and was directly used in the next reaction. 1H NMR
(CDCl3, 250 MHz): δ = 5.45 (dd, J7,8 = 7.1, J7,6 = 2.4 Hz, 1 H, 7-
H), 5.42–5.32 (m, 1 H, 4-H), 5.15 (ddd, J8,7 = 7.1 Hz, J8,9b = 5.7,
J8,9a = 2.7 Hz, 1 H, 8-H), 4.40 (dd, J9a,9b = 12.5, J9a,8 = 2.7 Hz, 1
H, 9a-H), 4.33 (dd, J6,5 = 10.7, J6,7 = 2.4 Hz, 1 H, 6-H), 4.18 (dd,
J5,6 = 10.7, J5,4 = 10.4 Hz, 1 H, 5-H), 4.04 (dd, J9b,9a = 12.5, J9b,8
= 5.7 Hz, 1 H, 9b-H), 3.86 (s, 3 H, CO2CH3), 2.76 (dd, J3eq,3ax
=
13.9, J3eq,4 = 4.8 Hz, 1 H, 3eq-H), 2.26 (dd, J3ax,3eq = 13.9, J3ax,4
= 11.2 Hz, 1 H, 3ax-H), 2.10, 2.06, 2.04, 2.03 (4ϫs, 12 H,
4ϫOAc), 1.89 (s, 3 H, NAc) ppm.
Methyl 5-Acetamido-2,4,7,8,9-penta-O-acetyl-3,5-dideoxy-
D-glycero-
α- -galacto-2-nonulopyranosonate (3a): A solution of 5 (1.0 g,
D
2.06 mmol) in anhydrous acetonitrile (20 mL) was stirred with an-
hydrous cesium acetate (600 mg, 2.94 mmol, 1.5 equiv.) overnight
at room temperature. The mixture was concentrated and then di-
luted with dichloromethane (200 mL), and the organic phase was
washed with water (40 mL) and concentrated. The residue was
eluted from a silica gel column with toluene/acetone, 2:1 to give 3a
(814 mg, 1.52 mmol, 74%). M.p. 106 °C (toluene/acetone). [αD]25889
Methyl 5-Acetamido-3,5-dideoxy-D-glycero-D-galacto-2-nonulopyr-
1
= +11.5 (c = 1.22, CHCl3) {ref.[22] [αD] = +13 (c = 1, CHCl3)}. H
anosonate (4): A solution of N-acetylneuraminic acid (2.0 g,
6.46 mmol) in methanol (100 mL) containing Dowex H+ resin
(500 mg) was stirred overnight at room temperature. The progress
of the reaction was monitored by TLC (EtOAc/iPrOH/H2O, 2:2:1).
The solution was filtered and the resin was washed several times
with methanol. The filtrate was then evaporated. The methyl ester
4 was obtained as a white solid (1.73 g, 5.36 mmol, 83%). M.p.
183 °C (EtOH) [ref.[20] m.p. 179–180 °C (MeOH)]. [αD]25889 = –27.5
(c = 0.59, MeOH) {ref.[20] [αD] = –28 (c = 1, H2O)}. 1H NMR
(D2O, 250 MHz): δ = 4.10–3.98 (m, 2 H, 6-H, 4-H), 3.90 (dd, J5,6
= 10.1, J5,4 = 10.0 Hz, 1 H, 5-H), 3.82 (s, 3 H, CO2CH3), 3.82 (dd,
J9a,9b = 11.6, J9a,8 = 2.5 Hz, 1 H, 9a-H), 3.71 (ddd, J8,7 = 8.9, J8,9b
NMR (CDCl3, 250 MHz): δ = 5.40 (d, JNH,5 = 9.3 Hz, 1 H, NH),
5.35 (dd, J7,8 = 7.1, J7,6 = 2.5 Hz, 1 H, 7-H), 5.16 (ddd, J8,7
7.1 Hz, J8,9b = 6.0, J8,9a = 2.7 Hz, 1 H, 8-H), 4.99 (ddd, J4,3ax
=
=
11.8, J4,5 = 10.3, J4,3eq = 4.7 Hz, 1 H, 4-H), 4.67 (dd, J6,5 = 10.7,
J6,7 = 2.5 Hz, 1 H, 6-H), 4.33 (dd, J9a,9b = 12.5, J9a,8 = 2.7 Hz, 1
H, 9a-H), 4.12 (ddd, J5,6 = 10.7, J5,4 = 10.4, J5,NH = 9.3 Hz, 1 H,
5-H), 4.03 (dd, J9b,9a = 12.5, J9b,8 = 6.0 Hz, 1 H, 9b-H), 3.73 (s, 3
H, CO2CH3), 2.52 (dd, J3eq,3ax = 13.1, J3eq,4 = 4.7 Hz, 1 H, 3eq-
H), 2.11, 2.08, 2.01 (3ϫs, 15 H, 5ϫOAc), 1.87 (s, 3 H, NAc) ppm.
MS (ESI): m/z = 556.2 [M + Na]+.
Preparation of a Solution of Samarium Diiodide in THF (0.1
M):
= 6.1, J8,9a = 2.5 Hz, 1 H, 8-H), 3.59 (dd, J9b,9a = 11.6, J9b,8
=
Samarium powder (0.190 g, 1.26 mmol) was placed in a dry flask
under argon. 1,2-Diiodoethane (0.280 g, 1.00 mmol) was added
and the mixture was stirred for 10 min. THF (10 mL) was slowly
added and the contents of the flask were magnetically stirred over-
night. For improved results in the coupling reactions with the an-
omeric acetates, this solution should be used within 2 d.
6.1 Hz, 1 H, 9b-H), 3.52 (dd, J7,8 = 8.9, J7,6 = 3.0 Hz, 1 H, 7-H),
2.28 (dd, J3eq,3ax = 13.0 Hz, J3eq,4 = 4.7 Hz, 1 H, 3eq-H), 2.03 (s, 3
H, NAc), 1.89 (dd, J3ax,3eq = 13.0, J3ax,4 = 11.4 Hz, 1 H, 3ax-
H) ppm. MS (ESI): m/z = 346.1 [M + Na]+.
Methyl 5-Acetamido-2,4,7,8,9-penta-O-acetyl-3,5-dideoxy-
D-glycero-
β- -galacto-2-nonulopyranosonate (3b): Acetic anhydride (5 mL)
was added to a suspension of methyl 5-acetamido-3,5-dideoxy--
glycero--galacto-2-nonulopyranosate 4 (400 mg, 1.2 mmol) in pyr-
D
General Procedure for the SmI2-Promoted Coupling Reaction with a
Carbonyl Compound: The SmI2-promoted coupling reactions were
performed at room temperature under Barbier conditions. A solu-
idine (10 mL). The resulting mixture was stirred overnight at room tion of SmI2 in THF (0.1 , 3 equiv.) was added to a stirred solu-
temperature. The end of the reaction was assessed by TLC (toluene/ tion of the sialic acid derivative (1 equiv.) and the carbonyl com-
acetone, 2:1). Solvents were concentrated and the resulting traces pound (2 equiv.) in THF at room temperature (blue solution). After
of pyridine were eliminated by co-evaporation with toluene. The
product was obtained as an α/β mixture in a 1:4 ratio. The residue
was purified by flash chromatography (toluene/acetone, 5:1) to af-
ford 3b (488 mg, 0.9 mmol, 74%). M.p. 98 °C (toluene/acetone).
[αD]52889 = –32 (c = 1.03, CHCl3) {ref.[22] [αD] = –32 (c = 1, CHCl3)}.
1H NMR (CDCl3, 250 MHz): δ = 5.46 (d, JNH,5 = 9.7 Hz, 1 H,
the mixture had been stirred until decoloration (yellow-green solu-
tion), saturated aqueous NH4Cl solution and CH2Cl2 were added
to the reaction mixture. The reaction time depended on the sub-
strate: 20 min from 3a and 2 h either from 3b or from a 3a/3b mix-
ture. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined organic phases were washed
Eur. J. Org. Chem. 2007, 3145–3157
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3151

A. Malapelle, A. Coslovi, G. Doisneau, J.-M. Beau
FULL PAPER
with a saturated aqueous NaHCO3 solution, dried with Na2SO4,
and filtered, and the solvents were evaporated. The residue was
purified by flash chromatography (toluene/acetone, 2:1) to afford
the C-sialosides.
(ESI): m/z = 610.1 [M + Na]+. HRMS: C27H41NNaO13 calcd. for
610.24756; found 610.24904.
Data for Isomer 8b (isolated after flash chromatography, toluene/
1
acetone, 4:1): H NMR (CDCl3, 250 MHz): δ = 5.29 (ddd, J8,7
=
7.8, J8,9b = 5.4, J8,9a = 2.5 Hz, 1 H, 8-H), 5.26 (dd, J7,8 = 7.8, J7,6
= 1.9 Hz, 1 H, 7-H), 5.21 (d, JNH,5 = 9.8 Hz, 1 H, NH), 4.83 (ddd,
J4,3ax = 12.0, J4,5 = 10.0, J4,3eq = 4.6 Hz, 1 H, 4-H), 4.32 (dd, J9a,9b
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-gly-
cero-α- -galacto-non-2-ulopyranosonate)cyclopentanol (6): C-Sialo-
D
side 6 was obtained by the general coupling procedure with cyclo-
pentanone as the electrophile in 97% yield from 3a and 82% yield
from 3b on a 0.04 mmol scale with respect to the acetate derivatives.
[αD]52889 = –9.5 (c = 0.93, CHCl3) {ref.[13b] [αD] = –10 (c = 0.9,
= 12.2, J9a,8 = 2.5 Hz, 1 H, 9a-H), 4.05 (dd, J6,5 = 10.0, J6,7
2.0 Hz, 1 H, 6-H), 4.02 (dd, J9b,9a = 12.2, J9b,8 = 5.4 Hz, 1 H, 9b-
H), 3.95 (m, 1 H, 5-H), 3.74 (s, 3 H, CO2CH3), 2.43 (dd, J3eq,3ax
=
=
CHCl3)}. 1H NMR (CDCl3, 250 MHz): δ = 5.45 (d, JNH,5
9.5 Hz, 1 H, NH), 5.37 (m, 1 H, 8-H), 5.29 (dd, J7,8 = 7.4, J7,6
1.9 Hz, 1 H, 7-H), 4.74 (ddd, J4,3ax = 11.8, J4,5 = 9.8, J4,3eq
=
=
=
12.8, J3eq,4 = 4.8 Hz, 1 H, 3eq-H), 2.13, 2.10, 2.02, 2.00 (4ϫs, 12
H, 4ϫOAc), 2.13 (dd, J3ax,3eq = 12.8, J3ax,4 = 12.0 Hz, 1 H, 3ax-
H), 1.85 (s, 3 H, NAc), 1.56–1.28 (m, 11 H, cyclohexyl) ppm. 13C
NMR (CDCl3, 90 MHz): δ = 171.2, 170.9, 170.7, 170.3, 170.2,
160.0 (CO, 4 ϫ OCOMe, NCOMe, CO2Me), 83.4 (C-2), 79.5
(COH), 73.4, 70.0, 69.1, 67.9 (C-6, C-8, C-4, C-7), 62.4 (C-9), 52.3
(CH3O), 49.6 (C-5), 39.8 (C of cyclohexyl), 34.9 (C-3), 31.8, 26.6,
26.5, 26.4, 26.0 (CH2 of cyclohexyl), 24.2, 21.3, 20.9, 20.7, 20.6
(4 ϫ CH3OCO, CH3CON) ppm. MS (ESI): m/z = 610.1 [M +
Na]+. HRMS: calcd. for C27H41NNaO13 610.24756; found
610.24850.
4.5 Hz, 1 H, 4-H), 4.32 (dd, J9a,9b = 12.4, J9a,8 = 2.4 Hz, 1 H, 9a-
H), 4.05 (m, 2 H, 6-H, 5-H), 3.96 (dd, J9b,9a = 12.4, J9b,8 = 6.6 Hz,
1 H, 9b-H), 3.76 (s, 3 H, CO2CH3), 2.50 (dd, J3eq,3ax = 12.8, J3eq,4
= 4.6 Hz, 1 H, 3eq-H), 2.14, 2.11, 2.03, 2.00 (4ϫs, 12 H, 4ϫOAc),
1.85 (s, 3 H, NAc), 1.70–1.60 (m, 8 H, cyclopentyl) ppm. MS (ESI):
m/z = 528.2 [M + Na]+. HRMS: calcd. for C25H37O13NNa
582.21571; found 528.21612.
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-gly-
3-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-gly-
cero-α- -galacto-non-2-ulopyranosylonate)-4-tert-butylcyclohexanol
D
cero-α- -galacto-non-2-ulopyranosonate)pentan-3-ol (9): C-Sialoside
D
(7): C-Sialoside 7 was obtained by the general coupling procedure
with 4-tert-butylcyclohexanone as the electrophile in 91 % yield
from 3a and 83% yield from 3b on a 0.035 mmol scale with respect
to the acetate derivatives. 1H NMR (CDCl3, 250 MHz): δ = 5.37
(m, 1 H, 8-H), 5.30 (dd, J7,8 = 7.4, J7,6 = 1.9 Hz, 1 H, 7-H), 5.26
(d, JNH,5 = 8.6 Hz, 1 H, NH), 4.71 (ddd, J4,3ax = 11.8, J4,5 = 9.8,
J4,3eq = 4.5 Hz, 1 H, 4-H), 4.28 (dd, J9a,9b = 12.4, J9a,8 = 2.8 Hz, 1
H, 9a-H), 4.06–3.94 (m, 3 H, 6-H, 5-H, 9b-H), 3.74 (s, 3 H,
CO2CH3), 2.42 (dd, J3eq,3ax = 12.9, J3eq,4 = 4.6 Hz, 1 H, 3eq-H),
2.13, 2.07, 2.01, 1.98 (4ϫs, 12 H, 4ϫOAc), 1.83 (s, 3 H, NAc),
1.47–1.34 (m, 8 H, cyclohexyl), 0.88 (s, 9 H, tBu) ppm. 13C NMR
(CDCl3, 90 MHz): δ = 170.8–169.1 (4 ϫ OCOMe, NCOMe,
CO2Me), 98.1 (C-2), 74.7 (COH), 73.4, 70.6, 68.8, 67.9 (C-6, C-8,
C-4, C-7), 62.4 (C-9), 52.7 (CH3O), 47.7 (C-5), 37.3 (C-3), 32.8–
29.6 (CH2 of cyclohexyl), 28.0 [C(CH3)3], 23.1, 22.1, 21.2, 20.8,
20.6 (4ϫCH3OCO, CH3CON) ppm. MS (ESI): m/z = 652.3 [M +
Na]+. HRMS: calcd. for C30H47NNaO13 652.29396; found
652.29411.
9 was obtained by the general coupling procedure with pentan-3-
one as the electrophile in 44% yield from 3a and 26% yield from
3b on a 0.035 mmol scale with respect to the acetate derivatives. 1H
NMR (CDCl3, 250 MHz): δ = 5.45 (ddd, J8,7 = 8.2, J8,9b = 5.9,
J8,9a = 2.6 Hz, 1 H, 8-H), 5.34 (dd, J7,8 = 8.2, J7,6 = 2.2 Hz, 1 H,
7-H), 5.21 (d, JNH,5 = 9.8 Hz, 1 H, NH), 4.85 (ddd, J4,3ax = 12.0,
J4,5 = 10.0, J4,3eq = 4.5 Hz, 1 H, 4-H), 4.30 (dd, J9a,9b = 12.5, J9a,8
= 2.6 Hz, 1 H, 9a-H), 4.11 (dd, J6,5 = 9.8, J6,7 = 2.2 Hz, 1 H, 6-
H), 4.10 (dd, J9b,9a = 12.5, J9b,8 = 5.9 Hz, 1 H, 9b-H), 3.95 (t, J5,6
= 9.8 Hz, 1 H, J5,4 = 10.0 Hz, 5-H), 3.85 (s, 3 H, CO2CH3), 2.50
(dd, J3eq,3ax = 12.5, J3eq,4 = 4.5 Hz, 1 H, 3eq-H), 2.15, 2.11, 2.02,
2.00 (4 ϫ s, 12 H, 4 ϫ OAc), 2.05 (dd, J3ax,3eq = 12.5, J3ax,4
=
12.0 Hz, 1 H, 3ax-H), 1.92 (s, 3 H, NAc), 1.69–1.47 (m, 4 H, CH2
of ethyl), 0.91 (t, J = 7.4 Hz, 3 H, CH3 of ethyl), 0.84 (t, J = 7.4 Hz,
3 H, CH3 of ethyl) ppm. MS (ESI): m/z = 584.2 [M + Na]+.
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-gly-
cero-α- -galacto-non-2-ulopyranosonate)octanol (10): C-Sialoside
D
10 was obtained by the general coupling procedure with octanal as
the electrophile in 39% yield from 3a and 33% yield from 3b on a
0.03 mmol scale with respect to the acetate derivatives. 1H NMR
(R/S)-1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D
-glycero-α-D-galacto-non-2-ulopyranosonate)-1-cyclohexylmeth-
anol (8ab): C-Sialosides 8a and 8b were obtained by the general
coupling procedure with cyclohexanecarbaldehyde as the electro-
phile in 87% yield from 3a and 83% yield from 3b, on a 0.1 mmol
scale with respect to the acetate derivatives. Data for isomer 8a (iso-
lated after flash chromatography, toluene/acetone, 4:1): 1H NMR
(CDCl3, 250 MHz): δ = 5.41 (ddd, J8,7 = 8.2, J8,9b = 5.9, J8,9a
=
2.6 Hz, 1 H, 8-H), 5.29 (dd, J7,8 = 8.2, J7,6 = 2.2 Hz, 1 H, 7-H),
5.20 (d, JNH,5 = 9.8 Hz, 1 H, NH), 4.75 (ddd, J4,3ax = 12.0, J4,5
10.0, J4,3eq = 4.5 Hz, 1 H, 4-H), 4.36 (dd, J9a,9b = 12.5, J9a,8
=
=
2.6 Hz, 1 H, 9a-H), 4.21 (dd, J6,5 = 9.8, J6,7 = 2.2 Hz, 1 H, 6-H),
4.12 (dd, J9b,9a = 12.5, J9b,8 = 5.9 Hz, 1 H, 9b-H), 4.00–3.95 (m, 1
(CDCl3, 250 MHz): δ = 5.36 (ddd, J8,7 = 8.7, J8,9b = 6.3, J8,9a
=
2.7 Hz, 1 H, 8-H), 5.26 (dd, J7,8 = 8.1, J7,6 = 2.4 Hz, 1 H, 7-H),
H, 5-H), 3.71 (s, 3 H, CO2CH3), 2.41 (dd, J3eq,3ax = 12.5, J3eq,4
=
5.16 (d, JNH,5 = 9.5 Hz, 1 H, NH), 4.75 (ddd, J4,3ax = 11.8, J4,5
10.2, J4,3eq = 4.4 Hz, 1 H, 4-H), 4.27 (dd, J9a,9b = 12.5, J9a,8
=
=
4.5 Hz, 1 H, 3eq-H), 2.13, 2.10, 2.09, 1.95 (4ϫs, 12 H, 4ϫOAc),
2.05 (dd, J3ax,3eq = 12.5, J3ax,4 = 12.0 Hz, 1 H, 3ax-H), 1.82 (s, 3
H, NAc), 1.27–1.20 and 0.88–0.81 (m, 15 H, octyl) ppm. MS (ESI):
m/z = 626.2 [M + Na]+.
2.5 Hz, 1 H, 9a-H), 4.16 (dd, J6,5 = 10.5, J6,7 = 2.5 Hz, 1 H, 6-H),
4.05 (m, 1 H, 5-H), 3.99 (dd, J9b,9a = 12.5, J9b,8 = 6.5 Hz, 1 H, 9b-
H), 3.72 (s, 3 H, CO2CH3), 2.34 (dd, J3eq,3ax = 12.8, J3eq,4 = 5.2 Hz,
1 H, 3eq-H), 2.13, 2.08, 2.02, 2.00 (4ϫs, 12 H, 4ϫOAc), 1.91 (dd,
J3ax,3eq = 12.8, J3ax,4 = 10.2 Hz, 1 H, 3ax-H), 1.85 (s, 3 H, NAc),
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-gly-
cero-α- -galacto-non-2-ulopyranosonate)-1-cyclohexylmethanone
D
1.46–1.36 (m, 11 H, cyclohexyl) ppm. 13C NMR (CDCl3, 90 MHz): (13): Molecular sieves (4 Å, 82 mg) and PCC (54 mg, 0.24 mmol)
δ = 171.2, 171.1, 171.0, 170.6, 170.3, 169.5 (4ϫOCOMe, NCOMe,
CO2Me), 84.1 (C-2), 79.1 (COH), 73.2, 70.1, 68.6, 67.8 (C-6, C-8,
C-4, C-7), 62.9 (C-9), 52.6 (CH3O), 49.5 (C-5), 39.4 (C of cyclo-
hexyl), 34.0 (C-3), 31.8, 26.7, 26.5, 26.2, 26.0 (CH2 of cyclohexyl),
23.2, 21.3, 20.9, 20.8, 20.6 (4 ϫ CH3OCO, CH3CON) ppm. MS
were added to a solution of the two diastereomers 8a and 8b
(29 mg, 0.05 mmol) in dichloromethane (1 mL). The resulting mix-
ture was stirred at room temperature and the progress of the reac-
tion was monitored by TLC (toluene/acetone, 2:1). After 30 min
the reaction mixture was diluted with diethyl ether and filtered
3152
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3145–3157

“α-C-Glycosides” from the Anomeric Acetates
FULL PAPER
through a pad of silica. The filtrate was concentrated and the resi-
with toluene the crude mixture was treated for 1 h with PCC (9.6 g,
44.8 mmol) in dichloromethane (150 mL) in the presence of molec-
due was purified by flash chromatography (toluene/acetone, 2:1) to
1
afford 13 (18 mg, 0.03 mmol, 50%). H NMR (CDCl3, 250 MHz): ular sieves (4 Å). After addition of diethyl ether (150 mL), the mix-
δ = 5.48–5.31 (m, 2 H, 7-H, 8-H), 5.20 (d, JNH,5 = 9.8 Hz, 1 H, ture was filtered through silica and the solvents were evaporated.
NH), 4.92 (ddd, J4,3ax = 11.8, J4,5 = 9.8, J4,3eq = 4.7 Hz, 1 H, 4- Flash chromatography on silica gel (cyclohexane/ethyl acetate, 3:1)
H), 4.32 (dd, J9a,9b = 12.3, J9a,8 = 2.1 Hz, 1 H, 9a-H), 4.09 (dd,
J9a,9b = 12.3, J9b,8 = 5.4 Hz, 1 H, 9b-H), 4.00 (ddd, J5,6 = 10.5,
gave 16 (1.86 g, 12 mmol, 46 %) as an oil. 1H NMR (CDCl3,
250 MHz): δ = 5.80 (dddd, J = 17.2, 10.4, 5.0, 5.0 Hz, 1 H), 5.18
(dq, J = 17.2, 1.8 Hz, 1 H), 5.13 (dq, J = 10.4, 1.7 Hz, 1 H), 3.92
(m, 2 H), 3.63 (tt, J = 6.6, 3.3 Hz, 1 H), 2.42 (m, 2 H), 2.10 (m, 2
H), 1.93 (m, 2 H), 1.80 (m, 2 H) ppm. 13C NMR (CDCl3, 90 MHz):
δ = 210.6, 135.0, 116.3, 72.0, 69.0, 37.0, 30.4 ppm. MS (ES): m/z =
177.1 [M + Na]+. HRMS: calcd. for C9H14O2Na 177.0891; found
177.0896.
J5,NH = J5,4 = 9.8 Hz, 1 H, 5-H), 3.93 (dd, J5,6 = 10.5 Hz, J6,7
=
2.4 Hz, 1 H, 6-H), 3.74 (s, 3 H, CO2Me), 2.68 (dd, J3eq,3ax = 13.4,
J3eq,4 = 4.7 Hz, 1 H, 3eq-H), 2.14, 2.11, 2.03, 2.01 (4ϫs, 12 H,
4ϫOAc), 1.87 (s, 3 H, NAc) ppm. MS (ESI): m/z = 608.3 [M +
Na]+. HRMS: calcd. for C27H39NNaO13 608.2319; found 608.2308.
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-
glycero-α- -galacto-non-2-ulopyranosonate)cyclohexanol (14): C-
D
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-
Sialoside 14 was obtained by the general coupling procedure with
cyclohexanone as the electrophile in 79% yield from a 3a/3b mix-
ture on a 0.035 mmol scale with respect to the acetate derivatives.
1H NMR (CDCl3, 250 MHz): δ = 5.32 (ddd, J8,7 = 8.5, J8,9b = 5.9,
J8,9a = 2.6 Hz, 1 H, 8-H), 5.30 (dd, J7,8 = 8.5, J7,6 = 2.1 Hz, 1 H,
7-H), 5.26 (d, JNH,5 = 8.6 Hz, 1 H, NH), 4.80 (ddd, J4,3ax = 11.5,
J4,5 = 9.8, J4,3eq = 4.4 Hz, 1 H, 4-H), 4.28 (dd, J9a,9b = 12.4, J9a,8
= 2.8 Hz, 1 H, 9a-H), 4.06–3.94 (m, 3 H, 6-H, 5-H, 9b-H), 3.70 (s,
glycero-α- -galacto-non-2-ulopyranosonate)-4-allyloxycyclohexanol
D
(17): C-Sialosides 17 were obtained as a 1:1 mixture by the general
coupling procedure with 4-(allyloxy)cyclohexanone (16) as the elec-
trophile in 83% yield from 3a/3b on a 0.04 mmol scale with respect
to the acetate derivatives. 1H NMR (CDCl3, 250 MHz): δ = 5.92
[dddd, J = 16.0, 10.5, 5.1, 5.0 Hz, 1 H, CH (allyl)], 5.42 (m, 2 H,
7-H, 8-H), 5.30 (d, JNH,5 = 7.9 Hz, 1 H, NH), 5.27 [ddt, J = 16.0,
2.0, 1.3 Hz, 1 H, CH (allyl)], 5.15 [ddt, J = 10.5, 2.0, 2.0 Hz, 1 H,
3 H, CO2CH3), 2.39 (dd, J3eq,3ax = 12.5, J3eq,4 = 4.4 Hz, 1 H, 3eq- CH (allyl)], 4.74 (ddd, J4,3ax = 11.3, J4,5 = 10.2, J4,3eq = 4.6 Hz, 1
H), 2.12, 2.10, 2.05, 1.98 (4ϫs, 12 H, 4ϫOAc), 2.04 (dd, J3ax,3eq H, 4-H), 4.37 (dd, J9a,9b = 12.4, J9a,8 = 2.5 Hz, 0.5 H, 9a-H), 4.35
= 12.5, J3ax,4 = 11.5 Hz, 1 H, 3ax-H), 1.85 (s, 3 H, NAc), 1.47–1.34 (dd, J9a,9b = 12.4, J9a,8 = 2.5 Hz, 0.5 H, 9a-H), 4.12–3.92 [m, 5 H,
(m, 8 H, cyclohexyl) ppm. 13C NMR (CDCl3, 90 MHz): δ = 170.7–
169.3 (CO, 4 ϫ OCOMe, NCOMe, CO2Me), 97.1 (C-2), 74.6
(COH), 72.4, 70.5, 68.6, 67.7 (C-6, C-8, C-4, C-7), 62.3 (C-9), 52.4
(CH3O), 47.5 (C-5), 37.8 (C-3), 32.6–29.1 (CH2 of cyclohexyl),
23.2, 22.1, 21.5, 20.8, 20.1 (4 ϫ CH3OCO, CH3CON) ppm. MS
(ESI): m/z = 596.2 [M + Na]+.
5-H, 6-H, 9b-H, CH2 (allyl)], 3.80 (s, 1.5 H, CO2CH3), 3.78 (s, 1.5
H, CO2CH3), 3.22 (m, 1 H), 2.75 (s, 0.5 H, OH), 2.68 (s, 0.5 H,
OH), 2.49 (dd, J3eq,3ax = 12.8, J3eq,4 = 4.5 Hz, 0.5 H, 3eq-H), 2.48
(dd, J3eq,3ax = 12.8, J3eq,4 = 4.5 Hz, 0.5 H, 3eq-H), 2.18 (s, 1.5 H,
OCOCH3), 2.17 (s, 1.5 H, OCOCH3), 2.13, 2.06, and 2.03 (3ϫs, 9
H, 3ϫOCOCH3), 1.88 (s, 3 H, NCOCH3) ppm. 13C NMR (CDCl3,
90 MHz): δ = 171.0, 170.8, 170.2, 170.0, 135.6, 135.5, 116.5, 115.8,
86.1, 85.7, 75.0, 74.2, 73.2, 71.6, 70.47, 70.3, 68.9, 68.7, 68.5, 67.8,
52.5, 52.3, 49.4, 32.9, 30.0, 29.9, 27.2, 27.0, 25.8, 25.4, 25.0, 23.1,
21.3, 20.8 ppm. MS (ES): m/z = 652.2 [M + Na]+. HRMS: calcd.
for C29H43NNaO14 652.2581; found 652.2589.
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-gly-
cero-α- -galacto-non-2-ulopyranosonate)-4-oxo-cyclohexanol (15):
D
C-Sialoside 15 was obtained by the general coupling procedure
with cyclohexane-1,4-dione as the electrophile in 30% yield from a
3a/3b mixture on a 0.035 mmol scale with respect to the acetate
derivatives, with 1.4 equiv. of cyclohexane-1,4-dione. 1H NMR
4-(tert-Butyldimethylsilyloxy)cyclohexanone (18): tert-Butyldimeth-
(CDCl3, 250 MHz): δ = 5.42 (ddd, J8,7 = 8.2, J8,9b = 6.4, J8,9a
=
ylsilyl chloride (6.45 g, 43 mmol) and imidazole (5.85 g, 86 mmol)
2.6 Hz, 1 H, 8-H), 5.30 (dd, J7,8 = 8.2, J7,6 = 1.7 Hz, 1 H, 7-H), were successively added to the commercial cis/trans mixture of cy-
5.24 (d, JNH,5 = 10.0 Hz, 1 H, NH), 4.73 (ddd, J4,3ax = 11.8, J4,5
9.6, J4,3eq = 4.3 Hz, 1 H, 4-H), 4.32 (dd, J9a,9b = 12.3, J9a,8
=
=
clohexane-1,4-diol (5.0 g, 43 mmol) in DMF (40 mL). After a night
at room temperature the reaction mixture was hydrolyzed by ad-
2.6 Hz, 1 H, 9a-H), 4.05 (dd, J6,5 = 10.2, J6,7 = 1.7 Hz, 1 H, 6-H), dition of water (40 mL). The aqueous phase was extracted with
3.99–3.97 (m, 2 H, 5-H, 9b-H), 3.80 (s, 3 H, CO2CH3), 3.21 (s, 1
H, OH), 2.74 (m, 4 H, CH2 of cyclohexyl), 2.47 (dd, J3eq,3ax = 12.6,
J3eq,4 = 4.3 Hz, 1 H, 3eq-H), 2.17, 2.12, 2.04, 2.01 (4ϫs, 12 H,
4ϫOAc), 2.03 (dd, J3ax,3eq = 12.6, J3ax,4 = 11.8 Hz, 1 H, 3ax-H),
CH2Cl2, the combined organic phases were dried with Na2SO4,
and the solvents were evaporated to dryness. After two successive
coevaporations with toluene the crude mixture was treated for 1.5 h
with PCC (12 g, 56 mmol) in dichloromethane (200 mL) the pres-
1.86 (s, 3 H, NAc), 1.85–1.80 (m, 4 H, CH2 of cyclohexyl) ppm. ence of molecular sieves (4 Å). After addition of diethyl ether
13C NMR (CDCl3, 90 MHz): δ = 192.0 (CO), 170.8, 170.7, 170.6, (200 mL) the mixture was filtered through silica and the solvents
170.4, 169.9, 169.5 (CO, 4ϫOCOMe, NCOMe, CO2Me), 85.4 (C-
were evaporated. Flash chromatography on silica gel (cyclohexane/
2), 73.8 (COH), 73.2, 70.0, 68.4, 67.7 (C-6, C-8, C-4, C-7), 62.6 (C-
ethyl acetate, 4:1) gave 18 (2.73 g, 12 mmol, 28%) as a colorless oil.
9), 52.6 (CH3O), 49.1 (C-5), 32.9 (C-3), 36.6, 36.4, 31.4, 31.3 (CH2 1H NMR (CDCl3, 250 MHz): δ = 4.07 (m, 1 H), 2.59 (m, 2 H),
of cyclohexyl), 23.0, 21.3, 20.8, 20.7, 20.5 (4 ϫ CH3OCO,
CH3CON) ppm. MS (ESI): m/z = 610.3 [M + Na]+. HRMS: calcd.
for C24H35NNaO13 610.2118; found 610.2145.
2.15 (m, 2 H), 1.85 (m, 2 H), 0.85 (s, 9 H, tBu), 0.03 (s, 6 H,
Me2Si) ppm. 13C NMR (CDCl3, 90 MHz): δ = 211.2, 65.8, 36.7,
34.1, 25.7, 17.9, –4.9 ppm. MS (ES): m/z = 251.1 [M + Na]+.
HRMS: calcd. for C12H24NaO2Si 251.1443; found 251.1448.
4-(Allyloxy)cyclohexanone (16): Sodium hydride (396 mg,
17.2 mmol) and allyl bromide (2.4 mL, 25.8 mmol) were success-
ively added to the commercial cis/trans mixture of cyclohexane-1,4-
diol (4.0 g, 34.5 mmol) in DMF (30 mL). After a night at room
temperature the reaction mixture was hydrolyzed by addition of
water (25 mL). The aqueous phase was extracted with CH2Cl2, the
combined organic phases were dried with Na2SO4, and the solvents
were evaporated to dryness. After two successive coevaporations
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D
glycero-α- -galacto-non-2-ulopyranosonate)-4-(tert-butyldimethylsi-
D
lyloxy)cyclohexanol (19): C-Sialosides 19 were obtained as a 1:1
mixture by the general coupling procedure with 4-(tert-butyldime-
thylsilyloxy)cyclohexanone (18) in 85 % yield from 3a/3b on a
0.04 mmol scale with respect to the acetate derivatives. 1H NMR
(CDCl3, 300 MHz): δ = 5.41 (ddd, J8,7 = 8.0, J8,9b = 6.6, J8,9a
=
Eur. J. Org. Chem. 2007, 3145–3157
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3153

A. Malapelle, A. Coslovi, G. Doisneau, J.-M. Beau
2.5 Hz, 1 H, 8-H), 5.31 (dd, J7,8 = 8.0, J7,6 = 1.1 Hz, 1 H, 7-H), 3.71 (2ϫs, 6 H, CO2CH3), 3.09 (s, 1 H, OH), 2.42 (2ϫdd, J3eq,3ax
FULL PAPER
5.24 (d, JNH,5 = 9.4 Hz, 1 H, NH), 4.76 (ddd, J4,3ax = 11.2, J4,5
10.4, J4,3eq = 4.5 Hz, 1 H, 4-H), 4.35 (dd, J9a,9b = 12.4, J9a,8
=
=
= 12.8, J3eq,4 = 4.6 Hz, 2 H, 3eq-H), 2.10, 2.09, 2.07, 1.99 (4ϫs,
12 H, 4ϫOAc), 2.00 (m, 1 H, 3ax-H), 1.91 (s, 3 H, NAc), 1.60–
1.50 (m, 2 H, CH2), 0.84 (s, 9 H, tBu), 0.01 (s, 6 H, Me2Si) ppm.
2.5 Hz, 0.5 H, 9a-H), 4.33 (dd, J9a,9b = 12.4, J9a,8 = 2.5 Hz, 0.5 H,
9a-H), 4.20–4.05 (m, 2 H, 5-H, 6-H), 4.00 (dd, J9b,9a = 12.4, J9b,8 13C NMR (CDCl3, 90 MHz): δ = 171.0, 170.9, 170.7, 170.6, 170.3,
= 6.6 Hz, 1 H, 9b-H), 3.80 (s, 1.5 H, CO2CH3), 3.78 (s, 1.5 H,
CO2CH3), 2.62 (s, 1 H, OH), 2.49 (dd, J3eq,3ax = 12.8, J3eq,4
and 170.1 (4ϫOCOCH3, NCOCH3, CO2CH3), 83.4 (C-2), 73.3,
70.2, 69.1, 68.8 (C-4, C-6, C-7, C-8), 70.1 (COH), 62.7 (C-9), 60.4
(CH2O), 52.5 (CH3O), 49.4 (C-5), 33.9 (CH2), 32.9 (C-3), 25.8
[(CH3)3], 23.1, 21.2, 20.8, 20.7, and 20.5 (8 ϫ CH3 OCO,
2ϫCH3CON), 18.2 [C(CH3)3], –5.4 [(CH3)2Si] ppm. MS (ESI): m/z
= 686.3 [M + Na]+.
=
4.5 Hz, 0.5 H, 3eq-H), 2.47 (dd, J3eq,3ax = 12.8, J3eq,4 = 4.5 Hz, 0.5
H, 3eq-H), 2.17, 2.13, 2.05, and 2.03 (4ϫs, 12 H, 4ϫOCOCH3),
1.88 (s, 3 H, NCOCH3), 1.87 (s, 3 H, NCOCH3), 0.89 (s, 9 H, tBu),
0.88 (s, 9 H, tBu), 0.05 (6 H, Me2Si), 0.04 (3 H, MeSi), 0.3 (3 H,
MeSi) ppm. 13C NMR (CDCl3, 90 MHz): δ = 171.1, 171.0, 170.6,
170.3, 170.2, 170.0, 86.0, 85.8, 75.5, 74.1, 73.3, 73.1, 71.1, 70.5,
70.2, 68.8, 68.6, 67.8, 67.7, 65.5, 62.6, 52.4, 52.2, 49.6, 33.0, 32.7,
30.8, 30.7, 30.2, 30.0, 29.7, 28.9, 28.7, 25.8, 25.5, 25.0, 23.1, 21.2,
20.9, 20.8, 18.1, 18.0, –4.5, –4.9 ppm. MS (ES): m/z = 726.2 [M +
Na]+. HRMS: calcd. for C32H53NNaO14Si 726.3133; found
726.3165.
D
-erythro-L-gluco-α-D-galacto-Pentadecopyranose, 11-(Ace-
tylamino)-8,12-anhydro-6,9,11-trideoxy-8-C-(methoxycarbonyl)-
1,2,3,4-bis-O-(1-methylthylidene)-10,13,14,15-tetraacetate (24): C-
Sialoside 24 was obtained by the general coupling procedure with
the galactose-derived aldehyde 23[24] in 30 % yield from a 3a/3b
mixture on a 0.04 mmol scale with respect to the acetate derivatives.
Data for the (R/S) mixture: 1H NMR (CDCl3, 360 MHz): δ = 5.49
(d, J1Ј,2Ј = 4.9 Hz, 1 H, 1Ј-H), 5.43 (ddd, J8,7 = 7.2, J8,9b = 6.4,
J8,9a = 2.5 Hz, 2 H, 8-H), 5.33–5.23 (m, 2 H, 7-H), 4.78 (ddd, J4,3ax
= 11.9, J4,5 = 10.1, J4,3eq = 4.4 Hz, 2 H, 4-H), 4.60 (dd, J = 7.8, J
= 2.5 Hz, 1 H, 2Ј-H), 4.37–3.85 (m, 20 H, 3Ј-H, 4Ј-H, 5Ј-H, 2 6Ј-
H, 5-H, 6-H, 9a-H, 9b-H, 7ЈЈ-H), 3.76 (s, 3 H, CO2Me), 3.74 (s, 3
H, CO2Me), 2.46 (dd, J3eq,3ax = 12.8, J3eq,4 = 4.4 Hz, 1 H, 3eq-H),
2.35 (dd, J3eq,3ax = 13.4, J3eq,4 = 4.58 Hz, 1 H, 3eq-H), 2.16, 2.15,
2.14, 2.13 (4ϫs, 12 H, OAc), 2.03, 2.02, 2.01, 2.00 (4ϫs, 12 H,
OAc), 1.88 (t, J3ax,3eq = 13.4, J3ax,4 = 11.9 Hz, 1 H, 3ax-H), 1.85
(s, 6 H, NAc), 1.54, 1.52, 1.49, 1.45, 1.38, 1.36, 1.31, 1.30 (8ϫs, 24
H, CH3) ppm. MS (ESI): m/z = 770.3 [M + Na]+. HRMS: calcd.
for C33H49NNaO18 770.2853; found 770.2845.
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D
glycero-α- -galacto-non-2-ulopyranosonate)cyclobutanol (20): C-
D
Sialoside 20 was obtained by the general coupling procedure with
cyclobutanone as the electrophile in 88% yield from a 3a/3b mix-
ture on a 0.04 mmol scale with respect to the acetate derivatives.
1H NMR (CDCl3, 250 MHz): δ = 5.40 (ddd, J8,7 = 7.9, J8,9b = 6.5,
J8,9a = 2.4 Hz, 1 H, 8-H), 5.30 (dd, J7,8 = 7.9, J7,6 = 2.6 Hz, 1 H,
7-H), 5.18 (d, JNH,5 = 10.1 Hz, 1 H, NH), 4.78 (ddd, J4,3ax
12.5 Hz, J4,5 = 9.9, J4,3eq = 4.8 Hz, 1 H, 4-H), 4.30 (dd, J9a,9b
=
=
12.3, J9a,8 = 2.4 Hz, 1 H, 9a-H), 4.15 (dd, J6,5 = 10.6, J6,7 = 2.6 Hz,
1 H, 6-H), 4.11–3.97 (m, 2 H, 5-H, 9b-H), 3.75 (s, 3 H, CO2CH3),
2.53 (dd, J3eq,3ax = 12.9, J3eq,4 = 4.8 Hz, 1 H, 3eq-H), 2.38 (m, 6
H, cyclobutyl), 2.14, 2.11, 2.03, 2.02 (4ϫs, 12 H, 4ϫOAc), 2.04
(dd, J3ax,3eq = 12.9, J3ax,4 = 12.5 Hz, 1 H, 3ax-H), 1.86 (s, 3 H,
NAc) ppm. 13C NMR (CDCl3, 90 MHz): δ = 171.0, 170.7, 170.6,
170.3, 170.1, 169.5 (4ϫOCOMe, NCOMe, CO2Me), 79.1 (C-2),
73.1, 70.2, 68.6, 67.8 (C-6, C-8, C-4, C-7), 62.8 (C-9), 52.4 (CH3O),
49.5 (C-5), 33.3 (C-3), 31.0, 30.3 (CH2 of cyclobutyl), 23.2, 21.3,
20.9, 20.7, 20.6 (4ϫCH3OCO, CH3CON), 13.0 (CH2 of cyclobu-
tyl) ppm. MS (ESI): m/z = 568.2 [M + Na]+. HRMS: calcd. for
C24H35NNaO13 568.2001; found 568.2010.
General Procedure for Deacetylation: A suspension of the acety-
lated sialic acid derivative (0.02 mmol) in methanol (2 mL) was
treated with a catalytic amount of sodium. The resulting mixture
was stirred overnight at room temperature. The progress of the re-
action was monitored by TLC (EtOAc/iPrOH/H2O, 2:2:1). The
mixture was neutralized with Amberlite IR-120 (H+) resin and fil-
tered. The resin was washed several times with methanol. The fil-
trate was evaporated and the residue was purified by flash
chromatography (CH2Cl2/MeOH, 95:5) to afford the correspond-
ing product.
3-(tert-Butyldimethylsilyloxy)propanal (21): PCC (10 g, 0.046 mol)
was added in one portion to a solution of 3-(tert-butyldimethylsilyl-
oxy)propanol (6.0 g, 0.031 mol) in dichloromethane (100 mL). The
mixture was then stirred for 3 h at room temperature. The solution
was separated from the black insoluble material, which was ex-
tracted with diethyl ether (4ϫ50 mL). The combined organic phase
was filtered through silica (10 g) and evaporated to afford aldehyde
1-C-(Methyl 5-Acetamido-3,5-dideoxy-D-glycero-α-D-galacto-non-2-
ulopyranosonate)cyclopentanol (11): Compound 11 was obtained by
the general deacetylation procedure in 90 % yield from 6 on a
0.02 mmol scale. 1H NMR (CD3OD, 250 MHz): δ = 3.86–3.40 (m,
3 H, 8-H, 9a-H), 3.79 (s, 3 H, CO2CH3), 3.68 (t, J5,6 = J5,NH = J5,4
= 10.5 Hz, 1 H, 5-H), 3.64 (dd, J9b,9a = 10.9, J9b,8 = 5.2 Hz, 1 H,
9b-H), 3.48 (dd, J7,8 = 9.0, J7,6 = 1.7 Hz, 1 H, 7-H), 3.45–3.40 (m,
2 H, 4-H, 6-H), 2.62 (dd, J3eq,3ax = 12.5, J3eq,4 = 4.4 Hz, 1 H, 3eq-
H), 2.01 (s, 3 H, NAc), 2.00 (dd, J3ax,3eq = 12.5, J3ax,4 = 8.4 Hz, 1 H,
3ax-H), 1.92–1.31 (m, 8 H, cyclopentyl) ppm. 13C NMR (CD3OD,
90 MHz): δ = 175.4, 174.7 (NCOMe, CO2Me), 86.5 (C-2), 82.0
(COH), 75.9, 72.9, 70.3, 69.4 (C-6, C-8, C-4, C-7), 64.8 (C-9), 54.1
(C-5), 53.2 (CH3O), 37.8 (C-3), 36.6, 35.6, 25.8, 24.9 (CH2 of cy-
clopentyl), 22.7 (CH3CON) ppm. MS (ESI): m/z = 414.1 [M +
Na]+. HRMS: calcd. for C17H29NNaO9 414.4025; found 414.4075.
1
21 (4.4 g, 0.023 mol, 76%). H NMR (CDCl3, 360 MHz): δ = 9.76
(d, J = 1.6 Hz, 1 H, CHO), 3.96 (t, J = 6.0 Hz, 2 H, CH2O), 2.57
(t, J = 6.0 Hz, 2 H, CH2CHO), 0.86 (s 9 H, tBu), 0.03 (s, 6 H,
Me2Si) ppm. 13C NMR (CDCl3, 90 MHz): δ = 202.0, 58.8, 46.6,
26.0, 18.3, and –5.5 ppm. MS (ESI): m/z = 211.1 [M + Na]+.
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-gly-
cero-α- -galacto-non-2-ulopyranosonate)-3-(tert-butyldimethylsilyl-
D
oxy)propanol (22): C-Sialosides 22 were obtained by the general
coupling procedure with 3-(tert-butyldimethylsilyloxy)propanal as
the electrophile in 26% yield from a 3a/3b mixture on a 0.03 mmol
scale with respect to the acetate derivatives. M.p. 78 °C (toluene/
acetone). Data for the (1:1) mixture of isomers: 1H NMR (CDCl3,
(R/S)-1-C-(Methyl 5-Acetamido-3,5-dideoxy-D-glycero-α-D-galacto-
non-2-ulopyranosonate)-1-cyclohexylmethanol (12a and 12b): Com-
pounds 12a and 12b were obtained by the general deacetylation
procedure in 92% yield both from 8a and from 8b on a 0.02 mmol
scale.
360 MHz): δ = 5.40–5.27 (m, 2 H, 8-H, 7-H), 4.75 (ddd, J4,3ax
=
11.9, J4,5 = 9.7, J4,3eq = 4.6 Hz, 1 H, 4-H), 4.32 and 4. 31 (2ϫdd,
J9a,9b = 12.2, J9a,8 = 2.4 Hz, 2 H, 9a-H), 4.11–3.93 (m, 3 H, 6-H, Data for Isomer 12a: 1H NMR (CD3OD, 250 MHz): δ = 3.86–3.79
5-H, 9b-H), 3.88–3.73 (m, 3 H, CH2OTBDMS, CHOH), 3.72 and (m, 2 H, 8-H, 9a-H), 3.79–3.71 (m, 1 H, 4-H), 3.79 (s, 3 H,
3154
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3145–3157

“α-C-Glycosides” from the Anomeric Acetates
CO2CH3), 3.68 (t, J5,6 = J5,NH = J5,4 = 10.5 Hz, 1 H, 5-H), 3.64 2.66 mmol) and borane–dimethyl sulfide complex (0.25 mL,
FULL PAPER
(dd, J9b,9a = 10.9, J9b,8 = 5.2 Hz, 1 H, 9b-H), 3. 54 (d, J = 4.3 Hz,
1 H, 1Ј-H), 3.48 (dd, J7,8 = 9.0, J7,6 = 1.7 Hz, 1 H, 7-H), 3.44 (dd,
2.66 mmol) were successively added to a magnetically stirred solu-
tion of acetal 28 (1.40 g, 2.22 mmol) in dry dichloromethane (7 mL)
J6,5 = 10.5, J6,7 = 1.7 Hz, 1 H, 6-H), 2.55 (dd, J3eq,3ax = 12.9, J3eq,4 cooled to –78 °C. After the mixture had been stirred at –78 °C for
= 4.2 Hz, 1 H, 3eq-H), 2.02 (s, 3 H, NAc), 1.85 (dd, J3ax,3eq = 12.9, 4 h, saturated aqueous sodium hydrogen carbonate was added and
J3ax,4 = 8.4 Hz, 1 H, 3ax-H), 1.80–1.10 (m, 11 H, cyclohexyl) ppm. the reaction mixture was extracted three times with CH2Cl2. The
13C NMR (CD3OD, 90 MHz): δ = 175.4, 174.7 (CO, NCOMe, combined organic phases were dried with Na2SO4 and the solvents
CO2Me), 85.6 (C-2), 80.9 (COH), 75.7, 72.5, 70.2, 69.2 (C-6, C-8,
C-4, C-7), 64.8 (C-9), 54.2 (C-5), 53.1 (CH3O), 40.6 (C of cyclo-
hexyl), 36.8 (C-3), 33.0, 28.5, 27.8, 27.5, 27.4 (CH2 of cyclohexyl),
22.7 (CH3CON) ppm. MS (ESI): m/z = 442.1 [M + Na]+. HRMS:
calcd. for C19H33NNaO9 442.20530; found 442.20567.
were evaporated. Flash chromatography on silica gel (toluene/ace-
tone, 1:1) gave 29 (1.28 g, 2.02 mmol, 91%). M.p.: 95 °C (toluene/
acetone). [αD]25889 = 50.4 (c = 0.11, CH2Cl2). 1H NMR (CDCl3,
360 MHz): δ = 5.40 (ddd, J8,7 = 8.3, J8,9b = 6.2, J8,9a = 2.6 Hz, 1
H, 8-H), 5.28 (dd, J7,8 = 8.3, J7,6 = 1.4 Hz, 1 H, 7-H), 4.73 (ddd,
J4,3ax = 11.1, J4,5 = 10.4, J4,3eq = 4.4 Hz, 1 H, 4-H), 4.31 (dd, J9a,9b
= 12.4, J9a,8 = 2.6 Hz, 1 H, 9a-H), 4.08–3.94 (m, 2 H, 5-H, 6-H),
3.98 (dd, J9b,9a = 12.4, J9b,8 = 6.2 Hz, 1 H, 9b-H), 3.77 (s, 3 H,
CO2CH3), 3.71 (t, J = 4.9 Hz, 2 H, OCH2), 3.56 (t, J = 4.9 Hz, 2
H, CH2OH), 3.19 (m, 1 H, CH of cyclohexyl), 2.67 (s, 1 H, OH),
2.45 (dd, J3eq,3ax = 12.7, J3eq,4 = 4.4 Hz, 1 H, 3eq-H), 2.15, 2.10,
1
Data for Isomer 12b: H NMR (CD3OD, 250 MHz): δ = 3.83 (dd,
J9a,9b = 11.4, J9a,8 = 2.4 Hz, 1 H, 9a-H), 3.82–3.72 (m, 1 H, 8-H),
3.81 (s, 3 H, CO2CH3), 3.76 (dd, J6,5 = 10.0, J6,7 = 1.9 Hz, 1 H, 6-
H), 3.69 (t, J5,6 = J5,NH = J5,4 = 10.0 Hz, 1 H, 5-H), 3.66 (dd, J9b,9a
= 11.4, J9b,8 = 5.7 Hz, 1 H, 9b-H), 3.63–3.58 (m, 1 H, 4-H), 3.51
(dd, J7,8 = 9.1, J7,6 = 1.9 Hz, 1 H, 7-H), 2.44 (dd, J3eq,3ax = 12.9,
2.03, and 2.00 (4ϫs, 12 H, OAc), 1.90 (dd, J3ax,3eq = 12.7, J3ax,4
=
J3eq,4 = 4.6 Hz, 1 H, 3eq-H), 2.17 (dd, J3ax,3eq = 12.9, J3ax,4
=
11.1 Hz, 1 H, 3ax-H), 1.85 (s, 3 H, NCOCH3), 1.80–1.60 (m, 8 H,
CH2 of cyclohexyl) ppm. 13C NMR (CDCl3, 90 MHz): δ = 170.8,
170.6, 170.5, 170.1, 169.9, and 169.8 (4 ϫ OCOCH3, NCOCH3,
CO2CH3), 85.7 (C-2), 77.9 (CH of cyclohexyl), 74.1 (COH), 73.2,
70.3, 68.7, 67.8 (C-4, C-6, C-7, C-8), 68.9 (OCH2), 62.6 (C-9), 62.0
(CH2OH), 52.5 (CH3O), 49.3 (C-5), 32.9 (C-3), 30.0, 29.9, 27.2,
and 27.0 (4ϫCH2 of cyclohexyl), 23.1, 21.4, 21.2, 20.8, and 20.7
(4ϫCH3OCO, CH3CON) ppm. MS (ES): m/z = 656.2 [M + Na]+.
HRMS: calcd. for C28H43NNaO15 656.2525; found 656.2539.
C28H43NO15 (633.65): calcd. C 53.07, H 6.84, N 2.21; found C
53.29, H 7.23, N 1.86.
11.1 Hz, 1 H, 3ax-H), 2.01 (s, 3 H, NAc), 1.94–1.10 (m, 11 H,
cyclohexyl) ppm. 13C NMR (CD3OD, 90 MHz): δ = 175.2, 175.0
(CO, NCOMe, CO2Me), 85.5 (C-2), 80.0 (COH), 75.9, 72.9, 70.3,
69.1 (C-6, C-8, C-4, C-7), 64.6 (C-9), 54.1 (C-5), 53.2 (CH3O), 42.3
(C of cyclohexyl), 39.1 (C-3), 32.9, 28.3, 27.8, 27.4, 27.3 (CH2 of
cyclohexyl), 22.8 (CH3CON) ppm. MS (ESI): m/z = 442.1 [M +
Na]+. HRMS: calcd. for C19H33NNaO9 442.20530; found
442.20549.
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-
glycero-α- -galacto-non-2-ulopyranosonate)-4-dioxolanylcyclohex-
D
anol (28): A freshly prepared solution of SmI2 in THF (0.1 ,
100 mL, 10 mmol of SmI2) was added at 20 °C under Ar to a
stirred THF (10 mL) solution of acetates 3a and 3b (1.77 g,
3.32 mmol) and 4-dioxolanocyclohexanone (1.00 g, 6.64 mmol).
After the mixture had been stirred for 2 h, saturated aqueous
NH4Cl was added and the reaction mixture was extracted three
times with CH2Cl2. The combined organic phases were washed
twice with water and dried with Na2SO4, and the solvents were
evaporated to dryness. Flash chromatography on silica gel (toluene/
acetone, 1:1) gave 28 (1.78 g, 85%). [αD]52889 = –36.4 (c = 0.14,
CH2Cl2). 1H NMR (CDCl3, 360 MHz): δ = 5.62 (d, JNH,5 = 9.5 Hz,
1 H, NH), 5.52 (ddd, J8,7 = 8.1, J8,9b = 6.6, J8,9a = 2.5 Hz, 1 H, 8-
H), 5.39 (dd, J7,8 = 8.1, J7,6 = 1.1 Hz, 1 H, 7-H), 4.84 (ddd, J4,3ax
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
D-
glycero-α- -galacto-non-2-ulopyranosonate)-4-(2Ј-allyloxyethoxy)cy-
D
clohexanol (30): Allyl trichloroacetimidate (678 mg, 3.34 mmol)
and trifluoromethanesulfonic acid (74 µL, 0.84 mmol) were suc-
cessively added to a stirred solution of alcohol 30 (1.06 g,
1.67 mmol) in a dry dichloromethane/cyclohexane mixture (6/
12 mL). After having been stirred for 4 h at room temperature, the
mixture was diluted with CH2Cl2 and the organic phase was
washed with saturated aqueous sodium hydrogen carbonate. The
aqueous phase was extracted with CH2Cl2, the combined organic
phases were dried with Na2SO4, and the solvents were evaporated.
Flash chromatography on silica gel (toluene/acetone, 1:1) gave 30
(697 mg, 1.03 mmol, 62%). M.p. 56 °C (toluene/acetone). [αD]25889
=
= 11.2, J4,5 = 10.4, J4,3eq = 4.5 Hz, 1 H, 4-H), 4.43 (dd, J9a,9b
=
–22.4 (c = 0.12, MeOH). 1H NMR (CDCl3, 360 MHz): δ = 5.83
(ddt, J = 16.1, J = 10.7, J = 5.5 Hz, 1 H, OCH2CHCH2), 5.46 (d,
JNH,5 = 9.6 Hz, 1 H, NH), 5.32 (ddd, J8,7 = 8.0, J8,9b = 6.7, J8,9a
= 2.3 Hz, 1 H, 8-H), 5.22 (dd, J7,8 = 8.0, J7,6 = 1.4 Hz, 1 H, 7-H),
5.19 (dd, J = 16.1, J = 1.2 Hz, 1 H, OCH2CHCH2), 5.09 (dd, J =
10.7, J = 1.2 Hz, 1 H, OCH2CHCH2), 4.66 (ddd, J4,3ax = 11.6, J4,5
12.4, J9a,8 = 2.5 Hz, 1 H, 9a-H), 4.22–3.97 (m, 2 H, 5,6-H), 4.21
(dd, J9b,9a = 12.4, J9b,8 = 6.6 Hz, 1 H, 9b-H), 4.05 [m, 4 H, O(CH2)2-
O], 3.89 (s, 3 H, CO2CH3), 2.95 (s, 1 H, OH), 2.58 (dd, J3eq,3ax
12.8, J3eq,4 = 4.5 Hz, 1 H, 3eq-H), 2.27, 2.22, 2.15, and 2.12 (4ϫs,
12 H, 4ϫOCOCH3), 1.96 (s, 3 H, NCOCH3), 1.94 (dd, J3ax,3eq
=
=
12.8, J3ax,4 = 11.2 Hz, 1 H, 3ax-H), 1.93–1.60 (m, 8 H, CH2 of
cyclohexyl) ppm. 13C NMR (CDCl3, 90 MHz): δ = 170.8, 170.7,
170.5, 170.1, 169.9, and 169.8 (4ϫOCOCH3, NCOCH3, CO2CH3),
108.1, 85.7 (C-2), 74.1 (COH), 73.1, 70.3, 68.7, 67.7 (C-4, C-6, C-
7, C-8), 64.9, 63.9 (OCH2CH2O), 62.9 (C-9), 52.2 (CH3O), 49.0 (C-
5), 32.9 (C-3), 29.9, 29.7, 29.2, and 28.9 (4ϫCH2 of cyclohexyl),
22.9, 21.1, 20.7, 20.6, and 20.5 (4 ϫ CH3OCO, CH3CON) ppm.
M.p. 208 °C (toluene/acetone). MS (ES): m/z = 654 [M + Na]+.
HRMS: calcd. for C28H41NNaO15 654.2368; found 654.2383.
C28H41NO15 (631.63): calcd. C 53.24, H 6.54, N 2.22; found C
53.33, H 6.44, N 1.94.
= 11.1, J4,3eq = 4.4 Hz, 1 H, 4-H), 4.26 (dd, J9a,9b = 12.4, J9a,8
=
2.3 Hz, 1 H, 9a-H), 4.03–3.89 (m, 3 H, 5-H, 6-H, 9b-H), 3.94 (m,
2 H, OCH2CHCH2), 3.71 (s, 3 H, CO2CH3), 3.55 (t, J = 5.0 Hz, 2
H, OCH2), 3.50 (t, J = 5.0 Hz, 2 H, CH2Oallyl), 3.18 (m, 1 H, CH
of cyclohexyl), 2.51 (s, 1 H, OH), 2.39 (dd, J3eq,3ax = 12.8, J3eq,4
=
4.4 Hz, 1 H, 3eq-H), 2.08, 2.04, 1.97, and 1.94 (4ϫs, 12 H, 4ϫOC-
OCH3), 1.84 (dd, J3ax,3eq = 12.8, J3ax,4 = 11.6 Hz, 1 H, 3ax-H), 1.79
(s, 3 H, NCOCH3), 1.80–1.60 (m, 8 H, CH2 of cyclohexyl) ppm.
13C NMR (CDCl3, 90 MHz): δ = 171.8, 171.5, 171.4, 170.2, 170.1,
a n d 1 6 9 . 9 ( 4 ϫ OCOCH3 , NCOCH 3 , CO2 CH3 ) , 134. 6
(OCH2CHCH2), 116.8 (OCH2CHCH2), 85.5 (C-2), 77.9 (CH of
cyclohexyl), 74.1 (COH), 73.9, 70.2, 68.6, 67.6 (C-4, C-6, C-7, C-
1-C-(Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
glycero-α-
clohexanol (29): Trimethylsilyl trifluoromethanesulfonate (0.48 mL,
D-
D-galacto-non-2-ulopyranosonate)-4-(2Ј-hydroxyethoxy)cy- 8), 72.0 (OCH2CHCH2), 69.6 (CH2Oallyl), 67.1 (OCH2), 62.5 (C-
9), 52.3 (CH3O), 49.1 (C-5), 32.8 (C-3), 29.9, 29.7, 27.0, and 26.8
Eur. J. Org. Chem. 2007, 3145–3157
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3155

A. Malapelle, A. Coslovi, G. Doisneau, J.-M. Beau
FULL PAPER
[5]
[6]
D. K. Ress, R. J. Linhardt, Curr. Org. Synth. 2004, 1, 31–46.
(4 ϫ CH2 of cyclohexyl), 23.0, 21.1, 20.7, 20.6, and 20.5
(4ϫCH3OCO, CH3CON) ppm. MS (ES): m/z = 696.4 [M + Na]+.
HRMS: calcd. for C31H47NNaO15 696.2838 found 696.2850.
C31H47O15N: calcd. C 55.27; H 7.03; N 2.08.
Selected recent reviews: J.-M. Beau, T. Gallagher, Top. Curr.
Chem. 1997, 187, 1–54; Y. Du, R. J. Linhardt, I. R. Vlahov,
Tetrahedron 1998, 54, 9913–9959; A. Dondoni, A. Marra,
Chem. Rev. 2000, 100, 4395–4422; L. Somsák, Chem. Rev. 2001,
101, 81–136; L. Liu, M. McKee, M. H. D. Postema, Curr. Org.
Chem. 2001, 5, 1133–1167.
Reviews with emphasis on C-oligomers: T. Skrydstrup, B. Vau-
zeilles, J.-M. Beau, in Oligosaccharides in Chemistry and Bi-
ology - A Comprehensive Handbook, vol. 1 (Eds.: B. Ernst, P.
Sinaÿ, G. Hart), Wiley-VCH, Weinheim, 2000, pp. 495–530; J.-
M. Beau, B. Vauzeilles, T. Skrydstrup: in Glycoscience: Chemis-
try and Chemical Biology, vol. 3 (Eds.: B. Fraser-Reid, K. Tat-
suta, J. Thiem), Springer Verlag, Heidelberg, 2001; see also A.
Dondoni, A. Marra, M. Mizuno, P. P. Giovannini, J. Org.
Chem. 2002, 67, 4186–4199 and references cited therein.
a) K. Luthman, M. Orbe, T. Waglund, A. Claesson, J. Org.
Chem. 1987, 52, 3777–3784; b) H. Paulsen, P. Matschulat, Lie-
bigs Ann. Chem. 1991, 487–495; c) K. Walliman, A. Vasella,
Helv. Chim. Acta 1991, 74, 1520–1532; d) J. Nagy, M. Bednar-
ski, Tetrahedron Lett. 1991, 32, 3953–3956.
W. Notz, C. Hartel, B. Waldscheck, R. R. Schmidt, J. Org.
Chem. 2001, 66, 4250–4260.
1-C-(Methyl 5-Acetamido-3,5-dideoxy-D-glycero-α-D-galacto-non-2-
ulopyranosonate)-4-(2Ј-allyloxyethoxy)cyclohexanol (31): Com-
pound 30 (400 mg, 0.59 mmol) was de-O-acetylated in dry meth-
anol (20 mL) containing K2CO3 (33 mg, 0.24 mmol). The mixture
was stirred overnight at room temperature. Neutralization with an
ion-exchange resin and filtration through silica gel (dichlorometh-
ane/methanol, 85:15) afforded product 31 (264 mg, 0.52 mmol,
88%). M.p. 72 °C (toluene/acetone). [αD]52889 = –21.8 (c = 0.11,
[7]
[8]
1
MeOH). H NMR (CD3OD, 360 MHz): δ = 5.90 (ddt, J = 16.5, J
= 10.5, J = 5.3 Hz, 1 H, OCH2CHCH2), 5.28 (dd, J = 16.5, J =
1.7 Hz, 1 H, OCH2CHCH2), 5.16 (dd, J = 10.5, J = 1.7 Hz, 1 H,
OCH2CHCH2), 4.02 (m, 2 H, OCH2CHCH2), 3.87–3.77 (m, 2 H,
8-H, 9a-H), 3.68–3.54 (m, 5 H, 9b-H, 7-H, 6-H, 5-H, 4-H), 3.51
(m, 4 H, OCH2CH2Oallyl), 3.30 (s, 3 H, CO2Me), 3.23 (m, 1 H,
CH of cyclohexyl), 2.55 (dd, J3eq,3ax = 12.5, J3eq,4 = 3.9 Hz, 1 H,
[9]
3eq-H), 2.01 (s, 3 H, NCOCH3), 1.85 (dd, J3ax,3eq = 12.5, J3ax,4
=
8.4 Hz, 1 H, 3ax-H), 1.80–1.40 (m, 8 H, CH2 of cyclohexyl) ppm.
MS (ES): m/ z = 5 28 . 3 [ M + N a ] + . H R M S : c a l c d . fo r
C23H39NNaO11 528.2415; found 528.2430.
[10]
[11]
I. R. Vlahov, P. I. Vlahova, R. J. Linhardt, J. Am. Chem. Soc.
1997, 119, 1480–1481.
Neutral hexoses: a) D. Mazéas, T. Skrydstrup, O. Doumeix, J.-
M. Beau, Angew. Chem. Int. Ed. Engl. 1994, 33, 1383–1386; b)
D. Mazéas, T. Skrydstrup, J.-M. Beau, Angew. Chem. Int. Ed.
Engl. 1995, 34, 909–912; c) T. Skrydstrup, D. Mazéas, M. El-
mouchir, G. Doisneau, C. Riche, A. Chiaroni, J.-M. Beau,
Chem. Eur. J. 1997, 3, 1342–1355; d) T. Skrydstrup, O. Jarreton,
D. Mazéas, D. Urban, J.-M. Beau, Chem. Eur. J. 1998, 4, 655–
671; e) O. Jarreton, T. Skrydstrup, J.-F. Espinosa, J. Jiménez-
Barbero, J.-M. Beau, Chem. Eur. J. 1999, 5, 430–441; f) N.
Miquel, G. Doisneau, J.-M. Beau, Angew. Chem. Int. Ed. 2000,
39, 4111–4114.
2-Acetamido-2-deoxy sugars: a) D. Urban, T. Skrydstrup, C.
Riche, A. Chiaroni, J.-M. Beau, Chem. Commun. 1996, 1883–
1884; b) D. Urban, T. Skrydstrup, J.-M. Beau, J. Org. Chem.
1998, 63, 2507–2516; c) L. Andersen, L. M. Mikkelsen, J.-M.
Beau, T. Skrydstrup, Synlett 1998, 1393–1395; d) S. Palmier, B.
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(5-Acetamido-3,5-dideoxy-D-glycero-α-D-galacto-non-2-ulopyranosi-
dic)acid-4-(2Ј-allyloxy ethoxy)cyclohexanol (32): The methyl ester
was cleaved under these conditions: compound 31 (6.0 mg,
0.020 mmol) in water (2 mL) containing an aqueous NaOH solu-
tion (1 , pH = 14) was stirred overnight at room temperature.
Neutralization with ion-exchange resin and filtration through silica
gel (dichloromethane/methanol, 85:15) afforded product 32
(9.3 mg, 0.019 mmol, 95%). 1H NMR (CD3OD, 360 MHz): δ =
5.90 (ddt, J = 16.5, J = 10.5, J = 5.3 Hz, 1 H, OCH2CHCH2), 5.28
(dd, J = 16.5, J = 1.7 Hz, 1 H, OCH2CHCH2), 5.14 (dd, J = 10.5,
J = 1.7 Hz, 1 H, OCH2CHCH2), 4.02 (m, 2 H, OCH2CHCH2),
3.87–3.77 (m, 2 H, 8-H, 9a-H), 3.68–3.54 (m, 5 H, 9b-H, 7-H, 6-
H, 5-H, 4-H), 3.51 (m, 4 H, OCH2CH2Oallyl), 3.20 (m, 1 H, CH
of cyclohexyl), 2.53 (dd, J3eq,3ax = 12.5, J3eq,4 = 3.9 Hz, 1 H, 3eq-
[12]
[13]
H), 2.01 (s, 3 H, NCOCH3), 1.85 (dd, J3ax,3eq = 12.5, J3ax,4
=
a) T. Polat, Y. Du, R. J. Linhardt, Synlett 1998, 1195–1196; b)
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B. Kuberan, S. A. Sikkander, H. Tomiyama, R. J. Linhardt,
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8.4 Hz, 1 H, 3ax-H), 1.80–1.40 (m, 8 H, CH2 of cyclohexyl) ppm.
MS (ES): m/z = 514.3 [M + Na]+.
[14]
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Z. Abdallah, G. Doisneau, J.-M. Beau, Angew. Chem. Int. Ed.
2003, 42, 5209–5212.
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Acknowledgments
We gratefully acknowledge the Ministère de la Recherche for a
Ph.D. grant to A. M. and Area Science Park and Friuli Venezia
Giulia Region for a mobility grant to A. C.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3145–3157

“α-C-Glycosides” from the Anomeric Acetates
FULL PAPER
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Received: February 28, 2007
Published Online: May 30, 2007
Eur. J. Org. Chem. 2007, 3145–3157
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3157