A straightforward synthesis of 1-adamantylmethyl glycosides, and their binding to cyclodextrins

Article abstract of DOI:10.1002/ejoc.200400141

A single-step synthesis of 1-adamantylmethyl α- and β-glycosides starting from commercially available peracetylated monosaccharides is reported. The α- and β-glucopyranosides 1a and 1b bind to β-cyclodextrin with association constants in the order of 10

Full text of DOI:10.1002/ejoc.200400141

FULL PAPER
A Straightforward Synthesis of 1-Adamantylmethyl Glycosides, and Their
Binding to Cyclodextrins
[a]
[a]
Florence Charbonnier* and Soledad Penad e´ s
Keywords: Cyclodextrins / Glycosides / Host-guest systems / Synthetic methods
A single-step synthesis of 1-adamantylmethyl α- and β-gly-
cosides starting from commercially available peracetylated
monosaccharides is reported. The α- and β-glucopyranosides
scopy. The carbohydrate moiety contributes to the binding
depending on the pyranose stereochemistry.
1
a and 1b bind to β-cyclodextrin with association constants ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
5
−1
1
in the order of 10
M
, as determined by H NMR spectro-
Germany, 2004)
Introduction
cavity. To succeed in such a study, a better fitting in shape
and size between the aglycon of the guest and the cyclodex-
As is the case with other biological molecules, the molec- trin cavity should be achieved. The globular shape of ada-
˚
ular recognition of carbohydrates is characterized by the mantane, with a diameter of about 7 A, matches almost
[
8]
confluence of many weak intermolecular forces, water prob- perfectly the size of the CD cavity.
ably playing the most important role. An important ques-
tion to be answered is how polar and nonpolar groups man- ation constants, ranging from 10
age to strip the water molecules from between the reactive mantane to 10  for 1-adamantanecarboxylic acid.
partners to make the process energetically favourable. To The crystal structure of the complex formed between
answer this question both structural and energetic infor- adamantanol and methylated β-CD confirmed the inclusion
Adamantane derivatives bind to β-CD with high associ-
3
Ϫ1

for bromoada-
[
9]
5
Ϫ1
[8]
[
10]
mation is required.
of the adamantane moiety inside the cavity.
Thus, 1-
Cyclodextrins (CDs)[
1,2]
and cyclophanes[3,4] have been (hydroxymethyl)adamantane was chosen as aglycon for the
shown to be useful models in the understanding of the non- preparation of a series of glycosides that are expected to
covalent bonding interactions in water. We have used CDs bind to CD with higher association constants than the
[
5Ϫ7]
and glycophanes
as model systems to evaluate and PNPGlys.
We report here a straightforward preparation of the α-
understand the interactions of carbohydrates in water. With
a model system consisting of α-cyclodextrin (α-CD) and a and β-anomers of a series of 1-adamantylmethyl glycosides
series of p-nitrophenyl glycosides (PNPGlys) we determined (AdaGlys) and present preliminary results obtained by
by calorimetry the thermodynamic parameters of complex means of NMR spectroscopy of the interaction of the α-
formation in water in an attempt to evaluate the contri- and β-glucopyranosides with β-CD in water. Our results
bution to the energetics of binding of the desolvation of the confirm the formation of inclusion complexes that are pre-
[
5]
carbohydrate moieties exposed to the bulk water. Al- sently under investigation by isothermal titration calorim-
though the results indicated an influence of the sugar etry.
stereochemistry on the thermodynamic parameters, the
binding constants between the PNPGlys and the α-CD were
too small (100Ϫ300  ) to allow us to draw clear con-
Ϫ1
Results and Discussion
clusions. Even smaller association constants were obtained
in the binding of PNPGlys to β-CD. We reasoned that
greater differences in the values of the enthalpic and en-
Synthesis
The synthesis of adamantylmethyl glycosides has not
tropic terms could be expected by increasing the binding been reported previously. However, the preparation of gly-
constants. In principle, this can be achieved by increasing cosides with a similar hydrophobic aglycon — adamantyl-
the favourable interactions between the aglycon and the CD carbonyl — has already been reported.[11] Because we re-
quired significant amounts of α- and β-anomers, we decided
[
a]
Grupo de Carbohidratos, Instituto de Investigaciones to use glycosylation conditions that can afford both ano-
Qu ´ı micas, CSIC
mers in the same reaction step. A simple procedure for the
stereoselective α-glycosidation of peracetylated sugars car-
rying a participating group at C-2 with aliphatic alcohols
Isla de la Cartuja, Am e´ rico Vespucio, s/n 41092 Seville, Spain
Fax: (internat.) ϩ 34-95-446-0565
E-mail: penades@iiq.csic.es
650
3
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400141
Eur. J. Org. Chem. 2004, 3650Ϫ3656

Synthesis of 1-Adamantylmethyl Glycosides
FULL PAPER
in the presence of FeCl as Lewis acid has been reported and α--manno- (αAdaMan, 4a) pyranosides, and their
3
recently. The α-anomer was obtained by in situ anomeriz- corresponding β-anomers 1bϪ3b in quantitative yields.
ation of the initially formed β-anomer.[ Control over the
12]
The β-mannoside (βAdaMan, 4b) was obtained using the
anomerization step, however, should lead to α/β mixtures trichloroacetimidate method also starting from the per-O-
depending on the anomerization conditions.[
13]
Classical acetylated mannose derivative (Scheme 2). Formation of the
glycosidation methods demand both selective activation of thiophenyl glycoside 9 followed by deacetylation and sub-
the anomeric centre and differently protected monosacchar- sequent benzylation gave compound 10 in 60% overall yield
ides for obtaining each anomer. In contrast, the FeCl3 (three steps). Selective deprotection of the anomeric centre
method, starting from the same readily available penta-O- and treatment with trichloroacetonitrile in the presence of
acetylated monosaccharides and without the need for an- DBU yielded the glycosyl donor 12 in 70% yield (two steps).
omeric activation, has allowed us to prepare the α- and β- Reaction of 12 with 1-(hydroxymethyl)adamantane in the
anomers in a single step.
presence of trimethylsilyl triflate gave a 1:2 α/β mixture of
According to this method we have prepared the α- and the benzylated glycosides 13 in 60% yield. The separation
β-(1-adamantylmethyl) glycosides (AdaGlys) of -glucose of both anomers was impossible at this stage. However, de-
(1a and 1b), -galactose (2a and 2b), -fucose (3a and 3b), protection of the benzyl groups in 13 followed by acety-
and the α-anomer of -mannose (4a) (Figure 1). The gen- lation allowed the separation of the acetylated isomers 14a
eral procedure for the preparation of the 1-adamantylme- (α, identical to 8a) and 14b (β). Zempl e´ n deprotection of
thyl glycosides is shown in Scheme 1.
14a and 14b yielded 4a and 4b, respectively, in quantitative
yield. The structure of the compounds was confirmed by
1
13
H and C NMR spectroscopy, elemental analysis and
MALDI-TOF mass spectrometry.
Binding Studies
The inclusion of small molecules into the cavity of CDs
has served as an excellent model system for understanding
noncovalent interactions in aqueous solution. NMR spec-
troscopy, in combination with calorimetric measurements,
has provided insight into the geometry and the energetics
[
2,14,15]
of complex formation.
Figure 1. Molecular structure of 1-adamantylmethyl glycosides and ties of complexation of CDs with neutral guests in water
the aglycon 1-(hydroxymethyl)adamantane
The thermodynamic proper-
[2,5]
(
favourable ∆H° offset by unfavourable T∆S°)
these studies good models for understanding the thermo-
Treatment of the corresponding peracetylated monosac- dynamics of carbohydrateϪlectin associations.[16]
charide with 1 equiv. of 1-(hydroxymethyl)adamantane in Our goal in synthesising the adamantylmethyl glycosides
the presence of 1 equiv. of FeCl in CH Cl below 5 °C was to carry out a calorimetric study to determine the en-
make
3
2
2
resulted in an α/β mixture of the expected glycosides thalpy, entropy, and heat-capacity changes in their interac-
Scheme 1). The pure α- and β-acetylated glycosides 5aϪ8a tion with CDs. A preliminary study, however, was necessary
(
and 5bϪ7b were obtained after chromatographic separation to confirm the inclusion of the AdaGlys into CDs. Moni-
on silica gel in reasonable yields (for yields and α/β ratios toring of the induced chemical shifts of the H and H pro-
β
γ
1
see Table 1). Zempl e´ n deprotection of the acetylated glyco- tons of the AdaGlys by H NMR titration was a simple and
sides gave the 1-adamantylmethyl α--gluco- (αAdaGlc, rapid way to gain insight into these associations. A similar
1a), α--galacto- (αAdaGal, 2a), α--fuco- (αAdaFuc, 3a), induced-shift pattern was observed for all glycosides upon
Scheme 1
Eur. J. Org. Chem. 2004, 3650Ϫ3656
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3651

F. Charbonnier, S. Penad e´ s
FULL PAPER
Table 1. Selected data of the 1-adamantylmethyl glycosides
AdaGly
Acetylated sugar
Yield
%]
α/β [
[α]
D
1H NMR
δ [ppm]
a]
[
ratio
1
2
3
4
a/1b
-Glucose (Glc)
-Galactose (Gal)
-Fucose (Fuc)
30
50
65
65
8:1
1:2
6:1
1:0
5.98 (α)
.72 (β)
108.25 (α)
.32 (β)
Ϫ102.78 (α)
3.23 (β)
4.71 (d, J ϭ 3.6 Hz, 1 H H-1α)
4.20 (d, J ϭ 8.5 Hz, 1 H H-1β)
4.75 (br. s, 1 H, H-1α)
4.16 (d, J ϭ 7.5 Hz, 1 H, H-1β)
4.67 (d, J ϭ 2.7 Hz, 1 H, H-1α)
4.23 (d, J ϭ 8 Hz, 1 H, H-1β)
4.63 (d, J ϭ 1 Hz, 1 H, H-1α)
4.43 (d, J ϭ 0.9 Hz, 1 H, H-1β)
1
a/2b
2
a/3b
1
a/4b[b]
-Mannose (Man)
51.15 (α)[
b]
Ϫ3.71 (β)
[
a]
The anomeric ratio were determined after separation of the acetylated glycosides. [b] The β-anomer was obtained by the trichloroacetim-
idate method.
Scheme 2
complexation with β- and γ-CDs, suggesting a similar bind-
ing geometry for all complexes.
The stability constants (K ) of the interaction between β-
a
CD and the α- and β-adamantylmethyl glucopyranosides
1
1
a and 1b in D O were determined by H NMR titration
2
at three different temperatures. The K of the free aglycon,
a
the 1-(hydroxymethyl)adamantane, was also determined to
evaluate the contribution of the pyranose moiety to the
binding. In our binding experiments, the guest concen-
tration (AdaGlys) was held constant while increasing the
concentration of the host (β-CD). Upon addition of the
host, the signals of the Hβ and H protons of the ada-
γ
mantane moiety shifted downfield (Figure 2).
The chemical shifts induced by β-CD on the adamantane
moiety were large enough (ca. 0.2 ppm) to be used for
NMR titration. Attempts to monitor the chemical-shift
changes of the H-3 and H-5 protons of the β-CD failed due
1
Figure 2. H NMR titration of 1-adamantylmethyl α--glucopyr-
anoside (1a) with increasing amounts of β-CD in D O at 298 K
2
to signal overlapping with the proton signals of the glucose were used. Association constants and calculated induced
moiety of the guest. The stability-constant values (K ), the shifts (CIS values at 100% binding) were obtained using two
a
[
17]
corresponding free energies of binding (Ϫ∆G) at 298, 303, different non-linear fitting programs. All titration curves
and 313 K, and the observed and calculated chemical-in- were carried out at least twice.
duced shifts for the H and H protons of the adamantane
The results obtained indicate that α- and β-adamantyl-
β
γ
moiety are given in Table 2. To calculate the K values, the methyl glucosides associate to β-CD with large association
a
5
Ϫ1
downfield chemical-shift changes of the H and H protons constants (10  ). These values are three orders of magni-
β
γ
of the adamantane moiety versus the β-CD concentration tude higher than those obtained for the binding of
3652
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2004, 3650Ϫ3656

Synthesis of 1-Adamantylmethyl Glycosides
FULL PAPER
Table 2. Association constant (K
glycosides 1a and 1b with β-CD at 298, 303 and 313 K in D
a
[Ϫ1]), free energies (Ϫ∆G° [kcal/mol]) and observed and calculated induced shifts [ppm] of α- and β-
2
O
Glycosides
T [K]
K
a
Ϫ∆G°
H
calcd.
β
H
γ
calcd.
obsd.
obsd.
5
5
5
5
5
5
5
αAdaGlc (1a)
βAdaGlc (1b)
298
(1.383 Ϯ 0.909) ϫ 10
(1.375 Ϯ 0.231) ϫ 10
(1.026 Ϯ 0.211) ϫ 10
(4.376 Ϯ 0.361) ϫ 10
(4.514 Ϯ 0.343) ϫ 10
(5.190 Ϯ 0.587) ϫ 10
(2.800 Ϯ 0.386) ϫ 10
6.98 Ϯ 0.9
7.09 Ϯ 0.2
7.15 Ϯ 0.2
7.66 Ϯ 0.1
7.81 Ϯ 0.1
8.15 Ϯ 0.1
7.40 Ϯ 0.2
0.220
0.212
0.198
0.241
0.225
0.198
0.175
0.246
0.207
0.191
0.208
0.205
0.195
0.174
0.127
0.120
0.110
0.167
0.157
0.152
Ϫ
0.125
0.118
0.106
0.143
0.139
0.135
Ϫ
3
3
03
13
298
3
3
03
13
AdaCH
2
OH
298
2
Ϫ1 [5]
PNPGlys to α-CD (10 
)
and one order of magnitude tations were measured with an optical Perkin-Elmer 341 polar-
imeter. Elemental analyses were determined with a Leco CHNS-
higher than those reported in the literature for the binding
of adamantane-1-carboxylate to β-CD.
[8,18]
932 apparatus.
The K value
a
for the aglycon AdaCH OH is similar to those of the glyco-
sides, indicating that the sugar moiety does not destabilise
2
Binding Studies: Titration experiments were performed with the
Bruker Avance DRX500 (1 H, 500 MHz) spectrometer at different
the binding. The differences in the free energy of binding temperatures (298, 303, and 313 K). Chemicals shifts in D O were
2
Ϫ1
(
2
∆∆G ϭ 0.6Ϫ1.0 kcal·mol ) between the α- and the β- referenced to internal D O (δ ϭ 4.79 ppm). Solutions of αAdaGly
glucosides clearly indicate that the presence of the pyranose (1a) and βAdaGly (1b) were freshly prepared for every new experi-
ment ([αAdaGlc] ϭ 0.152 m; [βAdaGlc] ϭ 0.160 m in D O solu-
2
moiety influences the binding depending on the sugar
[
5]
tion). Solutions of β-cyclodextrin (0.9 or 2 m) were prepared from
the guest solution in order to have a constant concentration of the
guest during the titration. Binding constants were determined by
adding aliquots of a solution of host (0, 2, 3, 4, 5, 10, 20, 50 µL)
to a solution of guest with a microsyringe. The H NMR spectrum
of each solution was recorded and the chemical shifts of the H
and H protons of the adamantylmethyl group, obtained at 16 dif-
stereochemistry. In addition, the free energy of binding of
the β-glycosides slightly increases with increased tempera-
ture, while in the α-glycosides no changes are observed. At-
tempts to evaluate the binding of 1a and 1b to αC-CD
failed, probably due to the non-inclusion of the aglycon
into the α-CD cavity.
1
β
γ
Ongoing isothermal titration calorimetry (ITC) measure- ferent host/guest concentration ratios were used in an interactive
ments also support the influence of the sugar stereochem- least-squares fitting procedure, assuming formation of a 1:1 com-
istry in the enthalpy and entropy of binding to cyclodex- plex.[ Each titration experiment was performed two or three
17]
[
19]
times and the association constants given in Table 2 are the
trins. Accurate thermodynamic data for the enthalpy and
entropy of binding of the different AdaGlys to α-, β-, and
γ-cyclodextrins could give a picture of the influence of the
sugar stereochemistry in the water rearrangement process
β γ
weighted averages of the protons H and H . The maximum per-
cent of estimated error was 20%.
3 3
General Procedure for FeCl -Promoted Glycosidation: FeCl (1
when the carbohydrate moiety is exposed to the bulk equiv.) was added slowly to a solution of penta-O-acetylated mono-
water.
[
16,20,21]
saccharide (1 equiv.) in CH
was stirred for 5 min. An equimolar amount of 1-(hydroxymeth-
yl)adamantane in CH Cl was then added portionwise to the reac-
2 2
Cl (60 mL) at 5 °C and the mixture
2
2
tion mixture over 15 min and stirred at room temperature. Continu-
ous TLC monitoring showed a significant degree of formation of
the α- and β-anomers. After complete disappearance of the alcohol,
the reaction mixture was poured into saturated aqueous sodium
hydrogen carbonate solution and extracted with Et O. Silica gel
2
chromatography of the resultant mixture gave the expected glyco-
sides.
Experimental Section
General Remarks: Chemicals, including 1-(hydroxymethyl)ada-
mantane, galactose, glucose, fucose, mannose, iron trichloride, and
β-cyclodextrin, were obtained from commercial sources (Sigma, Al-
drich or Fluka). Dichloromethane was distilled from calcium hy-
dride, methanol was distilled from sodium and diethyl ether from
sodium/benzophenone. TLC was performed on silica gel 60F254
1
(
(
-Adamantylmethyl
5a,b): Starting from penta-O-acetyl--glucopyranose (1 g) an α/β
8:1) mixture was obtained (30%) as a syrup. R (ethyl acetate/hex-
2,3,4,6-Tetra-O-acetyl-α/β-glucopyranoside
(
Merck) with detection by charring with 10% EtOH/H
phomolybdic acid/EtOH or Ce(SO in phosphomolybdic acid/
SO /H O. For flash chromatography, silica gel (Merck 15Ϫ200
2 4
SO , phos-
4 2
)
f
H
2
4
2
ane, 1:2) ϭ 0.40 (α), 0.34 (β). The mixture was chromatographed
on silica gel (ethyl acetate/hexane 1:4) to give the α-anomer 5a
mesh) was used. Chromatography eluents are given as volume/vol-
ume ratios (v/v). NMR spectra were recorded at 25 °C with Bruker
(
325 mg) and the β-anomer 5b (49 mg) as white solids.
1
1
Avance DPX300 ( H, 300 MHz) and Bruker Avance DRX500 ( H,
00 MHz) spectrometers with the solvent as internal reference. 1-Adamantylmethyl
5
2,3,4,6-Tetra-O-acetyl-α- -glucopyranoside
D
1
Chemical shifts are reported in ppm, and coupling constants are
reported in Hz. Signals were assigned by means of 2D spectra
3
(5a): H NMR (CDCl , 500 MHz): δ ϭ 5.42 (t, J ϭ 10 Hz, 1 H,
H-3), 5.05Ϫ5.95 (m, 2 H, H-4, H-1), 4.79 (dd J ϭ 4, J ϭ 10.5 Hz,
H-2), 4.21 (dd, J ϭ 4.5, J ϭ 12 Hz, 1 H, H-6a), 4.05 (dd, J ϭ 2.5,
(
COSY, HMQC). The deuterated solvents used were CDCl
purity), CD OD (99.8%, purity), and D
spectra were recorded with an HP-G2025 apparatus. Optical ro-
3
(99.8%
3
2
O (99.8% purity). Mass J ϭ 12 Hz, 1 H, H-6b), 3.95Ϫ3.91 (m, 1 H, H-5), 3.24 (d, J ϭ 9.5
Hz, 1 H, CH OAda), 2.87 (d, J ϭ 9 Hz, 1 H, CH OAda), 2.03,
2
2
Eur. J. Org. Chem. 2004, 3650Ϫ3656
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3653

F. Charbonnier, S. Penad e´ s
FULL PAPER
2
.00, 1.99, 1.96 (s, 12 H, 4 ϫ CH
3
CO), 1.94 (br. s, 3 H, CH
β
Ada), 5.31Ϫ5.29 (m, 1 H, H-2), 5.06 (dd, J ϭ 10.2, J ϭ 3.6 Hz, 1 H, H-
1.73Ϫ1.46 (m, 12 H, CH
2
Ada) ppm. 13C NMR (CDCl
3
, 125 MHz):
CO), 90.1 (C-1), 80.8, H-5), 3.25 (d, J ϭ 9.3 Hz, 1 H, CH
2.7, 72.2, 71.8, 71.6, 71.0, 68.9, 68.3, 62.2, 62.1 (C-2, C-3, C-4, C- H, CH OAda), 2.14, 2.04, 1.97 (s, 9 H, 3 ϫ CH
, C-6), 39.4, 37.0, 33.8, 28.1, 20.7, 20.6 (CH CO) ppm. MALDI- H, CHAda), 1.74Ϫ1.48 (m, 12 H, CH Ada), 1.12 (d, J ϭ 6.6 Hz,
) ppm. C NMR (125 MHz, CDCl ): δ ϭ 170.6, 170.5,
170.2 (CH CO), 96.5 (C-1), 79.1, 71.2 (C-2), 68.6, 68.4 (C-4, C-3),
4.0 (C-5), 39.4, 39.0, 37.2, 37.1; 28.2, 28.1, 20.8, 20.6 (CH CO),
5.9 (CH ) ppm. MALDI-TOF: calcd. 461.50 [C23 ϩ Na];
3), 4.98 (d, J ϭ 3.9 Hz, 1 H, H-1), 4.10 (br. q, J ϭ 12.3 Hz, 1 H,
OAda), 2.87 (d, J ϭ 9.6 Hz, 1
CO), 1.95 (br. s, 3
δ ϭ 170.7, 170.3, 169.8, 169.4, 169.2 (CH
7
5
3
2
2
3
3
2
ϩ
ϩ
13
TOF: m/z ϭ 520.0 [M ϩ Na ϩ H] , 536.0 [M ϩ K ϩ H] .
10 (496.56): calcd. C 60.41, H 7.25; found C 60.30, H 7.15.
3 H, CH
3
3
C
25
H
36
O
3
6
1
3
1-Adamantylmethyl 2,3,4,6-Tetra-O-acetyl-β- -glucopyranoside
D
3
34 8
H O
1
(5b): H NMR (500 MHz, CDCl ): δ ϭ 5.17 (t, J ϭ 10 Hz, 1 H,
3
ϩ
ϩ
found 461.7 [M ϩ Na] , 477.6 [M ϩ K] .
H-3), 5.05 (t, J ϭ 10 Hz, 1 H, H-4), 4.98 (dd, J ϭ 7.5, J ϭ 10 Hz,
H, H-2), 4.39 (d, J ϭ 7.5 Hz, 1 H, H-1), 4.24 (dd, J ϭ 7.5, J ϭ 1-Adamantylmethyl 2,3,4-Tri-O-acetyl-β- H
.5 Hz, 1 H, H-6a), 4.10 (dd, J ϭ 10, J ϭ 4.5 Hz, 1 H, H-6b), NMR (300 MHz, CDCl ): δ ϭ 5.24Ϫ5.17 (m, 2 H, H-4, H-2), 5.00
.67Ϫ3.61 (m, 1 H, H-5), 3.47 (d, J ϭ 10 Hz, 1 H, CH OAda),
(dd, J ϭ 10.5, JH3,H4 ϭ 3.3 Hz, 1 H, H-3), 4.35 (d, J ϭ 8.1 Hz, 1
L
-fucopyranoside (7b): 1
1
4
3
2
3
2
.95 (d, J ϭ 10 Hz, 1 H, CH
2
OAda), 2.06, 2.02, 1.99, 1.98 (s, 12 H, H1), 3.77 (br. q, J ϭ 12.3 Hz, 1 H, H-5), 3.53 (d, J ϭ 9.6 Hz,
Ada) ppm. 1 C NMR 1 H, CH
3
OAda), 2.95 (d, J ϭ 9.6 Hz, 1 H, CH
OAda), 2.17, 2.05,
H, 4 ϫ CH
3
CO), 1.72Ϫ1.44 (m, 12 H, CH
2
2
2
(
CDCl3, 125 MHz): δ ϭ 170.6, 170.1, 169.6 (CH
3
CO), 96.1 (C-1),
9.2, 71.1, 70.4, 68.7, 66.9, 61.9 (C-2, C-3, C-4, C-5, C-6), 39.4, (m, 12 H, CH
7.0, 33.8, 28.1, 20.7, 20.6 (CH CO) ppm. MALDI-TOF: m/z ϭ
1.98 (3s, 9 H, 3 ϫ CH
3
CO), 1.95 (br. s, 3 H, CHAda), 1.73Ϫ1.49
1
3
7
3
5
6
2
Ada), 1.21 (d, J ϭ 6.3 Hz, 3 H, CH
3
) ppm.
C
NMR (125 MHz, CDCl
10 (496.56): calcd. C 102.4(C-1), 81.0, 71.3, 70.4, 69.2, 69.0 (C-2, C-3, C-4, C-5), 39.5,
39.3, 37.2, 37.1, 33.9, 28.2, 28.1, 20.8, 20.7, 20.6 (CH CO), 16.1
3 3
): δ ϭ 170.8, 170.3, 169.4 (COCH ),
3
ϩ
ϩ
36
19.7 [M ϩ Na] , 535.7 [M ϩ K] . C25H O
0.41, H 7.25; found C 60.10, H 7.15.
3
ϩ
(
CH
3
) ppm. MALDI-TOF: m/z ϭ 461.9 [M ϩ Na] , 477.9
1
(
-Adamantylmethyl 2,3,4,6-Tetra-O-acetyl-α/β-D-galactopyranoside
ϩ
[M ϩ K] .
6a,b): Starting from penta-O-acetyl--galactopyranose (500 mg) a
mixture of 6a and 6b was obtained (50%, α/β, 1:2) as a white solid. 1-Adamantylmethyl
The mixture was chromatographed on silica gel (ethyl acetate/hex-
(8a): Starting from penta-O-acetyl--mannopyranose (200 mg)
ane, 1:4) to give the α-anomer 6a (105 mg) and the β-anomer 6b only the α-isomer 8a was obtained (136m g, 65%). R (ethyl acetate/
): δ ϭ 5.37Ϫ5.22
2,3,4,6-Tetra-O-acetyl-α-D-mannopyranoside
f
1
(200 mg) as white solids. R
f
(ethyl acetate/hexane, 1:2) ϭ 0.50 (α),
hexane, 1:2) ϭ 0.52. H NMR (300 MHz, CDCl
3
0
.45 (β).
(m, 3 H, H-2, H-3, H-4), 4.74 (br. s, 1 H, H-1), 4.27 (dd, J ϭ 12.3,
J ϭ 5.4 Hz, 1 H, H-6a), 4.11 (dd, J ϭ 12.3, J ϭ 2.4 Hz, 1 H, H-
1-Adamantylmethyl 2,3,4,6-Tetra-O-acetyl-α-
D
-galactopyranoside
6
2
b), 4.00Ϫ3.90 (m, 1 H, H-5), 3.27 (d, J ϭ 9 Hz, 1 H, CH
.97 (d, J ϭ 9 Hz, 1 H, CH OAda), 2.16, 2.11, 2.05, 2.00 (4s, 12
CO), 1.98 (br. s, 3 H, CHAda), 1.78Ϫ1.50 (m, 12 H,
Ada) ppm. 13C NMR (125 MHz, CDCl
): δ ϭ 170.6 (COCH ),
8.3 (C-1), 86.9, 79.2, 70.0, 69.7, 68.7, 66.7, 62.9 (C-2, C-3, C-4, C-
, C-6, CAda), 39.9, 37.4, 28.4 (CH CO) ppm. MALDI-TOF:
2
OAda),
1
(6a): H NMR (500 MHz, CDCl
3
): δ ϭ 5.46 (dd, J ϭ 3.3, J ϭ 1.2
2
Hz, 1 H, H-4), 5.28 (dd, J ϭ 10.5, J ϭ 3 Hz, 1 H, H-3), 5.04 (dd,
J ϭ 10.5, J ϭ 3 Hz, 1 H, H-2), 5.01 (d, J ϭ 3 Hz, 1 H, H-1),
H, 4 ϫ CH
CH
9
5
3
2
3
3
4
6
1
2
1
.14Ϫ4.12 (m, 1 H, H-5), 4.07 (dd, J ϭ 11.0, J ϭ 6 Hz, 1 H, H-
a), 4.02 (dd, J ϭ 11.0, J ϭ 6.0 Hz, 1 H, H-6b), 3.23 (d, J ϭ 9 Hz,
H, CH
.00, 1.95 (s, 12 H, 4 ϫ CH
.70Ϫ1.59 (m, 6 H, CH Ada), 1.48 (br. s, 6 H, CH
3
ϩ
ϩ
2
OAda), 2.86 (d, J ϭ 9.5 Hz, 1 H, CH
CO), 1.93 (br. s, 3 H, CHAda),
Ada) ppm.
2
OAda), 2.09, 2.01,
m/z ϭ 518.4 [M ϩ Na Ϫ H] , 534.3 [M ϩ K Ϫ H] . C25
496.55): calcd. C 60.50, H 7.30; found C 60.10, H 7.55.
36 10
H O
3
(
2
2
ϩ
Zempl e´ n Deacetylation: A solution of sodium methoxide in meth-
anol (1 , 0.1 equiv.) was added at room temperature to a solution
of the acetylated 1-adamantylmethyl glycosides (1.0 equiv.) in
methanol. After 2 h, the mixture was neutralised with Amberlite
resin IRA-120, the solution was filtered and the solvents were eva-
porated to give the corresponding 1-adamantylmethyl glycoside.
MALDI-TOF: m/z ϭ 520.4, [M ϩ Na ϩ H] , 536.4 [M ϩ K ϩ
H] . C25
H 6.95.
ϩ
36
H O10 (496.56): calcd. C 60.41, H 7.25; found. C 60.37,
1
-Adamantylmethyl 2,3,4,6-Tetra-O-acetyl-β-
D
-galactopyranoside
): δ ϭ 5.37Ϫ5.35 (m, 1 H, H-4),
.20 (dd, J ϭ J ϭ 8 Hz, 1 H, H-2), 4.99 (dd, J ϭ 10.5, J ϭ 3.5 Hz,
1
(6b): H NMR (500 MHz, CDCl
3
5
1
1
1-Adamantylmethyl α-
D-Glucopyranoside (1a): From 5a (325 mg,
H, H-3), 4.36 (d, J ϭ 8 Hz, 1 H, H1), 4.16 (dd, J ϭ 11, J ϭ 7 Hz,
H, H-6a), 4.10 (dd, J ϭ 11, J ϭ 7 Hz, 1 H, H-6b), 3.85 (m, 1 H,
1
.0 equiv.) in methanol (50 mL). 1a was obtained as a white solid
2
5
(
98%). R
f
1
(CH
2
Cl
2
/MeOH, 98:2) ϭ 0.29. [α]
D
ϭ 5.98 (c ϭ 1.0,
H-5), 3.49 (d, J ϭ 9.5 Hz, 1 H CH
CH OAda), 2.13, 2.04, 2.03, 1.96 (s, 12 H, 4 ϫ CH
s, 3 H, CHAda), 1.71Ϫ1.58 (m, 6 H, CH Ada), 1.48 (br. s, 6 H,
Ada) ppm. 13C NMR (125 MHz, CDCl
CH ): δ ϭ 97.9 (C-1), 78.0,
7
3
5
2
OAda), 2.96 (d, 1 H,
MeOH). H NMR (300 MHz, CD
3
OD): δ ϭ 4.71 (d, J ϭ 3.6 Hz,
2
3
CO), 1.93 (br.
1
H, H-1), 3.80 (dd, J ϭ 11.7, J ϭ 2.4 Hz, 1 H, H-6a), 3.71Ϫ3.63
2
(m, 2 H, H-3, H-6b), 3.61Ϫ3.55 (m, 1 H, H-5), 3.40 (dd, J ϭ 9.9,
J ϭ 3.9 Hz, 1 H, H-2), 3.36 (m, 1 H, H-4), 3.27 (d, J ϭ 9.0 Hz, 1
2
3
0.2, 69.2, 68.9, 68.3, 60.7 (C-2, C-3, C-4, C-5, C-6a, C-6b), 38.7,
6.2, 32.8, 27.5 ppm. MALDI-TOF: m/z ϭ 520.2 [M ϩ Na ϩ H] ,
36.3 [M ϩ K ϩ H] . C25H O10 (496.56): calcd. C 60.41, H 7.25;
36
ϩ
H, CH
3 H, CH
(
7
2
OAda), 2.94 (d, J ϭ 9.3 Hz, 1 H, CH
Ada), 1.81Ϫ1.75 (m, 12 H, CH Ada) ppm. C NMR
125 MHz, CD OD): δ ϭ 101.1 (C-1), 80.4, 76.0, 74.7, 74.4, 72.8,
3.6 (C-2, C-3, C-4, C-5, C-6), 41.6, 39.1, 30.6 ppm. MALDI-TOF:
2
OAda), 1.98 (br. s,
1
3
ϩ
β
2
found C 59.89, H 7.23.
3
ϩ
ϩ
1
-Adamantylmethyl 2,3,4-Tri-O-acetyl-α/β-
L
-fucopyranose (7a,b):
17 28 6
m/z ϭ 351 [M ϩ Na] , 367 [M ϩ K] . C H O (328): calcd. C
Starting from tetra-O-acetyl--fucopyranose (632 mg) a mixture of 62.0, H 8.5; found. C 61.9, H 7.81.
7
a and 7b was obtained (65%, α/β 6:1). R
f
(ethyl acetate/hexane,
1
-Adamantylmethyl β-
D
-Glucopyranoside (1b): From 5b (49 mg) in
(CH Cl
ϭ Ϫ21.7 (c ϭ 0.64, MeOH). H NMR
OD, 500 MHz): δ ϭ 4.20 (d, J ϭ 8.5 Hz, H-1), 3.93 (m, 1 H,
H-6a), 3.73 (dd, J ϭ 12.0, J ϭ 5.5 Hz, 1 H, H-6b), 3.56 (d, J ϭ
): δ ϭ 5.33 (d, J ϭ 3.3 Hz, 1 H, H-4), 10.0 Hz, 1 H, CH OAda), 3.50 (t, J ϭ 8.5 Hz, 1 H, H-3), 3.48Ϫ3.43
1:2) ϭ 0.66 (α), 0.50 (β). The mixture was chromatographed on
methanol (20 mL). 1b (99%) was obtained as a syrup. R
f
2
2
/
silica gel (ethyl acetate/hexane, 1:4) to give the α-anomer 7a
237 mg) and the β-anomer 7b (35 mg) as white solids.
2
5
1
MeOH, 98:2) ϭ 0.30. [α]
CD
D
(
(
3
1
1-Adamantylmethyl 2,3,4-Tri-O-acetyl-α- -fucopyranoside (7a): H
L
NMR (300 MHz, CDCl
3
2
3654
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3650Ϫ3656

Synthesis of 1-Adamantylmethyl Glycosides
FULL PAPER
(
1
m, 1 H, H-5), 3.39 (t, J ϭ 8.5 Hz, 1 H, H-4), 3.30 (t, J ϭ 8.5 Hz,
H, H-2), 3.24 (d, J ϭ 10.0 Hz, 1 H, CH OAda), 1.98 (br. s, 3 H,
CHAda), 1.77Ϫ1.55 (m, 12 H, CH
Ada) ppm. 13C NMR (MeOD, 1.94 (br. s, 3 H, CHAda), 1.78Ϫ1.55 (m, 12 H, CH
25 MHz): δ ϭ 106.1 (C-1), 82.5, 79.1, 78.7, 76.1, 72.6, 63.6 (C-2, NMR (125 MHz, MeOD): δ ϭ 100.4 (C-1), 77.7 (CAda), 73.1 (C-
C-3, C-4, C-5, C-6), 41.4, 39.2, 35.9, 30.6 ppm. MALDI-TOF: 5), 71.4 (C-3), 70.8 (C-2, C-6), 67.2 (C-4), 39.4, 36.8, 33.3, 28.4,
3.57 (t, J ϭ 10 Hz, 1 H, H-4), 3.52Ϫ3.46 (m, 1 H, H-5), 3.33 (d,
2
J ϭ 9 Hz, 1 H, CH
2
OAda), 2.89 (d, J ϭ 9 Hz, 1 H, CH
2
OAda),
Ada) ppm. 13
C
2
2
1
ϩ
ϩ
ϩ
calcd. 351.7 [C17
28 6
H O ϩ Na ]; found 351.7 and 367.6 [M ϩ K] . 28.3 ppm. MALDI-TOF: m/z ϭ 352.4 [M ϩ Na ϩ H] , 368.4 [M
ϩ
ϩ K ϩ H] . C17
1.60, H 8.65.
28 6
H O (328.40): calcd. C 62.00, H 8.60; found C
1
-Adamantylmethyl α-
D-Galactopyranoside (2a): From 6a (400 mg)
6
in methanol (30 mL). 2a (251 mg, 95%) was obtained as a white
solid. R
MeOH). H NMR (300 MHz, MeOD): δ ϭ 4.75 (br. s, 1 H, H-1),
5
f
(CH
2
Cl
2
/MeOH, 95:5) ϭ 0.33. [α]2
D
ϭ 108.2 (c ϭ 1.03,
Phenyl 2,3,4,6-Tetra-O-acetyl-1-thio-α-D-mannopyranoside (9):
Penta-O-acetyl-α--mannopyranose (300 mg, 1 equiv.) was dis-
1
3
3
2
1
.91 (br. s, 1 H, H-6a), 3.83Ϫ3.75 (m, 4 H, H-2, H-3, H-5, H-6b),
.74Ϫ3.69 (m, 1 H, H-4), 3.36 (d, J ϭ 9.3 Hz, 1 H, CH
.94 (d, J ϭ 9 Hz, 1 H, CH OAda), 1.98 (br. s, 3 H, CHAda),
.81Ϫ1.59 (m, 12 H, CH
Ada) ppm. 13C NMR (125 MHz, D
solved in chloroform (50 mL) and benzenethiol (1.5 equiv.,
2
OAda), 4.18 mL) and boron trifluorideϪdiethyl ether (3 equiv., 4.81 mL)
2
were added to this solution. The reaction was monitored by TLC
O): (ethyl acetate/hexane, 1:2). After 6 h, the solution was washed with
2
2
δ ϭ 97.9 (C-1), 78.0, 70.2, 69.2, 68.9, 68.3 (C-2, C-3, C-4, C-5), saturated aqueous sodium hydrogen carbonate and the organic
6
0.7 (C-6), 38.7, 36.2, 32.8, 27.5. MALDI-TOF: m/z ϭ 351.8 [M phase dried. Removal of the solvent gave a yellow syrup which
ϩ ϩ
ϩ Na] , 367.7 [M ϩ K] . C17
H
28
O
6
·H
2
O (346.41): calcd. C 58.88, crystallized on treatment with ethanol to afford 9 (83%) as colour-
less needles. Rf (ethyl acetate/hexane, 1:2) ϭ 0.4. H NMR
): δ ϭ 7.55Ϫ7.20 (m, 5 H, Ph), 5.47 (m, 2 H, H-
α, H-3), 5.35Ϫ5.25 (m, 2 H, H-2, H-4), 4.60Ϫ4.48 (m, 1 H, H-
H 8.66; found C 58.70, H 8.80.
1
(300 MHz, CDCl
3
1-Adamantylmethyl β- -Galactopyranoside (2b): From 6b (900 mg)
D
1
in methanol (60 mL). 2b (98%) was obtained as a white solid. R
f
/MeOH, 95:5) ϭ 0.30. [α]2
5
1
6a), 4.34Ϫ4.24 (dd, JH5,H6 ϭ 12.5, JH5,H4 ϭ 6 Hz, 1 H, H-5), 4.08
br. d, JH6,H5 ϭ 12 Hz, H-6b), 2.15, 2.08, 2.05, 2.00 (4 ϫ s, 12 H,
ϫ CH CO) ppm.
(CH
2
Cl
2
D
ϭ 2.32 (c ϭ 0.99, MeOH). H
(
NMR (300 MHz, MeOD): δ ϭ 4.16 (d, J ϭ 7.5 Hz, 1 H, H-1),
3
6
4
3
.84 (br. d, J ϭ 3.3 Hz, 1 H, H-4), 3.74 (br. d, J ϭ 5.7 Hz, 2 H, H-
a, H-6b) 3.58Ϫ3.41 (m, 4 H, CH2OAda, H-2, H-5, H-3), 3.06 (d,
Phenyl 2,3,4,6-Tetra-O-benzyl-1-thio-α-D-mannopyranoside (10): A
J ϭ 9.3 Hz, 1 H, CH
2
OAda), 1.96 (br. s, 3 H, CHAda), 1.80Ϫ1.60
Ada) ppm. 13C NMR (75 MHz, MeOD): δ ϭ 106.6
C-1), 82.5, 77.4, 75.9, 73.6, 71.2, 63.3 (C-3, C-5, C-2, C-4, C-6),
solution of sodium methoxide in methanol (1 , 591 µL, 0.1 equiv.)
was added to a solution of 9 (2.6 g) in methanol (70 mL). The mix-
ture was stirred for 1 h and then neutralised with Amberlite resin
(
(
m, 12 H, CH
2
ϩ
41.5, 39.2, 30.6 ppm. MALDI-TOF: m/z ϭ 351.9 [M ϩ Na] , 367.8
ϩ
IRA-120 (H ). After filtration and evaporation of the solvent, the
ϩ
[M ϩ K ]. C17
28 6 2
H O ·2H O (364.41): calcd. C 55.98, H 8.78; found
residue was dissolved in DMF (50 mL) and treated with NaH pow-
der (7 equiv., 624 mg) and the suspension was stirred at 20 °C for
C 55.50, H 8.60.
3
0 min. The mixture was then cooled to 0 °C and benzyl bromide
1
-Adamantylmethyl α-L-Fucopyranoside (3a): From 7a (240 mg) in
(
14 equiv., 6.06 mL, 8.72 g) was added. The reaction mixture was
methanol (8 mL). 3a (90%) was obtained as a white solid. R
f
/MeOH, 98:2) ϭ 0.30. [α]2
5
stirred at 25 °C until a clear solution had formed (24Ϫ48 h), and
was then quenched with methanol (10 mL) at 0 °C. The resulting
clear solution was concentrated to dryness. Ethyl acetate (50 mL)
and water (50 mL) were added to the residue. The ethyl acetate
layer was removed and washed with water (3 ϫ 40 mL), dried and
(
CH
2
Cl
2
D
ϭ Ϫ102.78 (c ϭ 1.04, MeOH).
1
H NMR (300 MHz, MeOD): δ ϭ 4.67 (d, J ϭ 2.7 Hz, 1 H, H-1),
3.93 (br. q, J ϭ 6.6 Hz, 1 H, H-5), 3.77Ϫ3.73 (m, 2 H, H-2, H-3),
3.67 (d, J ϭ 1.2 Hz, 1 H, H-4), 3.26 (d, J ϭ 9 Hz, 1 H, CH OAda),
2.95 (d, J ϭ 9 Hz, 1 H, CH OAda), 1.98 (br. s, 3 H, CHAda),
1.81Ϫ1.60 (m, 12 H, CH Ada), 1.22 (d, J ϭ 6.6 Hz, 3 H, CH
2
2
concentrated to yield a crystalline residue which was chromato-
2
3
)
1
13
graphed (ethyl acetate/hexane, 3:1) to give 10 in 81% yield.
NMR (300 MHz, CDCl
H1,H2 ϭ 1.5 Hz, 1 H, H-1α), 4.98Ϫ4.45 (m, 8 H, 4 ϫ CH
4.34Ϫ4.25 (m, 1 H, H-5), 4.20Ϫ3.70 (m, 5 H, H-2, H-3, H-4, H-
a, H-6b).
H
ppm. C NMR (125 MHz, MeOD): δ ϭ 101.5 (C-1), 80.6 (CAda),
): δ ϭ 7.60Ϫ7.10 (m, 25 H, Ph), 5.62 (d,
),
7
3
3
9
2.7 (C-4), 71.2 (C-2, C-3), 68.2 (C-5), 41.6, 41.1, 39.2, 39.1, 35.8,
0.6, 17.5 (CH ) ppm. MALDI-TOF: m/z ϭ 335.8 [M ϩ Na] ,
3
3
ϩ
J
2
ϩ
51.7 [M ϩ K] . C17
28 5 2
H O ·1/2H O (321.41): calcd. C 63.47, H
6
.02; found C 64.10, H 9.12.
1
-Adamantylmethyl β- -Fucopyranoside (3b): From 7b (160 mg) in
L
2,3,4,6-Tetra-O-benzyl-D-mannopyranose (11): N-Bromosuccinim-
methanol (5 mL). 3b (96%) was obtained as a white solid. R
f
ide (1.2 equiv., 540 mg) was added in the dark to a solution of 10
(1.6 g) in acetone (27.2 mL) at Ϫ25 °C. Then water (3.3 equiv., 150
µL) was added. The solution was stirred for 3 h and the tempera-
/MeOH, 98:2) ϭ 0.28. [α]2
5
(
CH
2
Cl
2
D
ϭ 13.23 (c ϭ 1.02, MeOH).
1
2
H NMR (300 MHz, D O): δ ϭ 4.23 (d, J ϭ 8 Hz, 1 H, H-1),
3
.74Ϫ3.67 (m, 1 H, H-5), 3.65 (d, J ϭ 3 Hz, 1 H, H-4), 3.54 (dd, ture was increased slowly to room temperature. Saturated aqueous
J ϭ 10, J ϭ 3.5 Hz, 1 H, H-3), 3.43 (d, J ϭ 10.5 Hz, 1 H,
sodium hydrogen carbonate was added and the acetone was evapo-
rated in vacuo. The reaction mixture was extracted with ethyl acet-
ate. The organic phase was dried and the solvents were evaporated
CH
CH
2
OAda), 3.42Ϫ3.38 (m, 1 H, H-2), 3.12 (d, J ϭ 10 Hz, 1 H,
) ppm. 1 C NMR
3
2
OAda), 1.17 (d, J ϭ 6.5 Hz, 3 H, CH
3
(
(
300 MHz, D
C-4), 72.9 (C-5), 72.3 (C-3), 41.1, 38.8, 35.5, 30.3, 17.2 (CH
2
O): δ ϭ 106.1 (C-1), 82.1 (CAda), 75.7 (C-2), 73.6 to give the α- and β-anomers of 11 as a syrup (75%). R
f
؍ 0.14.
): δ ϭ 5.26 (br. s, 1 H, H-1α),
4.97Ϫ4.47 (m, 8 H, 4 ϫ CH ), 4.12Ϫ4.03 (m, 1 H, H-5), 3.99 (dd,
1
) ppm.
H NMR (500 MHz, CDCl
3
3
ϩ
MALDI-TOF: m/z ϭ 336.0 [M ϩ NaϩH], 351.9 [M ϩ K] .
.1/2 H O (321.41): calcd. C 63.47, H 9.02; found: calcd.
C 63.00, H 9.45.
2
C
17
H
28
O
5
2
J
J
6
H3,H2 ϭ 3, JH3,H4 ϭ 9.3 Hz, 1 H, H-3), 3.87 (pseudo t, JH4,H3 ϭ
H4,H5 ϭ 9.6 Hz, 1 H, H-4), 3.83Ϫ3.57 (m, 3 H, H-2, H-6a, H-
b) ppm.
1-Adamantylmethyl α-D-Mannopyranoside (4a): From 8a (1800 mg)
in methanol (70 mL). 4a (99%) was obtained as a white solid. R
f
O-(2,3,4,6-Tetra-O-benzyl-α/β-
imidate (12): 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU; 1.2 equiv.,
33.4 µL) and trichloroacetonitrile (185 µL) were added to a solu-
D
-mannopyranosyl)
Trichloroacet-
/MeOH, 95:5) ϭ 0.30. [α]2
5
ϭ 51.15 (c ϭ 1.04, MeOH).
(
CH
2
Cl
2
D
1
H NMR (500 MHz, MeOD): δ ϭ 4.63 (d, J ϭ 1 Hz, 1 H, H-1),
3
.81Ϫ3.75 (m, 2 H, H-2, H-6a), 3.70Ϫ3.64 (m, 2 H, H-3, H-6b), tion of 11 (1 equiv., 100 mg) in CH
2
Cl
2
(5 mL). TLC monitoring
Eur. J. Org. Chem. 2004, 3650Ϫ3656
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3655

F. Charbonnier, S. Penad e´ s
FULL PAPER
(
ethyl acetate/hexane, 1:1) showed significant formation of the α-
J
H6a,H6b ϭ 5.7, JH6b,H5 ϭ 12 Hz, 1 H, H-6a), 3.58 (t, JH4,H3
9.3 Hz, 1 H, H-4), 3.56 (d, J ϭ 9.3 Hz, 1 H, CH OAda), 3.44 (dd,
H3,H2 ϭ 3.3, JH3,H4 ϭ 9.3 Hz, 1 H, H-3), 3.23Ϫ3.16 (m, 1 H, H-
5), 3.06 (d, J ϭ 9.3 Hz, 1 H, CH OAda), 1.97 (br. s, 3 H, CHAda),
.83Ϫ1.59 (m, 12 H, CH Ada) ppm. C NMR (125 MHz,
MeOD): δ ϭ 100.9 (C-1), 79.7, 76.4, 73.6, 70.6, 66.8, 38.8, 38.7,
8.6, 36.5, 33.1, 27.9 ppm. MALDI-TOF: calcd. 351.39 [C17
ϭ
and β-anomer. The mixture was concentrated under reduced press-
ure and used directly due to the very strong reactivity of these com-
pounds.
2
J
2
1
3
1
2
1
-Adamantylmethyl
2,3,4,6-Tetra-O-benzyl-α/β-mannopyranoside
(13a,b): A solution of 12 (1 equiv., 130 mg) and 1-(hydroxymeth-
3
28 6
H O
yl)adamantane (1.2 equiv., 38 mg) in dry dichloromethane (5 mL)
was stirred in the presence of molecular sieves (4 A) under argon
ϩ
ϩ
ϩ Na]; found 352.5 [M ϩ Na ϩ H] , 368.4 [M ϩ K ϩ H] .
˚
at room temperature for 10 min. Trimethylsilyl triflate (0.1 equiv.,
3
.4 µL) was then slowly added. The reaction mixture was stirred at
Acknowledgments
This work was supported by a DGES (Grant BQU2002-03734) and
an EU (Grant TMR-FMRXCT98-0231). F. C. thanks the EU for
financial support.
room temperature for 3 h, then concentrated to give 13 (55%;
α/β ϭ 1:4) as a yellow oil. The separation of both anomers was not
possible at this stage. Debenzylation and subsequent acetylation
allowed the purification of both anomers.
1
(
-Adamantylmethyl 2,3,4,6-Tetra-O-acetyl-α/β-
14): 10% Pd/C was added to a solution of 13 (1 equiv., 208 mg)
in CH Cl /MeOH (10Ϫ15 mL) and the mixture was stirred under
D
-mannopyranoside
[1]
K. A. Connors, Chem. Rev. 1997, 97, 1325Ϫ1357.
[2]
M. V. Rekharsky, Y. Inoue, Chem. Rev. 1998, 98, 1875Ϫ1917.
[
[
[
[
3]
4]
5]
6]
2
2
D. B. Smithrud, T. B. Wyman, F. Diederich, J. Am. Chem. Soc.
1991, 113, 5420Ϫ5426.
D. A. Stauffer, R. E. Barrans Jr., D. A. Dougherty, J. Org.
Chem. 1990, 55, 2762Ϫ2767.
E. Junquera, J. Laynez, M. Men e´ ndez, S. Sharma, S. Penad e´ s,
J. Org. Chem. 1996, 61, 6790Ϫ6798.
hydrogen at room temperature for 2 d. The mixture was filtered
and the solvents were evaporated under low pressure to give the
deprotected α- and β-anomers as a mixture. The residue (103 mg)
was acetylated with pyridine/acetic anhydric (2:1) and the mixture
was poured into ice/water and extracted with ethyl acetate. The
J. M. Coter o´ n, C. Vicent, C. Bosso, S. Penad e´ s, J. Am. Chem.
Soc. 1993, 115, 10066Ϫ10076.
2 4
combined organic phases were washed with a H SO solution (2 )
and with saturated aqueous sodium hydrogen carbonate, and then
dried with magnesium sulfate. Filtration and concentration of the
solution gave the α- and β-glycosides as a mixture (1:4) in 64%
yield. Chromatography of this mixture on silica gel (ethyl acetate/
hexane, 1:6) gave the α-isomer 14a (24 mg, 15%) and the β-isomer
[7]
J. C. Morales, S. Penad e´ s, Angew. Chem. Int. Ed. 1998, 37,
654Ϫ657.
[
[
8]
9]
M. R. Eftink, M. L. Andy, K. Bystrom, H. D. Perlmutter, D.
S. Kristol, J. Am. Chem. Soc. 1989, 111, 6765Ϫ6772.
P. M. Ivanov, D. Salvatierra, C. Jaime, J. Org. Chem. 1996,
6
1, 7012Ϫ7017.
14b (75 mg). R
f
(ethyl acetate/hexane, 1:2) ϭ 0.4 (α), 0.34 (β). Iso-
[10]
M. Czugler, E. Eckle, J. J. Stezowski, J. Chem. Soc., Chem.
Commun. 1981, 1291Ϫ1292.
mer 14a is identical to 8a already described.
[
[
11]
12]
1
-Adamantylmethyl
2,3,4,6-Tetra-O-acetyl-β-
D-mannopyranoside
P. Brajeswar, W. Korytnyk, Carbohydr. Res. 1984, 126, 27Ϫ43.
S. K. Chatterjee, P. Nuhn, Chem. Commun. 1998, 98,
1
(14b): H NMR (300 MHz, CDCl ): δ ϭ 5.48 (d, JH2,H3 ϭ 3.3 Hz,
3
1
729Ϫ1730.
1
J
1
6
3
2
H, H-2), 5.25 (pseudo t, JH4,H3 ϭJH4,H5 ϭ 9.9 Hz, 1 H), 5.05 (dd,
[13]
N. Ikemoto, O. K. Kim, L.-C. Lo, V. Satyanarayana, M.
Chang, K. Nakanishi, Tetrahedron Lett. 1992, 33, 4295Ϫ4298.
H.-J. Schneider, F. Hacket, V. Rüdiger, Chem. Rev. 1998, 98,
H3,H2 ϭ 3.3, JH3,H4 ϭ 9.9 Hz, 1 H, H-3), 4.56 (d, JH1,H2 ϭ 0.9 Hz,
H, H-1β), 4.30 (dd, JH6a,H6b ϭ 5.4, JH6b,H5 ϭ 12.3 Hz, 1 H, H-
a), 4.13 (dd, JH6b,H6a ϭ 5.4, JH6b,H5 ϭ 12.3 Hz, 1 H, H-6b),
[14]
[15]
1
755Ϫ1785.
.68Ϫ3.59 (m, 1 H, H-5), 3.49 (d, J ϭ 9.3 Hz, 1 H, CH
.99 (d, J ϭ 9.3 Hz, 1 H, CH OAda), 2.17, 2.08, 2.03, 2.00 (4s, 12
CO), 1.94 (br. s, 3 H, CHAda), 1.78Ϫ1.50 (m, 12 H,
Ada) ppm. 13C NMR (125 MHz, CDCl
): δ ϭ 170.6 (COCH ),
8.3 (C-1), 86.9, 79.2, 70.0, 69.7, 68.7, 66.7, 62.9 (C-2, C-3, C-4, C-
, C-6, CH Ada), 28.4 (CHAda, CH CO) ppm. MALDI-TOF:
10 ϩ Na]; found 520.6.
2
OAda),
M. V. Rekharsky, Y. Inoue, J. Am. Chem. Soc. 2000, 122,
4418Ϫ4435.
2
[
[
16]
17]
H, 4 ϫ CH
CH
9
5
3
N. F. Burkhalter, S. M. Dimick, E. J. Toone, in Carbohydrates
in Chemistry and Biology (Eds. B. Ernst, G. W. Hart, P. Sina y¨ ),
Wiley-VCH, Weinheim 2000, part I, vol. 2, p. 863Ϫ914.
Both Sigma Plot and Hunter’s curve fitting were used. We
thank Prof. C. A. Hunter (Sheffield University) for kindly pro-
viding the fitting program.
2
3
3
2
3
calcd. 519.54 [C25
36
H O
[
[
18]
19]
B. Zhang, R. Breslow, J. Am. Chem. Soc. 1993, 115,
1
-Adamantylmethyl β-D-Mannopyranoside (4b): A solution of so-
9
353Ϫ9354.
dium methoxide in methanol (1 , 0.1 equiv., 8.75 µL) was added
at room temperature to a solution of 14b (1 equiv., 43 mg) in meth-
anol (5 mL). After neutralisation with Amberlite resin IRA-77, the
F. Charbonnier, C. H. Hunter, S. Penad e´ s, unpublished results.
Preliminary results indicate that the enthalpy and entropy of
binding change with the sugar stereochemistry.
solution was filtered and the solvents were evaporated to give 4b
[20]
[21]
R. U. Lemieux, Acc. Chem. Res. 1996, 29, 373Ϫ380.
C. Clarke, R. J. Woods, J. Gluska, A. Cooper, M. A. Nutley,
G.-J. Boons, J. Am. Chem. Soc. 2001, 123, 12238Ϫ12247.
Received March 2, 2004
/MeOH, 95:5) ϭ 0.32. [α]2
5
ϭ Ϫ3.71 (c ϭ 0.07,
(99%). R
f
(CH
2
Cl
2
D
1
MeOH). H NMR (500 MHz, MeOD): δ ϭ 4.43 (d, JH1,H2
0
ϭ
.9 Hz, 1 H, H-1β), 3.91Ϫ3.85 (m, 2 H, H-2, H-6a), 3.76Ϫ3.70 (dd,
3656
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3650Ϫ3656