Horner-wadsworth-emmons reaction of unprotected sugars in water or in the absence of any solvent: One-step access to C-glycoside amphiphiles

Article abstract of DOI:10.1002/ejoc.200901286

The synthesis of C-glycosides in water or in the absence of any solvent from free sugars and β-keto phosphonates is reported. The methodology permits a one-step access to C-glycoside amphiphiles in moderate-to-good yields. The selectivity (??/β and furanoside/pyranoside) is discussed and a process that leads to pure β-C-pyranosides is also described.

Full text of DOI:10.1002/ejoc.200901286

FULL PAPER
DOI: 10.1002/ejoc.200901286
Horner–Wadsworth–Emmons Reaction of Unprotected Sugars in Water or in
the Absence of Any Solvent: One-Step Access to C-Glycoside Amphiphiles
Adeline Ranoux,[a,b] Loïc Lemiègre,[a] Maud Benoit,[a] Jean-Paul Guégan,[a] and
Thierry Benvegnu*[a]
Keywords: Carbohydrates / C-Glycosides / Solvent-free reactions / Surfactants / Green chemistry / Amphiphiles
The synthesis of C-glycosides in water or in the absence of
coside amphiphiles in moderate-to-good yields. The selec-
any solvent from free sugars and β-keto phosphonates is re- tivity (α/β and furanoside/pyranoside) is discussed and a pro-
ported. The methodology permits a one-step access to C-gly-
cess that leads to pure β-C-pyranosides is also described.
condensation of symmetrical or unsymmetrical β-diketones
and unprotected sugars in alkaline aqueous solutions has
been successfully investigated.[4–7] The synthesis relies on a
Knoevenagel condensation between the carbanion of a β-
diketone and the formyl group of an unprotected sugar. A
C-xyloside alcohol resulting from the reduction of a β-keto-
C-glycoside obtained by this method was found to stimulate
sulfated glycosaminoglycan (GAG) synthesis: this has re-
cently been developed in cosmetic skincare products as pro-
Introduction
In recent years, C-glycosides have gained increasing im-
portance because of their abilities to promote high chemical
and enzymatic stabilities and to display interesting bio-
logical properties.[1,2] Some of them have been reported to
exhibit anti-tumour, anti-bacterial, anti-viral and glycosi-
dase inhibitory activities.[3] The major feature of C-glyco-
sides is their unique chemical reactivity. The absence of an-
omeric effects and principally the resistance of the C-anom-
eric linkage towards acid/enzymatic hydrolysis make them
attractive candidates as stable carbohydrate mimetics of O-
glycosides. However, the synthetic problems posed by the
replacement of the exo-anomeric oxygen atom by a methyl-
ene group still represent a real challenge in carbohydrate
chemistry.
Most of the synthetic approaches to C-glycosides devel-
oped over the past few years are based upon electrophilic
or nucleophilic substitutions, transition-metal-mediated C-
glycosylations, anomeric radical reactions, rearrangements
and cycloadditions, and sugar ring formation reactions.[1,2]
These methods generally require additional steps before and
after the formation of the C-glycosidic bond that could in-
volve the activation of the anomeric carbon and/or the pro-
tection/deprotection of the hydroxy groups. Recently, a
straightforward synthesis of β-δ-C-glycosidic β-ketones by
XylaneTM [8]
However, until now, no straightforward ap-
.
proach has been described for the synthesis of amphiphilic
C-glycosides from unprotected sugars in organic solvent-
free media. The development of such an approach could be
invaluable for the preparation of green surfactant formula-
tions based on C-glycosides.
With the aim of finding an alternative direct synthetic
route that does not need organic media either as solvents
or as co-solvents even for the introduction of highly hydro-
phobic chains, we explored the Horner–Wadsworth–
Emmons (HWE) reaction of unprotected sugars under un-
usual conditions. The HWE reaction is a well-known
method for the formation of olefins from aldehydes and
ketones. In the case of unprotected carbohydrates,[9] the al-
dehyde is masked in the form of a hemiacetal. Conse-
quently, the HWE reaction has to drive the equilibrium be-
tween the cyclic hemiacetalic form and the corresponding
ring-opened sugar incorporating the reactive aldehyde func-
tionality to provide an acyclic olefin. Once produced, this
hydroxy-olefin can finally cyclize in situ to form the ex-
pected four C-glycosides (α/β-pyranosides or -furanosides;
Scheme 1).
[a] Ecole Nationale Supérieure de Chimie de Rennes, CNRS,
UMR 6226
Université européenne de Bretagne,
Avenue du Général Leclerc, CS 50837, 35708 Rennes Cedex 7,
France
The condensation reactions of phosphonates with unpro-
tected sugars have so far been investigated only in organic
solvents and led mainly to C-furanoside derivatives.[10,11]
Convenient protection of the carbohydrates is necessary to
achieve in one step a perfect control of the cyclization to
the pyranoside or the furanoside form.[10–12] Therefore the
Fax: +33-2-23238046
E-mail: thierry.benvegnu@ensc-rennes.fr
[b] Armor Protéines,
Le Pont, 35460 Saint Brice en Coglès, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901286.
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One-Step Access to C-Glycoside Amphiphiles
Synthesis Under Aqueous Conditions
Four representative sugars, in terms of disaccharidic and
monosaccharidic reactivities [lactose (1), -glucose (2), -
galactose (3) and -xylose (4)], and two β-keto phosphon-
ates 5a,b with different alkyl chain lengths were selected.
The mineral bases K2CO3, NaOH and NaHCO3 were con-
sidered to furnish the basic conditions required for the
HWE reaction (Scheme 2). The results of the HWE reac-
tions performed in water are reported in Table 1.
Scheme 1. General route for the formation of both C-pyranoside
and C-furanoside by the HWE reaction.
access to six-membered C-glycoside amphiphiles in pure
form under organic solvent-free conditions and from un-
protected sugars remains a challenge.
Results and Discussion
To develop a general and environmentally friendly syn-
thetic route to β-keto-C-glycosides we investigated new ver-
sions of the HWE reaction in water or in the absence of
any solvent from unprotected carbohydrates and commer-
cially or readily available dimethyl 2-oxoalkylphosphonates
(see Schemes 2 and 3, Tables 1 and 2). In particular, our
major objective was to establish methods that permitted the
synthesis of keto-C-glycosides with a wide range of alkyl
chain lengths in a chemoselective and stereocontrolled man-
ner.[13]
Scheme 2. Reaction of β-keto phosphonates 5a and 5b with lactose
(1), -glucose (2), -galactose (3), and -xylose (4) in water
(Table 1).
Table 1. Reaction of β-keto phosphonates 5a–b with lactose (1), -glucose (2), -galactose (3), -xylose (4), in water.
1
[a] Determined by H NMR spectroscopy.
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A. Ranoux, L. Lemiègre, M. Benoit, J.-P. Guégan, T. Benvegnu
FULL PAPER
We first studied the reaction of the water-soluble phos-
phonate 5a in basic aqueous media (K2CO3, 9 equiv.) at
60 °C (Table 1, entries 1–4). The reaction of the disaccha-
ride (lactose 1) proceeded cleanly to provide the pure β-C-
pyranoside βpyr-6a in 67% yield (Table 1, entry 1). The
same conditions applied to monosaccharides 2–4 also led
to a selective reaction in favour of the β-C-pyranosides
βpyr-7a–9a, although careful analysis of the NMR spectra
revealed the presence of small amounts of αpyr-7a–9a and
α/βfur-7a–9a derivatives (Table 1, entries 2–4). Switching
the base to sodium hydroxide influenced the pyranoside/
furanoside and α/β ratios and led to the C-glucoside pyr-7a
in an α/β ratio of 5:95 (Table 1, entry 5).
The better diastereoselectivity observed with NaOH was
reached to the detriment of the yield, which decreased from
75 to 28%. Conversely, the use of a weaker base (NaHCO3)
afforded a higher yield, but with a lower β-pyranoside selec-
tivity (Table 1, entry 6). These results can be explained by
the existence of a faster equilibration towards the thermo-
dynamic product (β-pyranoside) when a strong base is used.
Furthermore, they show that the keto-C-glycosides may be
sensitive to strong basic media. Therefore the use of K2CO3
in HWE reactions of unprotected sugars in water remained
a good compromise in terms of yields and selectivities. As
expected, the poor solubility of the phosphonate 5b pos-
sessing a C7 alkyl chain led to lower yields (25–35%) irre-
spective of the sugar used (Table 1, entries 7–8). Even
though these aqueous conditions were found to be efficient
for a water-soluble phosphonate, we rapidly sought alterna-
tive reaction conditions that would provide a general access
to C-glycoside surfactants irrespective of the chain length
of the phosphonate.
Scheme 3. Synthesis of β-keto phosphonates 5a–e.
mum of 15 equiv. of phosphonates 5a–e was necessary to
afford the corresponding C-glycosides in moderate-to-good
yields (Scheme 4, Table 2).
Scheme 4. Reaction of β-keto phosphonates 5a–e with lactose (1),
-glucose (2) and -galactose (3) following procedure A (see
Table 2 for structures).
Under these new conditions, the C-lactoside 6a was ob-
tained in a similar yield (64%) as under aqueous conditions
(Table 2, entry 1). However, we observed a dramatic in-
crease in the yield of the C-lactoside 6b possessing a C7
chain (71 instead of 35%; Table 2, entry 2). This process
Synthesis Under Solvent-Free Conditions
The development of solvent-free reactions usually re- was then applied to -glucose leading to the corresponding
quires the use of an excess of reactant. In this case, the C-glucosides 7b in 51% yield. Increasing the carbon chain
consideration of such conditions as a greener process thus length of the phosphonate (C13 5c and C19:0 5d) also led to
implies the recycling of the reactant. With this in mind, we satisfactory yields for both lactose 1 and the monosaccha-
studied the HWE olefination/cyclization process in the rides 2 and 3 (48–70%, Table 2, entries 4–8). The reaction
phosphonate itself. Our study was based upon the use of proceeded with the same efficiency with the unsaturated
phosphonates with carbon chain lengths ranging from C3 phosphonate 5e (C19:1) and sugars 1 and 2 providing C-
to C19 (5a–e). Non-commercial β-keto phosphonates 5c–e glycosides 6e and 7e in 58 and 50% yields, respectively. This
were prepared from the corresponding fatty acids 10–12 methodology therefore affords a simple access to C-glyco-
(Scheme 3). The conversion of 10–12 to the Weinreb amides side amphiphiles that may be incorporated into various sur-
was achieved by reaction with carbonyldiimidazole (CDI) factant formulations.
and methoxymethylamine. Then addition of the lithium salt
As mentioned before, we envisaged a solvent-free HWE
of dimethyl methylphosphonate to the Weinreb amide de- reaction, which implies the recycling of the excess phos-
rivatives led to the desired β-keto phosphonates 5c–e in phonate. We then confirmed the possibility of recovering
good yields (60–90% over the two steps).
and reusing the phosphonates 5a–e in other HWE reactions
The β-keto phosphonates 5a–e were then subjected to with similar performances. A typical procedure (reduced
HWE reactions with various carbohydrates [lactose (1), - pressure distillation) afforded 40–78% of recovered phos-
glucose (2) and -galactose (3)] in the absence of any sol- phonate 5a–e.
vent. As under aqueous conditions, we used potassium car-
In terms of selectivity, note that the reaction of lactose
bonate to furnish basic conditions, however, the amount of with 5a or 5b (15 equiv.) yielded isomers αpyr-6a and αpyr-
base was reduced to 3 equiv. for solubility reasons. A mini- 6b as the major products (Table 2, entries 1 and 2) instead
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One-Step Access to C-Glycoside Amphiphiles
Table 2. Reaction of β-keto phosphonates 5a–e with lactose (1), -glucose (2) and -galactose (3) in the absence of solvent (procedure
A).[a]
1
[a] Procedure A: one step, neat, K2CO3 (3 equiv.), 80 °C, 24h. [b] Determined by H NMR spectroscopy. [c] α/β (fur): 67:37.
of the β-pyranoside forms that were obtained quasi-exclu- phosphonate) followed by treatment with an aqueous base
sively under aqueous conditions (Table 1, entries 1 and 7). [aq. K2CO3 (9 equiv.), 60 °C, 12 h; Scheme 5]. This simple
Also, glucose gave a 50:50 pyr/fur ratio and here again the additional basic treatment applied to C-lactoside, C-gluco-
α/β ratio of the C-glucoside is in favour of the α isomer side or C-galactoside isomer mixtures (6b–8b and 6c)
both for the pyranoside and furanoside derivatives (Table 2, yielded pure pyranoside compounds[11] with α/β ratios rang-
entry 3). These observations show that equilibration be- ing from 5:95 to 0:100 (Table 3, entries 1–4).
tween the four furanoside and pyranoside isomers was
reached at a lower rate in the absence of solvent than in
aqueous media. The same observations were made in the
reactions of dimethyl 2-oxoalkylphosphonates 5c–e with
longer alkyl chains, with the α-pyranoside C-glycosides pre-
dominating (Table 2, entries 4–10).
The production of mixtures of isomers or even crude
mixtures can be satisfactory enough when these C-glycoside
amphiphiles are intended to be used in surfactant formula-
tions. However, for a better physicochemical understanding
and to widen the range of applications, we elaborated an-
other procedure that permitted selective access to β-py-
ranosides.
Thus, with the aim of obtaining stereochemically pure
compounds we next investigated a stereocontrolled route
(procedure B) that involved the same HWE reaction condi-
tions as in procedure A (including the recovery of unreacted -glucose (2) and -galactose (3) following procedure B.
Scheme 5. Reaction of β-keto phosphonates 5b,c with lactose (1),
Eur. J. Org. Chem. 2010, 1314–1323
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A. Ranoux, L. Lemiègre, M. Benoit, J.-P. Guégan, T. Benvegnu
FULL PAPER
Table 3. Selective access to β-pyr-C-glycosides 6b–8b and 6c (procedure B).[a]
[a] Procedure B: i) neat, K2CO3 (3 equiv.), 80 °C, 24 h, distillation of the residual phosphonate, ii) H2O, K2CO3 (9 equiv.), 60 °C, 12 h.
1
[b] Determined by H NMR spectroscopy.
These interesting results suggest that the α/β-furanosides tion mixture. This methodology represents an environmen-
and α-pyranosides initially formed in solvent-free reaction tally friendly process for the synthesis of C-glycoside surfac-
media could be isomerized to the thermodynamic β-pyr- tants covering a wide range of hydrophobic/hydrophilic bal-
anoside products when heated in basic aqueous solutions. ances. Physicochemical evaluations of this ecofriendly sur-
The isomerization pathway would follow a ring-opening/ factant family are in progress.
closing equilibrium involving an α,β-unsaturated hydroxy
ketone and lead to the thermodynamically favoured β-pyr-
anoside isomer (Scheme 6).
Experimental Section
General: Commercially available chemicals were used without fur-
ther purification. Analytical TLC was performed on Merck 60
F254 silica gel non-activated plates. A solution of 5% H2SO4 in
EtOH was used to develop the plates. Merck 60 H (5–40 mm) silica
gel was used for column chromatography. 1H and 13C NMR spectra
were recorded at 400 and 100 MHz, respectively, with a Bruker
Avance III spectrometer. In the NMR data, the numbering and α/
β designations are in accordance with carbohydrate nomenclature.
“f” and “p” refer to furanoside and pyranoside derivatives respec-
tively. MS spectra were recorded with a Waters Micromass Q-TOF
spectrometer equipped with a Z-spray ion source. IR spectra were
recorded with a Thermo Nicolet 320 FTIR spectrometer and op-
tical rotations were recorded with a Perkin–Elmer 341 polarimeter.
General Procedure for the Synthesis of Phosphonates 5c–e. Synthesis
of the Weinreb Amides: Under nitrogen, carbonyldiimidazole
Scheme 6. Isomerization of pyranoside/furanoside mixtures in
(27.5 mmol, 1.1 equiv.) was added slowly at room temperature to a
aqueous basic media (shown for glucoside derivatives).
solution of fatty acid 10–12 (25 mmol, 1 equiv.) in anhydrous
dichloromethane (250 mL). After 40 min, methoxymethylammo-
nium chloride (27.5 mmol, 1.1 equiv.) and triethylamine
(27.5 mmol, 1.1 equiv.) were added. The reaction mixture was
stirred at room temperature for 4 h and was quenched by the ad-
Conclusions
dition of a saturated solution of ammonium chloride (40 mL). The
aqueous phase was extracted by dichloromethane. The combined
organic phases were then washed with brine, dried with MgSO4
and concentrated under reduced pressure. Flash chromatography
on silica gel (dichloromethane) afforded the corresponding amide
as a colourless oil.
We have developed a one-step HWE synthesis of amphi-
philic C-glycosides from unprotected mono- and disaccha-
rides. The general procedure described herein was carried
out in the absence of any solvent with recyclable β-keto
phosphonates. Moreover, it was applied to the introduction
of short (C3) to long (C19) alkyl chain lengths. Furthermore,
the thermodynamic compounds (β-C-pyranosides) were ob-
tained by using aqueous basic HWE reaction conditions or
Synthesis of the Phosphonates 5c–e: Under nitrogen, BuLi
(30 mmol, 1.2 equiv., 1.6  in hexane) was added at –78 °C to a
by aqueous basic treatment of the solvent-free crude reac- solution of dimethyl methylphosphonate (30 mmol, 1.2 equiv.) in
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One-Step Access to C-Glycoside Amphiphiles
anhydrous THF (150 mL). The reaction mixture was stirred for
30 min at the same temperature and then a solution of the Weinreb
amide (25 mmol, 1 equiv.) in THF (50 mL) was added slowly. The
reaction mixture was warmed to –45 °C over 3 h and then a satu-
rated solution of ammonium chloride (40 mL) was added. The
aqueous phase was extracted with Et2O. The combined organic
phases were then washed with brine, dried with MgSO4 and con-
centrated under reduced pressure. Flash chromatography on silica
gel (DCM/AcOEt, 1:1) afforded the corresponding β-keto phos-
phonates 5c–e.
(quint., J = 7.6 Hz, 2 H, CH2), 1.27 (d, J = 19.2 Hz, 20 H, CH2),
0.87 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 177.3 (CO), 129.9, 129.7 (2 CH), 61.1 (O-CH3), 31.90 (N-CH3),
31.85 (CH2), 29.72, 29.68, 29.5, 29.4, 29.3, 29.1, 27.2, 24.6, 22.6,
14.1 (CH3) ppm. HRMS (ESI+): calcd. for C20H39NO2 [M + Na]+
348.28785; found 348.2880; [M + H]+ 326.30590; found 326.3049.
Dimethyl 2-Oxononadec-10-enylphosphonate (5e): Yield 78%.
Colourless oil. Rf (DCM/AcOEt, 1:1) = 0.6. 1H NMR (CDCl3,
400 MHz): δ = 5.30 (m, 2 H, CH), 3.07 (d, JH,P = 22.8 Hz, 2 H, P-
CH2), 3.76 (d, JH,P = 11.2 Hz, 6 H, O-CH3), 2.59 [t, J = 7.2 Hz, 2
H, CO(CH2)], 1.98 [q, J = 6.8 Hz, 4 H, CH(CH2)], 1.56 (quint., J
= 7.2 Hz, 2 H, CH2), 1.25 [m, 16 H, (CH2)11], 0.85 (t, J = 6.8 Hz,
3 H, CH3) ppm. 31P NMR (CDCl3, 162 MHz): δ = 22.9 ppm. 13C
NMR (CDCl3, 100 MHz): δ = 202.0 (d, JC,P = 5.9 Hz, CO), 129.9,
129.6 (2 CH), 52.9 (d, JC,P = 6.5 Hz, OCH3), 44.1 [d, JC,P = 1.4 Hz,
CO(CH2)], 41.8 (d, JC,P = 123 Hz, P-CH2), 31.8, 29.7, 29.6, 29.4,
29.22, 29.19, 29.0, 28.8, 27.12, 27.07, 23.3, 22.6, 14.0 (CH3) ppm.
HRMS (ESI+): calcd. for C21H41O4P [M + Na]+ 411.26402; found
411.2641; [M + H]+ 389.28207; found 389.2828.
Dimethyl 2-Oxotridecylphosphonate (5c). Amide Derivative: Yield
1
99%. Rf (DCM) = 0.5. H NMR (CDCl3, 400 MHz): δ = 3.67 (s,
3 H, O-CH3), 3.17 (s, 3 H, N-CH3), 2.40 [t, J = 7.6 Hz, 2 H,
CO(CH2)], 1.62 (quint., J = 7.6 Hz, 2 H, CH2), 1.25 [m, 16 H,
(CH2)8], 0.87 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 174.8 (CO), 61.2 (O-CH3), 32.0 (N-CH3), 31.9
(CH2), 29.6, 29.5, 29.41, 29.39, 29.3, 24.7, 22.7 [(CH2)8], 14.1
(CH3) ppm. HRMS (ESI+): calcd. for C-14H29NO2 [M + Na]+
266.2096; found 266.2098; [M + H]+ 244.22765; found 244.2286.
C14H29NO2 (243.39): calcd. C 69.09, H 12.01, N 5.75; found C
68.90, H 12.05, N 5.54.
General Procedure for the HWE Reactions
Dimethyl 2-Oxotridecylphosphonate (5c): Yield 91%. White solid.
Rf (DCM/AcOEt: 1:1) = 0.4. 1H NMR (CDCl3, 400 MHz): δ =
3.76 (d, JH,P = 11.2 Hz, 6 H, O-CH3), 3.07 (d, JH,P = 22.8 Hz, 2
H, P-CH2), 2.59 [t, J = 7.2 Hz, 2 H, CO(CH2)], 1.56 (quint., J =
7.2 Hz, 2 H, CH2), 1.24 [m, 16 H, (CH2)8], 0.87 (t, J = 6.8 Hz, 3
H, CH3) ppm. 31P NMR (CDCl3, 162 MHz): δ = 22.8 ppm. 13C
NMR (CDCl3, 100 MHz): δ = 202.1 (d, JC,P = 5.9 Hz, CO), 53.0
(d, JC,P = 6.5 Hz, OCH3), 44.2 [d, JC,P = 1.4 Hz, CO(CH2)], 41.2
(d, JC,P = 128 Hz, P-CH2), 31.9, 29.6, 29.4, 29.30, 28.9 (COCH2-
CH2), 23.4, 22.6, [(CH2)8], 14.1 (CH3) ppm. HRMS (ESI+): calcd.
for C15H30O4P [M + Na]+ 329.18577; found 329.1856; [M + H]+
307.20382; found 307.2043. C15H31O4P (306.38): calcd. C 58.80, H
10.20; found C 58.56, H 10.40.
Syntheses Under Aqueous Conditions: -Glucose, lactose, -galac-
tose or -xylose (1 equiv.) and K2CO3 (9 equiv.) were dissolved in
water heated at 60 °C. Dimethyl 2-oxoalkylphosphonate (3 equiv.)
was added and the reaction mixture was stirred at 60 °C for 24 h.
The reaction media was then neutralized with a few drops of a
5% aq. hydrochloric acid solution and freeze-dried. Flash column
chromatography on silica gel afforded pure C-glycoside.
Syntheses Under Solvent-Free Conditions. Procedure A: -Glucose,
lactose, or -galactose (1 equiv.) and K2CO3 (3 equiv.) were dis-
solved in dimethyl 2-oxoalkylphosphonate (15 equiv.). The reaction
mixture was stirred at 80 °C for 24 h. The excess phosphonate was
then removed by distillation under reduced pressure. Flash column
chromatography on silica gel afforded the pure C-glycoside.
Dimethyl 2-Oxononadecylphosphonate (5d). Amide Derivative: Yield
1
78%. Rf (DCM) = 0.65. H NMR (CDCl3, 400 MHz): δ = 3.67 (s,
Procedure B: -Glucose, -galactose or lactose (1 equiv.) and
K2CO3 (3 equiv.) were dissolved in dimethyl 2-oxoalkylphosphon-
ate (15 equiv.). The reaction mixture was stirred at 80 °C for 24 h.
The excess of phosphonate was then removed by distillation under
reduced pressure. Next the residue was dissolved in water (10 mL)
in the presence of additional K2CO3 (9 equiv.). The reaction mix-
ture was stirred at 60 °C for 12 h. The reaction media was then
neutralized with a few drops of a 5% aq. hydrochloric acid solution
and freeze-dried. Flash column chromatography on silica gel af-
forded pure C-glycoside.
3 H, O-CH3), 3.15 (s, 3 H, N-CH3), 2.38 [t, J = 7.6 Hz, 2 H,
CO(CH2)], 1.60 (quint., J = 7.6 Hz, 2 H, CH2), 1.25 [m, 28 H,
(CH2)14], 0.85 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 174.9 (CO), 61.2 (O-CH3), 32.2 (N-CH3), 31.9
(CH2), 29.7, 29.52, 29.47, 29.45, 29.44, 29.43, 29.36, 24.7, 22.7
[(CH2)14], 14.1 (CH3) ppm. HRMS (ESI+): calcd. for C-20H41NO2
[M + Na]+ 350.30350; found 350.3035; [M + H]+ 328.32155; found
328.3214. C20H41NO2 (327.55): calcd. C 73.34, H 12.62, N 4.28;
found C 72.94, H 12.31, N 3.88.
Dimethyl 2-Oxononadecylphosphonate (5d): Yield 80%. White so-
1
lid. Rf (DCM/AcOEt: 1:1) = 0.6. H NMR (CDCl3, 400 MHz): δ
1-(β-C-Lactosyl)-2-propanone (βpyr-6a): Compound βpyr-6a was
= 3.76 (d, JH,P = 11.2 Hz, 6 H, O-CH3), 3.07 (d, JH,P = 22.8 Hz, 2
H, P-CH2), 2.59 [t, J = 7.2 Hz, 2 H, CO(CH2)], 1.55 (quint., J =
6.8 Hz, 2 H, CH2), 1.24 [m, 28 H, (CH2)14], 0.87 (t, J = 6.8 Hz, 3
H, CH3) ppm. 31P NMR (CDCl3, 162 MHz): δ = 22.9 ppm. 13C
NMR (CDCl3, 100 MHz): δ = 202.1 (d, JC,P = 5.9 Hz, CO), 53.0
(d, JC-P = 6.5 Hz, OCH3), 44.2 [d, JC,P = 1.4 Hz, CO(CH2)], 41.9
(d, JC,P = 127.7 Hz, P-CH2), 31.9, 29.6, 29.44, 29.36, 29.32, 28.9,
23.4, 22.7, 14.1 (CH3) ppm. HRMS (ESI+): calcd. for C21H43O4P
[M + Na]+ 413.27967; found 413.2795; [M + H]+ 391.29772; found
391.2997. C21H43O4P (390.54): calcd. C 64.58, H 11.10; found C
64.65, H 11.10.
prepared from
0.833 mmol) under aqueous conditions (2 mL of water). Flash
chromatography on silica gel (EtOAc/MeOH/H2O, 15:4:1; Rf
0.30 with EtOAc/iPrOH/H2O, 5:4:1) followed by freeze-drying af-
forded 6a as white crystals in 67% yield (70.9 mg); m.p. 162 °C
1 (100 mg, 0.277 mmol) and 5a (138 mg,
=
(decomp.). [α]D = +4.1 (c = 1, MeOH). IR (KBr): ν = 1050, 1705,
˜
1945, 3394 cm–1. 1H NMR (D2O, 400 MHz): δ = 4.39 (d, J =
7.7 Hz, 1 H, 1Ј-H), 3.50–3.75 (m, 12 H, 1,3–6,2Ј–6Ј-H), 3.24 (t, J
= 9.3 Hz, 1 H, 2-H), 2.99 (dd, J = 17.0, 2.9 Hz, 1 H, CH2), 2.68
(dd, J = 17.0, 9.5 Hz, 1 H, CH2), 2.23 (s, 3 H, CH3) ppm. 13C
NMR (D2O, 100 MHz): δ = 213.6 (CO), 103.2 (C-1Ј), 78.72 (C-5),
78.70 (C-5Ј), 76.1 (C-3), 75.7 (C-3Ј), 75.4 (C-1), 73.1 (C-2), 72.9
(C-4), 71.3 (C-2Ј), 68.9 (C-4Ј), 61.4 (C-6Ј), 60.4 (C-6), 49.2 (CH2),
30.2 (CH3) ppm. HRMS (ESI+): calcd. for C15H26O11 [M + Na]+
Dimethyl 2-Oxononadec-10-enylphosphonate (5e). Amide Derivative:
Yield 77%. Rf (DCM) = 0.6. 1H NMR (CDCl3, 400 MHz): δ =
5.33 (m, 2 H, CH), 3.66 (s, 3 H, O-CH3), 3.16 (s, 3 H, N-CH3),
2.39 [t, J = 7.6 Hz, 2 H, CO(CH2)], 2.00 (m, 4 H, CH-CH2), 1.61 405.13728; found 405.1373; [M + K]+ 421.11122; found 421.1127.
Eur. J. Org. Chem. 2010, 1314–1323
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1319

A. Ranoux, L. Lemiègre, M. Benoit, J.-P. Guégan, T. Benvegnu
FULL PAPER
1-(C-Glucosyl)-2-propanone (7a):[14] A mixture of compounds α/
βpyr-7a and α/βfur-7a was prepared from 2 (100 mg, 0.555 mmol)
and 5a (277 mg, 1.67 mmol) under aqueous conditions (2 mL of
water). Flash chromatography on silica gel (EtOAc/MeOH/H2O,
15:4:1; Rf = 0.51 with EtOAc/iPrOH/H2O, 5:4:1) followed by
freeze-drying afforded 7a as a colourless oil in 75% yield (91.6 mg).
1H NMR (D2O, 400 MHz): δ = 5.01 and 4.97 (m, 2 H, 1fα,1fβ-H),
4.55 (d, J = 4.8 Hz, 1 H, 2fα-H), 4.37 (d, J = 4.8 Hz, 1 H, 2fβ-H),
in 57% yield (72.3 mg). 1H NMR (CDCl3, 400 MHz): δ = 3.80 (dd,
J = 11.2, 5.2 Hz, 1 H, 5-H), 3.56 (td, J = 9.4, 2.8 Hz, 1 H, 1-H),
3.40 (m, 1 H, 4-H), 3.28 (t, J = 9.4 Hz, 1 H, 3-H), 3.14 (t, J =
11.2 Hz, 1 H, 5-H), 3.05 (t, J = 9.4 Hz, 1 H, 2-H), 2.80 (dd, J =
16.0, 2.8 Hz, 1 H, CH2), 2.54 (dd, J = 16.0, 9.4 Hz, 1 H, CH2),
2.17 (s, 3 H, CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 210.1
(CO), 79.7 (C-3), 78.2 (C-1), 75.1 (C-2), 71.5 (C-4), 71.0 (C-5), 47.2
(CH2), 30.7 (CH3) ppm. HRMS (ESI+): calcd. for C-13H24O6 [M
4.17 (m, 1 H, 1pα-H), 3.45–3.90 and 3.40–3.20 (m, 1pβ,2pα,3–6- + Na]+ 213.07389; found 213.0738.
H), 3.15 (t, J = 9.3 Hz, 1 H, 2pβ-H), 2.95 (dd, J = 16.0, 8.0 Hz, 1
1-(C-Lactosyl)heptan-2-one (6b): A mixture of α/βpyr-6b was pre-
H, pα-CH2), 2.94 (dd, J = 16.6, 3.2 Hz, 1 H, pβ-CH2), 2.80 (dd, J
= 16.0, 5.2 Hz, 1 H, pα-CH2), 2.66 (dd, J = 16.6, 9.2 Hz, 1 H, pβ-
CH2), 2.39 (dd, J = 14.0, 8.0 Hz, 1 H, fα-CH2), 2.34 (dd, J = 14.0,
7.6 Hz, 1 H, fβ-CH2), 2.20, 2.17, 2.16, 2.14 (s, 3 H, CH3), 1.94 (dd,
J = 14.0, 3.2 Hz, 1 H, fβ-CH2), 1.88 (dd, J = 14.0, 3.6 Hz, 1 H, fα-
CH2) ppm.
pared from 1 (50 mg, 0.139 mmol) and 5b (462 mg, 2.08 mmol) un-
der solvent-free conditions (Procedure A: yield 71%, 43.2 mg) or
from 1 (50 mg, 0.139 mmol) and 5b (92.5 mg, 0.417 mmol) under
aqueous conditions (1 mL of water, 35% yield, 15.2 mg). Flash
chromatography on silica gel (CH2Cl2/MeOH, 9:1; Rf = 0.55 with
EtOAc/iPrOH/H2O, 5:4:1) followed by freeze-drying afforded 6b as
yellowish crystals. 1H NMR (CD3OD, 400 MHz): δ = 4.38 (dt, J =
7.6, 5.2 Hz, 1 H, 1α-H), 4.26 (d, J = 7.6 Hz, 1 H, 1Јβ-H), 4.23 (d,
J = 7.6 Hz, 1 H, 1Јα-H), 3.95–3.50 (m, 12 H, 1β,2α,3–6,2Ј–6Ј-H),
3.05 (t, J = 9.4 Hz, 1 H, 2β-H), 2.85 [dd, J = 16.2, 3.2 Hz, 1 H, β-
CH2(CO)], 2.75 [m, 1 H, α-CH2(CO)], 2.60 [dd, J = 16.2, 9.2 Hz,
1 H, β-CH2(CO)], 2.52 [m, 2 H, (CO)CH2], 1.55 (m, 2 H, CH2
alkyl), 1.25 (m, 4 H, CH2 alkyl), 0.85 (t, J = 7.2 Hz, 3 H,
CH3) ppm.
Compound βpyr-7a was prepared from 2 (100 mg, 0.555 mmol) and
5a (277 mg, 1.667 mmol) under aqueous conditions (2 mL of water)
and using NaOH instead of K2CO3. Flash chromatography on sil-
ica gel (EtOAc/MeOH/H2O, 15:4:1; Rf = 0.51 with EtOAc/iPrOH/
H2O, 5:4:1) followed by freeze-drying afforded 7a as a colourless
oil in 28% yield (34.2 mg). [α]D = –3.0 (c = 1, MeOH). IR (Nujol):
1
ν = 1095, 1709, 1940, 3405 cm–1. H NMR (D O, 400 MHz): δ =
˜
2
3.76 (dd, J = 12.2, 2.0 Hz, 1 H, 6-H), 3.72 (td, J = 9.5, 3.2 Hz, 1
H, 1-H), 3.59 (dd, J = 12.4, 5.1 Hz, 1 H, 6-H), 3.40 (t, J = 9.3 Hz,
1 H, 3-H), 3.32 (ddd, J = 8.7, 5.1, 2.0 Hz, 1 H, 5-H), 3.27 (t, J =
8.7 Hz, 1 H, 4-H), 3.15 (t, J = 9.3 Hz, 1 H, 2-H), 2.94 (dd, J =
16.6, 3.2 Hz, 1 H, CH2), 2.66 (dd, J = 16.6, 9.2 Hz, 1 H, CH2),
2.20 (s, 3 H,CH3) ppm. 13C NMR (D2O, 100 MHz): δ = 213.2
(CO), 79.5 (C-5), 77.2 (C-3), 75.3 (C-1), 73.1 (C-2), 69.7 (C-4), 60.7
(C-6), 45.6 (CH2), 29.8 (CH3) ppm. HRMS (ESI+): calcd. for
C9H16O6; [M + Na]+ 243.08446; found 243.0855.
Compound βpyr-6b was prepared from 1 (50 mg, 0.139 mmol) and
5b (462 mg, 2.08 mmol) under solvent-free conditions (Procedure
B). Flash chromatography on silica gel (CH2Cl2/MeOH, 9:1; Rf
= 0.55 with EtOAc/iPrOH/H2O, 5:4:1) followed by freeze-drying
afforded 6b as a yellowish crystals in 61% yield (37.1 mg). [α]D
=
+10.4 (c = 1, MeOH); m.p. 144 °C. IR (neat): ν = 1055, 1088, 1138,
˜
1374, 1705, 2930, 3381 cm–1. 1H NMR (CD3OD, 400 MHz): δ =
4.26 (d, J = 7.2 Hz, 1 H, 1Ј-H), 3.87–3.68 (m, 7 H, 1,5Ј,6,6Ј,4-H),
3.60 (ddd, J = 7.2, 4.4, 0.8 Hz, 1 H, 5-H), 3.56–3.47 (m, 3 H,
3Ј,2Ј,3-H), 3.36 (t, J = 2.8 Hz, 1 H, 4Ј-H), 3.05 (t, J = 9.4 Hz, 1 H,
2-H), 2.85 [dd, J = 16.2, 3.2 Hz, 1 H, CH2(CO)], 2.60 [dd, J = 16.2,
9.2 Hz, 1 H, CH2(CO)], 1.55 (m, 2 H, CH2 alkyl), 2.52 [m, 2 H,
(CO)CH2], 1.25 (m, 4 H, CH2 alkyl), 0.85 (t, J = 7.2 Hz, 3 H,
CH3) ppm. 13C NMR [(CD3)2CO, 100 MHz]: δ = 213.5 (CO), 104.7
(C-1Ј), 80.7 (C-5), 79.9 (C-4Ј), 77.6 (C-3), 77.0, 74.4 (C-1,5Ј), 73.4
(C-2), 72.5, 71.7 (C-2Ј,3Ј), 70.2 (C-4), 62.6, 61.9 (C-6,6Ј), 44.3
[CH2(CO)], 40.4 [(CO)CH2], 32.3 (CH2 alkyl), 24.4 (CH2 alkyl),
23.6 (CH2 alkyl), 14.8 (CH3) ppm. HRMS (ESI+): calcd. for
C19H34O11 [M + Na]+ 461.19988; found 461.1999.
1-(C-Galactosyl)-2-propanone (8a):[7] Compounds α/βpyr-8a and α/
βfur-8a were prepared from 3 (100 mg, 0.555 mmol) and 5a
(277 mg, 1.67 mmol) under aqueous conditions (2 mL of water).
The crude residue was purified by flash column chromatography
(EtOAc/MeOH/H2O, 15:4:1; Rf = 0.48 with EtOAc/iPrOH/H2O,
5:4:1) followed by freeze-drying to afford 8a as white crystals in
1
85% yield (103.8 mg). H NMR (D2O, 400 MHz): δ = 4.72 (m, 1
H, 1fα-H), 4.50 (m, 1 H, 1fβ-H, 2fα-H), 4.14 (m, 1 H, 1pα-H), 4.34
(m, 1 H, 2fβ-H), 3.55–3.90 (m, sugars), 3.37 (t, J = 9.6 Hz, 1 H,
2pβ-H), 2.95 [dd, J = 16.8, 2.8 Hz, 1 H, pβ-CH2(CO)], 2.78 (m, 1
H, pα-CH2), 2.66 (dd, J = 16.8, 9.2 Hz, 1 H, pβ-CH2), 2.33 (m, 1
H, fα-CH2), 2.22 (m, 1 H, fβ-CH2), 2.19 (s, 3 H, CH3), 2.18 (m, 1
H, fβ-CH2), 2.03 (m, 1 H, fα-CH2) ppm.
1-(C-Glucosyl)heptan-2-one (7b): A mixture of α/βpyr-7b and α/
βfur-7b was prepared from 2 (50 mg, 0.277 mmol) and 5b (925 mg,
4.17 mmol) under solvent-free conditions (Procedure A: yield 51%,
39.0 mg) or from 2 (50 mg, 0.277 mmol) and 5b (184.5 mg,
0.831 mmol) under aqueous conditions (1 mL of water, yield 25%,
19.1 mg). Flash chromatography on silica gel (CH2Cl2/MeOH, 9:1;
Rf = 0.25 with EtOAc/MeOH, 9:1). followed by freeze-drying af-
Pure βpyr-8a was isolated as white crystals. [α]D = +8.0 (c = 1,
MeOH); m.p. 173 °C. IR (KBr): ν = 1057, 1079, 1145, 1277, 1710,
˜
1
2865, 2918, 3282, 3384 cm–1. H NMR (D2O, 400 MHz): δ = 3.88
(d, J = 3.2 Hz, 1 H, 4-H), 3.68 (td, J = 9.2, 2.8 Hz, 1 H, 1-H),
3.66–3.60 (m, 3 H, 5,6-H), 3.55 (dd, J = 9.6, 3.6 Hz, 1 H, 3-H),
3.37 (t, J = 9.6 Hz, 1 H, 2-H), 2.95 (dd, J = 16.8, 2.8 Hz, 1 H, CH2),
2.66 (dd, J = 16.8, 9.2 Hz, 1 H, CH2), 2.19 (s, 3 H, CH3) ppm. 13C
NMR (D2O, 100 MHz): δ = 213.4 (CO), 78.6 (C-5), 75.7 (C-1),
73.8 (C-3), 70.4 (C-2), 69.1 (C-4), 61.2 (C-6), 45.7 (CH2), 29.8
(CH3) ppm. HRMS (ESI+): calcd. for C9H16O6 [M + Na]+
243.08446; found 243.0846.
1
forded 7b as a colourless oil. H NMR (CD3OD, 400 MHz): δ =
4.93 (m, 1 H, 1fα-H), 4.60 (m, 1 H, 1fβ-H), 4.31 (d, J = 3.6 Hz, 1
H, 2fα-H), 4.05 (dt, J = 8.4, 5.2 Hz, 1 H, 1pα-H), 3.85–3.40 (m,
sugars), 3.08 (t, J = 8.8 Hz, 1 H, 2pβ-H), 2.84 [dd, J = 16.4, 8.4 Hz,
1 H, pα-CH2(CO)], 2.80 [dd, J = 15.6, 2.8 Hz, 1 H, pβ-CH2(CO)],
2.73 [dd, J = 16.4, 5.2 Hz, 1 H, pα-CH2(CO)], 2.49 [m, 3 H, (CO)-
1-(β-C-Xylosyl)-2-propanone (βpyr-9a):[7] Compound βpyr-9a was CH2, pβ-CH2(CO)], 2.32 [dd, J = 13.6, 7.6 Hz, 1 H, fα-CH2(CO)],
prepared from 4 (100 mg, 0.671 mmol) and 5a (334 mg, 2.01 mmol)
under aqueous conditions (2 mL of water). Flash chromatography
on silica gel (EtOAc/MeOH, 9:1; Rf = 0.50 with EtOAc/iPrOH/
H2O, 6:4:1) followed by freeze-drying afforded 9a as a yellowish oil
2.19 [dd, J = 13.6, 7.6 Hz, 1 H, fβ-CH2(CO)], 1.91 [dd, J = 13.6,
4.8 Hz, 1 H, fβ-CH2(CO)], 1.78 [m, 1 H, fα-CH2(CO)], 1.51 (q, J
= 7.2 Hz, 2 H, CH2 alkyl), 1.29 (m, 4 H, CH2 alkyl), 0.90 (t, J =
7.2 Hz, 3 H, CH3) ppm.
1320
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1314–1323

One-Step Access to C-Glycoside Amphiphiles
Compound βpyr-7b was prepared from 2 (50 mg, 0.277 mmol) and
5b (925 mg, 4.17 mmol) under solvent-free conditions (Procedure
B). Flash chromatography on silica gel (CH2Cl2/MeOH, 9:1; Rf =
0.25 with EtOAc/MeOH, 9:1) followed by freeze-drying afforded
7b as a colourless oil in 50% yield (34.4 mg). [α]D = –15.9 (c = 1,
H, 3,2Ј,4Ј,5Ј-H), 3.33 (t, J = 3.2 Hz, 1 H, 4-H), 3.06 (t, J = 9.6 Hz,
1 H, 2-H), 2.77 [dd, J = 16.0, 2.8 Hz, 1 H, CH2(CO)], 2.51 [dd, J
= 16.0, 9.2 Hz, 1 H, CH2(CO)], 2.42 [t, J = 5.6 Hz, 2 H, CO(CH2)],
1.45 (m, 2 H, CH2), 1.20 (m, 16 H, CH2), 0.90 (t, J = 6.8 Hz, 3 H,
CH3) ppm. 13C NMR (CD3OD, 100 MHz): δ = 212.29 (CO),
105.12 (C-1Ј), 80.81, 80.19 (C-4), 77.87, 77.17, 77.09 (C-1), 74.84,
74.76 (C-2), 72.56, 70.40, 62.58, 61.92 (C-6, C-6Ј), 46.24
MeOH). IR (neat): ν = 1049, 1090, 1382, 1455, 1716, 2884, 2974,
˜
3340 cm–1. 1H NMR (CD3OD, 400 MHz): δ = 3.70 (d, J = 10.8 Hz,
1 H, 6-H), 3.68 (td, J = 9.6, 3.2 Hz, 1 H, 1-H), 3.59 (dd, J = 11.0, [CH2(CO)], 44.34 [(CO)CH2], 33.10, 30.78, 30.68, 30.63, 30.50,
5.2 Hz, 1 H, 6-H), 3.36 (t, J = 8.6 Hz, 1 H, 3-H), 3.33 (t, J =
24.59, 23.77 (CH2 alkyl), 14.48 (CH3) ppm. HRMS (ESI+): calcd.
8.6 Hz, 1 H, 4-H), 3.23 (ddd, J = 9.2, 5.2, 2.8 Hz, 1 H, 5-H), 3.08 for C25H46O11 [M + Na]+ 545.29378; found 545.2941.
(t, J = 8.8 Hz, 1 H, 2-H), 2.80 [dd, J = 15.6, 2.8 Hz, 1 H, CH2(CO)],
1-(C-Glucosyl)tridecan-2-one (α/βpyr-7c): A mixture of α/βpyr-7c
2.49 [m, 3 H, (CO)CH2, CH2(CO)], 1.51 (q, J = 7.2 Hz, 2 H, CH2
was prepared from 2 (25 mg, 0.139 mmol) and 5c (637 mg,
alkyl), 1.29 (m, 4 H, CH2 alkyl), 0.90 (t, J = 7.2 Hz, 3 H,
2.08 mmol) under solvent-free conditions (Procedure A). Flash
chromatography on silica gel (AcOEt; Rf = 0.57 with EtOAc/
MeOH, 9:1) followed by freeze-drying afforded 7c as a yellowish
CH3) ppm. 13C NMR [(CD3)2CO, 100 MHz]: δ = 210.0 (CO), 82.1
(C-5), 80.6 (C-3), 78.0 (C-1), 75.9 (C-2), 73.0 (C-4), 64.0 (C-6), 47.3
[CH2(CO)], 44.6 [(CO)CH2], 33.1 (CH2 alkyl), 24.8 (CH2 alkyl),
solid in 48% yield (24.0 mg). IR (KBr): ν = 1081, 1262, 1423, 1713,
˜
24.2 (CH2 alkyl), 15.2 (CH3) ppm. HRMS (ESI+): calcd. for
C13H24O6 [M + Na]+ 299.14706; found 299.1469.
1
2854, 2926, 3396 cm–1. H NMR (CDCl3/CD3OD: 9:1, 400 MHz):
δ = 4.93 (dt, J = 8.0, 3.6 Hz, 1 H, 1fα-H), 4.60 (td, J = 7.6, 5.2 Hz,
1 H, 1fβ-H), 4.31 (d, J = 3.6 Hz, 1 H, 2fα-H), 4.03 (dt, J = 7.6,
5.6 Hz, 1 H, 1pα-H), 3.91–3.51 (m, 5 H, sugars), 3.30 (m, 1 H,
sugars), 3.07 (t, J = 9.2 Hz, 1 H, 2pβ-H), 2.85 [dd, J = 16.0, 3.0 Hz,
1 H, pβ-CH2(CO)], 2.84 [dd, J = 16.6, 7.6 Hz, 1 H, pα-CH2(CO)],
1-(β-C-Galactosyl)heptan-2-one (βpyr-8b): Compound βpyr-8b was
prepared from 3 (50 mg, 0.277 mmol) and 5b (925 mg, 4.17 mmol)
under solvent-free conditions (Procedure B). Flash chromatog-
raphy on silica gel (CH2Cl2/MeOH, 9:1; Rf = 0.25 with EtOAc/
MeOH, 9:1) followed by freeze-drying afforded 8b as white hygro- 2.73 [dd, J = 16.6, 5.6 Hz, 1 H, pα-CH2(CO)], 2.54 [dd, J = 16.0,
scopic crystals in 32% yield (24.5 mg). [α]D = –0.7 (c = 1, MeOH).
9.2 Hz, 1 H, pβ-CH2(CO)], 2.43 [t, J = 5.2 Hz, 2 H, (CO)CH2],
2.25 [dd, J = 14.0, 8.0 Hz, 1 H, fα-CH2(CO)], 2.15 [dd, J = 13.6,
7.6 Hz, 1 H, fβ-CH2(CO)], 1.91 [dd, J = 13.6, 5.2 Hz, 1 H, fβ-
CH2(CO)], 1.77 [dd, J = 14.0, 3.6 Hz, 1 H, fα-CH2(CO)], 1.51 [t, J
= 6.8 Hz, 2 H, (COCH2)CH2], 1.21 (m, 16 H, CH2), 0.90 (t, J =
1
IR (KBr): ν = 1150, 1333, 1450, 1703, 2855, 2935, 3340 cm–1. H
˜
NMR (CD3OD, 400 MHz): δ = 3.93 (t, J = 3.0 Hz, 1 H, 4-H),
3.70–3.60 (m, 3 H, 1,6-H), 3.50–3.45 (m, 3 H, 2,3,5-H), 2.82 [dd, J
= 15.6, 2.8 Hz, 1 H, CH2(CO)], 2.53 [dd, J = 15.6, 9.2 Hz, 1 H,
CH2(CO)], 2.49 [td, J = 7.2, 2.8 Hz, 2 H, (CO)CH2], 1.53 (q, J = 6.8 Hz,
3
H, CH3) ppm. 13C NMR (CDCl3/CD3OD: 9:1,
7.6 Hz, 2 H, CH2 alkyl), 1.28 (m, 4 H, CH2 alkyl), 0.87 (t, J = 100 MHz): δ = 211.4 (CO), 89.8 (C-2fα), 86.9 (C-1fα), 85.2 (C-1fβ),
7.2 Hz, 3 H, CH3) ppm. 13C NMR [(CD3)2CO, 100 MHz]: δ = 82.2, 81.6, 81.1, 80.2, 79.8, 79.2 (C-1pβ), 78.0 (C-2pβ), 77.6 (C-
210.09 (CO), 80.61 (C-5), 78.46 (C-1), 77.12 (C-3), 73.33 (C-2), 1fβ), 76.6, 75.8, 75.1, 73.9, 73.2, 70.6, 70.4, 69.9, 64.2, 63.8 (C-6),
71.45 (C-4), 63.38 (C-6), 47.33 [CH2(CO)], 44.62 [(CO)CH2], 33.08,
24.88, 24.16 (CH2 alkyl), 15.23 (CH3) ppm. HRMS (ESI+): calcd.
for C13H24O6 [M + Na]+ 299.14706; found 299.1474.
44.8 [pα-CH2(CO)], 43.8 [pβ-CH2(CO)], 42.3 [fα-CH2(CO)], 42.1
[(CO)CH2], 39.1 [fβ-CH2(CO)], 31.8, 29.62, 29.55, 29.47, 29.42,
29.40, 29.3, 29.2, 29.1, 28.9, 24.4, 23.5, 22.6 (CH2 alkyl), 13.90
(CH3) ppm. HRMS (ESI+): calcd. for C19H36O6 [M + Na]+
383.24096; found 383.2407; [M + K]+ 399.21490; found 399.2153.
1-(C-Lactosyl)tridecan-2-one (6c): A mixture of α/βpyr-6c was pre-
pared from 1 (25 mg, 0.070 mmol) and 5c (319 mg, 1.04 mmol) un-
der solvent-free conditions (Procedure A: yield 50%, 18.1 mg).
Flash chromatography on silica gel (AcOEt; Rf = 0.56 with EtOAc/
1-(C-Galactosyl)tridecan-2-one (8c): A mixture of compounds 8c
was prepared from 3 (25 mg, 0.139 mmol) and 5c (637 mg,
2.08 mmol) under solvent-free conditions (Procedure A). Flash
iPrOH/H2O, 5:4:1) followed by freeze-drying afforded 6c as a yel-
1
lowish solid. H NMR (CDCl3/CD3OD, 9:1, 400 MHz): δ = 4.37 chromatography on silica gel (AcOEt; Rf = 0.57 with EtOAc/
(dt, J = 8.4, 5.2 Hz, 1 H, 1α-H), 4.25 (d, J = 7.2 Hz, 1 H, 1Јβ-H), MeOH, 9:1) followed by freeze-drying afforded 8c as a yellowish
4.22 (d, J = 7.2 Hz, 1 H, 1Јα-H), 3.80–3.47 (m, 12 H, sugars), 3.06 solid in 64% yield (32 mg). IR (KBr): ν = 1100, 1636, 1910,
˜
1
(t, J = 9.6 Hz, 1 H, 2β-H), 2.77 [dd, J = 16.0, 2.8 Hz, 1 H, β-
CH2(CO)], 2.68 [m, 2 H, α-CH2(CO)], 2.51 [dd, J = 16.0, 9.2 Hz,
3449 cm–1. H NMR (CDCl3/CD3OD, 9:1, 400 MHz): δ = 4.64 (t,
J = 5.2 Hz, 1 H, 1fα-H), 4.39 (dd, J = 4.8, 0.8 Hz, 1 H, 2fα-H),
1 H, β-CH2(CO)], 2.42 [t, J = 5.6 Hz, 2 H, (CO)CH2], 1.45 (m, 2 4.31 (td, J = 6.4, 3.6 Hz, 1 H, 1pα-H), 4.15–3.90 (m, sugars), 3.82
H, CH2 alkyl), 1.20 (m, 16 H, CH2), 0.90 (t, J = 6.8 Hz, 3 H, (dd, J = 3.6, 0.8 Hz, 1 H, 2pα-H), 3.73–3.52 (m, 5 H, sugars), 2.73
CH3) ppm. 13C NMR (CD3OD, 100 MHz): δ = 212.6, 212.4 (CO), [m, 2 H, pα-CH2(CO)], 2.40 [t, J = 6.5 Hz, 2 H, (CO)CH2], 2.11
105.01, 104.97 (C-1Ј), 80.7, 80.6, 80.1, 77.9, 77.14, 77.07, 74.7, [d, J = 14.2 Hz, 1 H, fα-CH2(CO)], 1.85 [dd, J = 14.2, 5.2 Hz, 1
73.85, 73.62, 73.55, 72.6, 72.0, 70.3, 62.5, 61.94, 61.86, (C-6, C-6Ј),
H, fα-CH2(CO)], 1.47 (t, J = 6.8 Hz, 2 H, CH2 alkyl), 1.17 (m, 16
46.3 [(CO)CH2, CH2(CO)], 44.3, 44.2, 40.4, 33.1, 30.81, 30.75, H, CH2), 0.80 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3/
30.65, 30.60, 30.5, 30.3, 24.7, 24.6, 23.8 (CH2 alkyl), 14.5
(CH3) ppm.
CD3OD, 9:1, 100 MHz): determined from HMBC and HSQC ex-
periments: δ = 211.6 (CO), 87.7, 85.8, 83.8, 83.4 (C-1fα), 80.4, 79.1,
78.2, 77.9, 76.9 (C-1pα), 76.7 (C-2pα), 71.9, 63.5, 62.8 (C-6), 43.7
[(CO)CH2], 42.1 [fα-CH2(CO)], 41.9 [pα-CH2(CO)], 31.8, 30.11,
30.05, 29.8, 23.6, 22.60, (CH2 alkyl), 14.9 (CH3) ppm. HRMS
(ESI+): calcd. for C19H36O6 [M + Na]+ 383.24096; found 383.2409.
Compound βpyr-6c was prepared from 1 (25 mg, 0.070 mmol) and
5c (319 mg, 1.042 mmol) under solvent-free conditions (Procedure
B). Flash chromatography on silica gel (CH2Cl2/MeOH, 9:1; Rf
= 0.56 with EtOAc/iPrOH/H2O, 5:4:1) followed by freeze-drying
afforded 6c as a yellowish solid in 69% yield (25.0 mg). [α]D = –2.4
1-(C-Lactosyl)nonadecan-2-one (6d): A mixture of α/βpyr-6d was
prepared from 1 (25 mg, 0.070 mmol) and 5d (406 mg, 1.04 mmol)
(c = 1, MeOH); m.p. 132 °C. IR (KBr): ν = 1024, 1076, 1136, 1379,
˜
1
1464, 1715, 2851, 2920, 3415 cm–1. H NMR (CDCl3/CD3OD 9:1, under solvent-free conditions (Procedure A). Flash chromatog-
400 MHz): δ = 4.25 (d, J = 7.2 Hz, 1 H, 1Ј-H), 3.80–3.69 (m, 6 H, raphy on silica gel (AcOEt/CH2Cl2, 1:1, then AcOEt; Rf = 0.69
5,6,3Ј,6Ј-H), 3.65 (td, J = 9.2, 2.8 Hz, 1 H, 1-H), 3.57–3.47 (m, 4
with EtOAc/iPrOH/H2O, 5:4:1) followed by freeze-drying afforded
Eur. J. Org. Chem. 2010, 1314–1323
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1321

A. Ranoux, L. Lemiègre, M. Benoit, J.-P. Guégan, T. Benvegnu
FULL PAPER
6d as a white solid in 70% yield (29.0 mg); m.p. 115 °C. IR (KBr): HRMS (ESI+): calcd. for C31H56O11 [M + Na]+ 627.37203; found
ν = 1048, 1266, 1422, 1712, 2927, 2975, 3043 cm–1. 1H NMR ([D ] 627.3721.
˜
6
DMSO, 400 MHz): δ = 4.35 (dt, J = 8.8, 5.6 Hz, 1 H, 1α-H), 4.23
1-(C-Glucosyl)nonadec-10-en-2-one (7e): A mixture of compounds
and 4.21 (d, J = 7.6 Hz, 1 H, 1Јα,1Јβ-H), 3.74–3.33 (m, 11 H,
7e was prepared from 2 (25 mg, 0.139 mmol) and 5e (808 mg,
sugars), 3.01 (m, 1 H, 2β-H), 2.75 [dd, J = 16.0, 2.8 Hz, 1 H, β-
2.08 mmol) under solvent-free conditions (Procedure A). Flash
CH2(CO)], 2.65 [m, 2 H, α-CH2(CO)], 2.41 [dd, J = 16.0, 9.6 Hz,
chromatography on silica gel (CH2Cl2 then CH2Cl2/MeOH, 9:1; Rf
1 H, β-CH2(CO)], 2.36 [m, 2 H, (CO)CH2], 1.43 (m, 2 H, CH2
= 0.20 with CH2Cl2/MeOH, 9:1) followed by freeze-drying afforded
alkyl), 1.18 (m, 28 H), 0.81 (t, J = 6.4 Hz, 3 H, CH3) ppm. 13C
7e as a colourless oil in 50% yield (30.7 mg). IR (KBr): ν = 1036,
˜
NMR ([D6]DMSO, 100 MHz): determined from HMBC and
HSQC experiments: δ = 210.5 (CO), 104.2 (C-1Ј), 81.5, 75.9, 75.8,
73.7, 72.3, 71.2, 70.6, 68.6, 61.5, 61.4 (C-6, C-6Ј), 60.9, 45.6 [β-
CH2(CO)], 43.1 [(CO)CH2], 39.4 [α-CH2(CO)], 32.6, 31.5, 30.8,
30.1, 29.7, 29.5, 29.4, 29.2, 28.7, 27.6, 26.7, 23.7, 23.4, 22.5, 22.3,
14.2 (CH3) ppm. HRMS (ESI+): calcd. for C31H58O11 [M + Na]+
629.38768; found 629.3877.
1264, 1455, 1716, 2854, 2927, 3320 cm–1. 1H NMR (CDCl3,
400 MHz): assignments were made on the basis of 1D TOCSY ex-
periments: δ = 5.32 (m, 2 H, CH=CH), 4.98 (quint., J = 4.2 Hz, 1
H, 1fα-H), 4.81 (t, J = 4.5 Hz, 1 H, 1fβ-H), 4.50 (d, J = 5.0 Hz, 1
H, 2fα-H), 4.43 (dt, J = 7.0, 3.6 Hz, 1 H, 1pα-H), 4.41 (d, J =
3.9 Hz, 1 H, 2fβ-H), 4.20–4.07 (m, sugars), 4.00–3.75 (m, sugars),
3.72–3.30 (m, sugars), 3.09 (t, J = 8.8 Hz, 1 H, 2pβ-H), 2.89 [dd, J
= 17.1, 4.8 Hz, 1 H, pα-CH2(CO)], 2.83 [dd, J = 15.9, 2.4 Hz, 1 H,
pβ-CH2(CO)], 2.73 [dd, J = 17.1, 6.3 Hz, 1 H, pα-CH2(CO)], 2.56
[dd, J = 15.9, 9.0 Hz, 1 H, pβ-CH2(CO)], 2.45 [m, 2 H, (CO)CH2],
2.26 [dd, J = 14.1, 7.5 Hz, 1 H, fα-CH2(CO)], 2.11 [dd, J = 15.3,
10.2 Hz, 1 H, fβ-CH2(CO)], 1.94 [m, 1 H, fβ-CH2(CO)], 1.93 [m, 4
H, CH2(CH=CH)], 1.85 [dd, J = 14.1, 3.6 Hz, 1 H, fα-CH2(CO)],
1.48 (m, 2 H, CH2 alkyl), 1.21 (m, 20 H, CH2), 0.89 (t, J = 6.8 Hz,
3 H, CH3) ppm. 13C NMR (CDCl3, 100 MHz): determined from
HMBC and HSQC experiments: δ = 210.5 (CO), 129.8 (CH=CH),
86.9 (C-2fα), 89.8 (C-2fβ), 82.6 (C-1fβ), 82.0 (C-1fα), 81.50, 80.2,
81.1, 79.7, 78.2, 77.8, 77.6, 77.0, 76.6 (C-1pα), 75.7, 75.0, 73.5, 71.1,
70.4, 69.6, 64.0, 61.6, 48.9, 48.0, 46.3 [pα-CH2(CO)], 43.5 [fα-
CH2(CO)], 43.3, 41.8 [pβ-CH2(CO)], 39.6 [(CO)CH2], 39.4, 32.6
(CH2 alkyl), 31.7, 30.7, 29.7, 29.0, 28.8, 28.10, 27.1, 26.5
[CH2(CH=CH)], 24.4, 23.5, 23.4, 22.6, 22.4, 13.9 (CH3) ppm.
HRMS (ESI+): calcd. for C25H46O6 [M + Na]+ 465.31921; found
465.3193.
1-(C-Glucosyl)nonadecan-2-one (7d): A mixture of compounds 7d
was prepared from 2 (25 mg, 0.139 mmol) and 5d (812 mg,
2.08 mmol) under solvent-free conditions (Procedure A). Flash
chromatography on silica gel (CH2Cl2 then CH2Cl2/MeOH, 9:1; Rf
= 0.43 with CH2Cl2/MeOH, 9:1) followed by freeze-drying afforded
7d as a white solid in 63% yield (38.8 mg). IR (KBr): ν = 880, 1048,
˜
1
1268, 1382, 1698, 2539, 2973, 2975, 3331 cm–1. H NMR (CDCl3,
400 MHz): δ = 4.93 (dt, J = 7.6, 3.6 Hz, 1 H, 1fα-H), 4.77 (t, J =
4.8 Hz, 1 H, 1fβ-H), 4.53 (td, J = 7.6, 5.2 Hz, 1 H, 1pα-H), 4.50
(d, J = 4.0 Hz, 1 H, 2fα-H), 4.43 (d, J = 4.4 Hz, 1 H, 2fβ-H), 4.19
(d, J = 3.2 Hz, 1 H, 3pα-H), 4.14 (dd, J = 3.2, 0.8 Hz, 1 H, 3fα-
H), 4.10 (m, 1 H, 2pα-H), 3.90–3.35 (m, sugars), 3.03 (t, J = 9.2 Hz,
1 H, 2pβ-H), 2.85 [dd, J = 16.0, 3.6 Hz, 1 H, pβ-CH2(CO)], 2.84
[dd, J = 16.4, 7.6 Hz, 1 H, pα-CH2(CO)], 2.70 [dd, J = 16.4, 5.6 Hz,
1 H, pα-CH2(CO)], 2.52 [dd, J = 16.0, 3.2 Hz, 1 H, pβ-CH2(CO)],
2.42 [m, 2 H, (CO)CH2], 2.19 [dd, J = 14.0, 7.6 Hz, 1 H, fα-
CH2(CO)], 2.12 [dd, J = 14.8, 7.6 Hz, 1 H, fβ-CH2(CO)], 1.96 [dd,
J = 14.8, 5.6 Hz, 1 H, fβ-CH2(CO)], 1.79 [dd, J = 14.0, 3.2 Hz, 1
H, fα-CH2(CO)], 1.50 (m, 2 H, CH2 alkyl), 1.21 (m, 28 H, CH2),
0.81 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 211.1, 210.88, 210.85, 210.7 (CO), 86.5 (C-1pα), 82.2, 81.7 (C-
1fα), 81.0, 80.0, 79.8, 79.4, 79.3, 79.0, 76.5, 75.33, 75.25, 74.4, 73.7,
73.2, 73.1, 71.2, 70.4, 69.8, 67.6, 63.8, 63.6, 63.5, 61.1, 61.2, 46.0
[pα-CH2(CO)], 44.8 [pβ-CH2(CO)], 43.2 [fα-CH2(CO)], 42.88 [fβ-
CH2(CO)], 42.87 [(CO)CH2], 23.1 (CH2 alkyl), 31.4 (CH2 alkyl),
29.4–28.6 (CH2), 22.1, 13.3 (CH3) ppm. HRMS (ESI+): calcd. for
C25H48O6 [M + Na]+ 467.3348; found 467.3346.
Supporting Information (see also the footnote on the first page of
this article): 13C NMR spectra of the previously unknown com-
pounds 6a–e, 7b–e and 8a–c.
Acknowledgments
We thank the Association Nationale de la Recherche et de la Tech-
nologie (ANRT) and Armor Protéines for a grant to A. R. and for
funding.
1-(C-Lactosyl)nonadec-10-en-2-one (6e): A mixture of α/βpyr-6e was
prepared from 1 (25 mg, 0.070 mmol) and 5e (404 mg, 1.04 mmol)
under solvent-free conditions (Procedure A). Flash chromatog-
raphy on silica gel (AcOEt/CH2Cl2, 1:1, then AcOEt; Rf = 0.67
with EtOAc/iPrOH/H2O, 5:4:1) followed by freeze-drying afforded
[1] D. E. Levy, C. Tang, The Chemistry of C-Glycosides, Pergamon
Press, Tarrytown, NY, 1995.
[2] M. H. D. Postema, C-Glycoside Synthesis, CRC Press, Boca
Raton, 1995.
[3] H. Shao, Z. Wang, E. Lacroix, S.-H. Wu, H. J. Jennings, W.
Zou, J. Am. Chem. Soc. 2002, 124, 2130–2131.
[4] F. Rodrigues, Y. Canac, A. Lubineau, Chem. Commun. 2000,
2049–2050.
6d as a white solid in 58% yield (24.7 mg); m.p. 98 °C. IR (KBr):
1
ν = 745, 1078, 1262, 1384, 1708, 2853, 2924, 3364 cm–1. H NMR
˜
(CDCl3/CD3OD, 9:1, 400 MHz): δ = 5.30 (m, 2 H, CH=CH), 4.50
(dt, J = 7.8, 5.5 Hz, 1 H, 1α-H), 4.34 (d, J = 7.6 Hz, 1 H, 1Јβ-H),
4.31 (d, J = 7.5 Hz, 1 H, 1Јα-H), 3.84–3.45 (m, 11 H, sugars), 3.15
(t, J = 8.8 Hz, 1 H, 2β-H), 2.86 [dd, J = 16.0, 2.76 Hz, 1 H, β-
CH2(CO)], 2.79 [m, 2 H, α-CH2(CO)], 2.57 [dd, J = 16.0, 9.1 Hz,
1 H, β-CH2(CO)], 2.49 [m, 2 H, (CO)CH2], 1.99 [m, 4 H,
CH2(CH=CH)], 1.54 (m, 2 H, CH2 alkyl), 1.27 (m, 11 H, CH2
alkyl), 0.86 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3/
CD3OD, 1:9, 100 MHz): δ = 211.7, 209.9 (CO), 130.9, 130.6, 130.4,
129.6 (CH=CH), 104.6, 104.5 (C-1Ј), 80.7, 80.6, 79.6, 78.9, 78.7,
77.5, 76.6, 76.5 (C-1α), 74.3, 74.2, 73.4, 73.1, 72.9, 72.1, 71.5, 69.8,
62.2, 61.7, 45.9 [(CO)CH2], 43.9 [α-CH2(CO)], 40.2 [β-CH2(CO)],
32.6–32.4 (CH2), 30.5–29.5 (CH2), 27.9, 23.4, 14.5 (CH3) ppm.
[5] Y. Hersant, R. Abou-Jneid, Y. Canac, A. Lubineau, M. Phil-
ippe, D. Semeria, X. Radisson, M.-C. Scherrmann, Carbohydr.
Res. 2004, 339, 741–745.
[6] N. Bragnier, M.-C. Scherrmann, Synthesis 2005, 814–818.
[7] I. Riemann, M. A. Papadopoulos, M. Knorst, W. D. Fessner,
Aust. J. Chem. 2002, 55, 147–154.
[8] A. Cavezza, C. Boulle, A. Guéguiniat, P. Pichaud, S. Trouille,
L. Ricard, M. Dalko-Csiba, Bioorg. Med. Chem. Lett. 2009,
19, 845–849.
[9] S. Jarosz, J. Carbohydr. Chem. 2001, 20, 93–107.
[10] S. Jeanmart, R. J. K. Taylor, Tetrahedron Lett. 2005, 46, 9043–
9048.
[11] A. H. Davidson, L. R. Hughes, S. S. Qureshi, B. Wright, Tetra-
hedron Lett. 1988, 29, 693–696.
1322
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1314–1323

One-Step Access to C-Glycoside Amphiphiles
[12] V. Aucagne, D. Gueyrard, A. Tatibouët, A. Quinsac, P. Rollin,
Tetrahedron 2000, 56, 2647–2654.
[13] The compound numbering used in this article is defined as fol-
lows: α and β relate to the configuration at C-1 of the sugar
moiety, pyr and fur refer, respectively, to pyranoside and fu-
ranoside derivatives and the letter relates to the alkyl chain
length.
[14] S. Howard, S. G. Withers, J. Am. Chem. Soc. 1998, 120, 10326–
10331.
Received: November 9, 2009
Published Online: January 18, 2010
Eur. J. Org. Chem. 2010, 1314–1323
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1323