Experimental and computational study of the complexation of adamantyl glycosides with β-cyclodextrin

Article abstract of DOI:10.1016/j.tet.2013.06.097

Complexation of α- and β-anomers of adamantyl galactosides and adamantyl mannosides, having different configuration of the chiral linker connecting the sugar and the adamantamine (AMA) subunits, with β-cyclodextrin (β-CD) was investigated by means of NMR spectroscopy, microcalorimetric titrations and computational studies. The synthesis of adamantyl galactosides is also reported. The experimental investigations are consistent with the formation of 1:1 complexes in which the hydrophilic part of the guest protruded out of the secondary rim. The β-cyclodextrin was shown to be a rather efficient binder for the examined guests in water, primarily as a consequence of the enthalpically favourable inclusion of the adamantyl moiety within the hydrophobic cavity of the host. The structures of AMA derivatives complexes were modelled by combination of molecular and quantum mechanics - B3LYP/6-31G(d) in implicitly modelled water (PCM). The differences in the stability of primary and secondary complexes were observed. The main reasons for that could be more pronounced dehydration of the hydrophilic part of the guest upon complete adamantane inclusion in the complexes of primary type and the different hydrogen bonding pattern at the primary and secondary CD rims.

Full text of DOI:10.1016/j.tet.2013.06.097

Tetrahedron 69 (2013) 8051e8063
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Experimental and computational study of the complexation
of adamantyl glycosides with
b
-cyclodextrin
y
y
y
ꢀ
ꢀ
ꢁ
ꢀ
ꢁ
Zeljka Car , Ivan Kodrin , Josip Pozar , Rosana Ribic, Davor Kovacevic,
*
ꢁ
ꢁ
Vesna Petrovic Perokovic
Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
Complexation of
ferent configuration of the chiral linker connecting the sugar and the adamantamine (AMA) subunits,
with -cyclodextrin ( -CD) was investigated by means of NMR spectroscopy, microcalorimetric titrations
and computational studies. The synthesis of adamantyl galactosides is also reported.
The experimental investigations are consistent with the formation of 1:1 complexes in which the hy-
a- and b-anomers of adamantyl galactosides and adamantyl mannosides, having dif-
Received 30 November 2012
Received in revised form 12 June 2013
Accepted 27 June 2013
b
b
Available online 4 July 2013
drophilic part of the guest protruded out of the secondary rim. The b-cyclodextrin was shown to be
Keywords:
a rather efficient binder for the examined guests in water, primarily as a consequence of the enthalpically
favourable inclusion of the adamantyl moiety within the hydrophobic cavity of the host.
The structures of AMA derivatives complexes were modelled by combination of molecular and
quantum mechanics - B3LYP/6-31G(d) in implicitly modelled water (PCM). The differences in the stability of
primary and secondary complexes were observed. The main reasons for that could be more pronounced
dehydration of the hydrophilic part of the guest upon complete adamantane inclusion in the complexes of
primary type and the different hydrogen bonding pattern at the primary and secondary CD rims.
Ó 2013 Elsevier Ltd. All rights reserved.
Adamantyl glycoconjugates
b
-Cyclodextrin
Inclusion complexes
Microcalorimetry
Molecular modelling
NMR studies
1. Introduction
Among the variety of hydrophobic groups, which can be em-
bedded into the most frequently investigated b-CD (Fig. 1), the in-
Cyclodextrins (CDs) are cyclic oligosaccharides comprised of (
a
-
clusion of adamantyl residue, with its nearly spherical shape and the
1,4)-linked
and characteristic lipophilic central cavity. Naturally occurring CDs
are of and types, containing six, seven and eight glucopyr-
a-
D-glucopyranose units with a truncated cone shape
radius almost perfectly fitting in the host cavity,5 is quite favourable.
Indeed, the efficient binding of several adamantane derivatives by b-
a,
b
g
CD has been documented in the literature.5e15 Most of the work done
was primarily focused on the complexation thermodynamics,5,11e14
while the structure of the complexes formed (i.e., the position of
the hydrophilic part of guest with respect to the primary and to the
secondary rim of macrocycle) was less frequently explored.6,7,10
The understanding of all the factors leading to thermodynami-
cally advantageous binding of adamantane-based compounds with
anose units, respectively.1 During the past few decades, these
macrocyclic receptors have been extensively studied because of
their ability to host wide variety of hydrophobic compounds and
hydrophobic moieties of amphiphilic molecules in water.2,3 The
embedding of lipophilic groups within cyclodextrins is primarily
attributed to hydrophobic hydration of both host and guest cavities
and, to a lesser extent, the van der Waals interactions realized upon
inclusion.3,4 In addition, the hydrophilic part of an amphiphilic
guest can often be involved in hydrogen bonding with the hydroxyl
groups of host, located at both secondary (wide) and primary
(narrow) rim of macrocyclic ring.3,4 This can in turn influence the
penetration depth of hydrophobic groups within the macrocycle
and the structure of complex (the protrusion of hydrophilic moiety
out of the secondary or the primary rim).3,4
b-CD is held to be of great importance. These complexes are often
considered as model compounds, the stability of which can, at least
partially, explain the affinity of adamantane towards cell mem-
branes and hydrophobic compounds in general. This is becoming
ever more significant because adamantane-based molecules have
a potential use as therapeutics for viral infections, neurodegener-
ative disorders, type 2 diabetes, cancer and other diseases, pre-
sumably due to their lipophilic properties.16 Moreover, the covalent
attachment of the adamantyl group to several drug molecules
seems to notably enhance their bioavailability.16
Additionally to the experimental investigations, considerable
efforts directed towards the computational modelling of cyclo-
dextrins and their inclusion complexes have been made. Typically,
* Corresponding author. Tel.: þ385 1 4646409; fax: þ385 1 4606401; e-mail
ꢁ
address: vpetrovi@chem.pmf.hr (V.P. Perokovic).
y
These authors contributed equally to the work.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.097

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
Fig. 1. (a) General structure of the guest molecules. (b) Structural formula of the host, b-CD. (c) Truncated cone shape model of b-CD.
structure, energy and thermodynamic functions of host, guest and
corresponding complexes are reported, most often in vacuo.17e19
Such large molecules are quite often treated with molecular me-
chanics and semi-empirical methods.20 However, the computa-
tionally more expensive density functional theory (DFT) is
becoming more frequently used, especially when the interactions
between guest and cyclodextrins are of interest.21 Recently, com-
putational investigations of the complexes of several pharmaceu-
corresponding reaction thermodynamics. For that purpose, NMR
(1H and ROESY) and microcalorimetric investigations were per-
formed. Finally, the theoretical results were compared with the
experimental findings.
2. Results and discussion
tical compounds with
b
-CD have been performed in the solvent
2.1. Synthesis of AMA galactoconjugates
modelled as polarizable continuum.22
Our interest is especially focused on the glycoconjugates con-
taining monosaccharides such as mannose, galactose, N-acetylga-
lactosamine and N-acetylglucosamine, which can serve as
recognition determinants in specific recognition of glycoconjugates
by lectins.23 In the framework of our research, we have previously
reported the synthesis of several adamantane-derived O-manno-
sides.24,25 These biologically active compounds should be especially
AMA galactoconjugates (Scheme 1) were prepared according to
the procedure previously described for analogous O-mannosyl
derivatives.24 Benzylated
a,b-D-galactopyranosyltrichloroacetimi-
date was used as glycosyl donor.26 O-Galactosylation of methyl (R)-
or (S)-3-hydroxy-2-methylpropionate was promoted by the cata-
lytic amount of boron trifluoride diethyl etherate (BF3$Et2O) in
dichloromethane at 0 ꢀC. Under specified reaction conditions
trichloroacetimidate-mediated O-glycosylations gave anomeric
suited for complexation with b-CD in water due to the fact that in
addition to the expected adamantane inclusion within the hydro-
phobic cavity, the hydrophilic part of guest can be involved in the
favourable hydrogen bonding with the macrocycle.8,9 We have
therefore synthesized adamantyl galactosides and decided to study
mixtures of the corresponding O-galactosides 1
(65%). In both mixtures the ratio was 2:1. Pure anomers 1
and 2
The hydrolysis of methyl esters of each anomer 1 and 2 was
a
,
b
(61%) and 2
a
,
b,
b
a
/b
a
, 1
2a
b were obtained by column chromatography on silica gel.
the binding of adamantyl glycoconjugates, namely
anomers of adamantyl galactosides and adamantyl mannosides
with different configuration of chiral linker connecting the sugar
and the adamantamine (AMA) subunits (Fig.1), with b-cyclodextrin
by an integrated experimental and computational approach.
The computational study was performed to address the possible
conformers of 1:1 inclusion complexes and to explore the com-
plexation energetics. The main goal of the experimental research
was to explore the structure of the complexes and to investigate the
a
- and
b
-
performed by saponification leading to 79e84% yield of acids 3 and
4. The next step was the activation of the free carboxyl group and
condensation with AMA using EDC$HCl/HOBt coupling reagents for
amide bond formation. Glycoconjugates 5 and 6 were obtained in
good yield (55e66%). Debenzylation of compounds 5 and 6 was
performed by catalytic hydrogenolysis and gave the desired AMA
conjugates 7 and 8 (91e95%).
The complexation of galactosyl conjugates (7
a, 7b
, 8a
and 8
b)
and the analogous mannose derivatives (9 , 9
a
b
, 10a
and 10b,

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
8053
Scheme 1. Synthesis of galactoseeAMA derivatives: (a) NaOH (1 M), dioxane, 79e84% yield; (b) (i) EDC$HCl, Et3N, dry CH2Cl2; (ii) HOBt$H2O; (iii) AMA$HCl, Et3N, 55e66% yield; (c)
H2 (4 bar), Pd/C (10%), CH3OH, 91e95% yield.
Fig. 2)24 with
b-CD was investigated by means of NMR, microca-
lorimetric titrations and DFT based computational studies.
Fig. 2. Structures of mannoseeAMA derivatives.
2.2. NMR investigations
The structure of the supramolecular complexes formed from the
prepared guest molecules and
means of NMR. As an example of the results obtained, the 1H NMR
spectra of the 8 glycoconjugate upon cyclodextrin addition are
given in Fig. 3. By inspecting the presented data it can be seen that
upon going from the pure guest to the 2:1 molar ratio of added
CD with respect to glycoconjugate, the signals of all protons on the
adamantane subunit (H , H and H ) of 8 experience a downfield
shift. The addition of the host is accompanied by changes in the
shape of the methylene H signal on the AMA subunit from a broad
singlet to what appears to be two separate doublets. On the other
hand, no significant changes in the position and the signal shape of
the other guest protons upon host addition could be observed. Only
the relatively small, downfield chemical shift displacement of the
linker protons of the glycoconjugates was noticed. The complexa-
tion of guest molecule with the host was also evident from the
changes in the resonance spectra of cyclodextrin. An appreciable
upfield shift of resonant signals of the protons situated within the
b-CD in water was investigated by
b
b
-
a
b
g
b
Fig. 3. 1H NMR spectra of adamantane region of 8
w¼25.0 ꢀC.
b upon b-CD addition in D2O at
g
thermodynamically advantageous inclusion of the hydrophobic
subunit into the host cavity. The formation of stable 1:1 complexes
(4.5ꢁlog Kꢁ4.6) with all investigated guests was confirmed by
means of titration calorimetry (Section 2.3), which was used for
detailed thermodynamic investigations of the complexation re-
actions. The reason for the choice of this technique lies in the fact
that this experimental technique, unlike NMR, it allows for the si-
multaneous determination of all standard thermodynamic func-
tions of complexation (DcGꢀ, DcHꢀ, DcSꢀ) from only one titration
experiment.
cavity (H-3 and H-5) in the presence of the 8b occurred. The de-
scribed results indicate that the complexation is primarily realized
by the inclusion of the hydrophobic part of guest molecules within
the cavity of the macrocycle. This is in accord with the results re-
ported for complexes of adamantyl derivatives with
the structure of which was investigated by means of NMR.6,7
The stability constant of the 1:1 complex formed (8 $CD), was
b
-CD in water,
To deduce the structure of the complexes formed with all other
examined guest molecules the 1H NMR spectra of the reaction
mixture at 2:1 host to guest ratio and similar concentrations of both
reactants as in the previously described experiment were recorded.
b
calculated by processing the collected NMR titration data using
HypNMR2006 software. The obtained value (log K¼4.1) indicates
The obtained results with the galactosyl conjugates (7a, 7b, 8a and

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
8
b
) and the analogous mannosyl derivatives (9
a
, 9
b
, 10
a
and 10
b
) at
macrocycle (i.e., whether the primary or the secondary complex
was formed). The formation of the secondary complex resulted in
visible cross peaks between all adamantane protons and H-3 and
H-5 protons of macrocycle, indicating the deep inclusion of this
group within the cavity of the host. By contrast, the inclusion of the
adamantane with the hydrophilic moiety situated at the primary
rim (complex of the primary type) was more partial. Only the cross
the above molar ratio of reactants can be summarized as follows.
The addition of the host to the examined guests led to qualitatively
and quantitatively almost identical changes in the spectra of both
reactants as in the case of 8b, irrespectively of the sugar type and
the absolute configuration of the chiral linker atom. This is clearly
illustrated by the changes in the chemical shifts of the adamantane
protons observed upon macrocycle addition (Dd), which are en-
listed in Table 1. Consequently, we suggest that the structure of all
the reaction products is quite similar to the structure of the 8b$CD
complex.
peaks between Hb and Hg and the H-3 and H-5 protons of CD were
visible. Additionally, the cross peaks between the methyl protons
of the guest and H-3 and H-5 protons of macrocycle were of weak
intensity in the case of both the primary and the secondary com-
plexes, suggesting only partial dehydration of hydrophilic part of
the guest.7 Expectedly, the secondary complex was more stable
than the primary one.
Table 1
The difference in the chemical shifts (Dd) of the guest AMA protons between the
complex (at 2:1 host to guest molar ratio) and the pure guest at w¼25.0 ꢀC in
Since the results of 1H NMR investigations indicated that all the
D2O (c(guest)¼3ꢂ10ꢃ3 mol dmꢃ3
)
herein reported adducts of
similar structures, the ROESY experiments were performed only in
the case of 10 and 10 derivatives. As an example of obtained
b-CD and AMA glycoconjugates have
Guest
Dd (AMA)
(CH2)
a
b
H
g
H
a
(CH2)
Hb (CH)
results, the spectrum recorded upon the addition of host to 10b (1:1
molar ratio) is shown in Fig. 4.
7
7
8
8
9
9
a
b
a
b
a
b
0.10
0.09
0.08
0.09
0.09
0.08
0.09
0.09
0.13
0.14
0.15
0.14
0.14
0.15
0.14
0.14
0.20
0.20
0.19
0.19
0.19
0.19
0.19
0.19
The clearly visible cross peaks between H-3 and H-5 protons of
the host and all the protons of AMA subunit (H , H and H , Fig. 1)
confirm the deep inclusion of adamantane into the hydrophobic
cavity of the -CD. On the other hand, the absence of strong cross
a
b
g
b
10
10
a
b
peaks between the signals of the linker protons of both derivatives
and those of the cyclodextrin indicates larger distances between
the atoms in the hydrophilic part of guest and the atoms of the
macrocycle. Consequently, the hydrophilic part of the guest mole-
cule and the hydroxyl groups of b-CD most likely remain partially
hydrated upon complexation. Their participation in the complex-
ation process can therefore be characterized as weak.
By taking into account the results of the herein reported NMR
investigations, as well as the results of Tato et al.,7 one could con-
clude that the complexes between the examined guests and cy-
clodextrin are of secondary type. Namely, the inclusion of
adamantane subunit of the examined glycoconjugates into the
cavity of the macrocycle was found to be almost complete, as in the
In principle, much lower changes in the resonant frequencies of
the linker and the sugar protons of the guest do not a priori ex-
clude the hydrogen bonding of suitable donor and acceptor atoms
in the hydrophilic part of AMA glycoconjugates and the hydroxyls
of the macrocycle. To shed more light on the structure of the
complexes formed, particularly to deduce the position of the sugar
moiety and the linker atoms with respect to the macrocycle, the
Rotating-frame Overhauser Effect Spectroscopy (ROESY) was
employed. In the recent study,7 the ROESY technique was suc-
cessfully applied for resolving the structure of the complexes of
covalently modified cyclodextrins and rimantidine. A notable dif-
ference in spectra of solution prepared by mixing the reactants was
noticed, depending on whether the hydrophilic part of guest pro-
truded out of the primary or out of the secondary rim of
case of the secondary rimantidine adducts with b-CD. Likewise, no
significant involvement of the hydrophilic part of the examined
glycoconjugates and the macrocycle in the hosting process could be
observed.
Fig. 4. Partial contour plot of the ROESY spectrum of the reaction mixture containing 10
b
and
b
-CD (molar ratio 1:1) at w¼25.0 ꢀC in D2O.

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
8055
2.3. Microcalorimetry
participation of the linker atoms and the sugar subunits in the
hosting process is evident from the standard reaction parameters,
which are very close to the corresponding values for the secondary
rimantidine complex, also characterized by the weak involvement
of the guest amino group in the complexation process.7
The microcalorimetric titrations of examined guests with the
host were performed in order to investigate the thermodynamics of
the corresponding reactions. As an example of obtained results,
a thermogram recorded by titrating 10
is shown in Fig. 5a. The stepwise addition of
b
with cyclodextrin at 25 ꢀC
-CD resulted in
In general, the thermodynamically advantageous inclusion of
adamantane within the hydrophobic cavity of b-CD is, by large, held to
b
exothermic enthalpy changes, which was also the case for all other
adamantyl glycoconjugates reported in this paper. The formation of
1:1 complexes was observed for all investigated glycoconjugates.
The standard reaction enthalpy and the equilibrium constant
(hence the standard reaction Gibbs energy) for the complexation of
guest molecule with the macrocycle were calculated by a least-
squares non-linear regression analysis of calorimetric titration
data (Fig. 5b). Standard complexation entropy was calculated from
the complexation enthalpy and Gibbs energy.
be the result of displacement of the ‘high energy’ water molecules
(with respect to water molecules in liquid) situated within the hy-
drophobic cavity of host and the favourable adamantane de-
hydration.3,4,27 Because of the saturated hydrocarbon structure of the
host cavity and adamantane, only the relatively weak dispersive in-
teractions between host and guest can be expected, which are most
likely not favourable enough to account for the reported reaction en-
thalpies. Though it should be noted that becauseof the large size of the
guest and the cavity, their portion in DrHꢀ is certainly not negligible.5
45
40
0.0
-0.2
35
(a)
(b)
-0.4
30
25
20
15
10
-0.6
-0.8
-1.0
-1.2
0.0
0.5
1.0
1.5
2.0
/ n
0
40
80
120
160
200
n
β
CD 10
t / min
Fig. 5. (a) Thermogram of the microcalorimetric titration of 10
of successive enthalpy changes on host to guest molar ratio. - experimental; e calculated.
b
(c0¼6ꢂ10ꢃ4 mol dmꢃ3, V0¼1.42 mL) with CD (c¼5ꢂ10ꢃ3 mol dmꢃ3) in water; w¼(25.0ꢄ0.1) ꢀC. (b) The dependence
The obtained thermodynamic parameters are given in Table 2.
The presented data indicate that the complexation process is
favourable both in terms of standard reaction enthalpy and entropy,
leading to relatively high affinity of the macrocycle towards in-
vestigated guests. However, the enthalpic contribution to the DcGꢀ
is notably larger than the entropic one. Evidently, no considerable
influence of the sugar part of glycoconjugates and the configuration
of chiral linker atom on the thermodynamic parameters of com-
plexation could be observed. The values of the standard reaction
parameters are quite similar, irrespective of the type of the hy-
drophilic group covalently attached to adamantyl unit.
Recent MD investigations of cyclodextrin structure and hydra-
tion energetics support the thesis regarding high energy water
molecules within the cavity.28 The extent of hydrogen bonding
within the macrocycle was noticed to be considerably lower than in
the bulk. The endothermic transfer enthalpies (DtrHꢀ) of ada-
mantane from the unstructured to the hydrogen bonding solvents
(
DtrHꢀ of adamantane from cyclohexane to ethanol and methanol
are 4.08 kJ molꢃ1 and 6.80 kJ molꢃ1, respectively)29 indicate that its
dehydration could be exothermic since the enthalpies of ada-
mantane transfer among unstructured solvents (n-hexane, cyclo-
hexane, carbon tetrachloride) are all very close to zero.30 This
might, combined with the displacement of ‘high energy’ water
molecules explain the favourable complexation enthalpies.
Table 2
Thermodynamic parameters of complexation of adamantyl glycoconjugates with b-
CD in water; w¼(25.0ꢄ0.1) ꢀC
On the other hand, the classical view on the hydrophobic sol-
vation suggests the enthalpically favourable formation of the
clathrate-like water cages around lipophilic solute molecules.31,32 If
that is the case the dehydration of the organic compounds like
adamantane should be entropically favoured and enthalpically
disfavoured.27,31,32 Consequently, the enthalpically advantageous
inclusion of adamantane in that case can be ascribed to the dis-
placement of the high energy water molecules from the cavity and
the realized dispersive interactions. Likewise, the low standard
reaction enthalpy could be due to the favourable adamantane de-
hydration, and the entropically unfavourable release of the water
molecules situated within the cavity of the macrocycle.
Guest
log KꢄSE
(
DrHꢀ/kJ molꢃ1)ꢄSE
(
DrSꢀ/J Kꢃ1 molꢃ1)ꢄSE
7
7
8
8
9
9
a
b
a
b
a
b
4.549ꢄ0.004
4.617ꢄ0.004
4.497ꢄ0.004
4.552ꢄ0.002
4.511ꢄ0.003
4.603ꢄ0.003
4.474ꢄ0.008
4.577ꢄ0.005
ꢃ23.42ꢄ0.09
ꢃ19.73ꢄ0,05
ꢃ21.88ꢄ0.06
ꢃ22.88ꢄ0.02
ꢃ18.83ꢄ0.06
ꢃ22.34ꢄ0.07
ꢃ18.24ꢄ0.07
ꢃ21.9ꢄ0.1
8.5ꢄ0.4
22.5ꢄ0.4
12.7ꢄ0.1
10.38ꢄ0.08
23.2ꢄ0.1
13.2ꢄ0.2
24.5ꢄ0.3
14.1ꢄ0.5
10
10
a
b
SE¼standard error of the mean (N¼3e4).
As noted in the previous chapter, the NMR experiments revealed
that the adamantane inclusion results with the formation of the
secondary complex in which the hydrophilic part of the guest, most
likely, forms hydrogen bonds with water molecules. The weaker
To conclude, the results of the carried out experimental in-
vestigations indicate that the release of water molecules situated
within the cavity of
b-CD and the thermodynamically favourable
dehydration of adamantane subunit as well as the dispersive

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
interactions realized can be considered as the most important
factors, which determine the stability of investigated inclusion
complexes.
The glycosidic oxygen atoms of CD were placed in the xy-plane and
the corresponding centroid was defined as the origin of the co-
ordinate system. The guest was allowed to approach the host along
the z-axis coinciding with NeC (adamantamine) bond in the in-
ꢂ
crements of 1 A, defined by the distances between the centroid and
2.4. Computational studies
one of the atoms connected by a bond (arbitrarily chosen N). Two
directions of insertion for each orientation of glycoconjugate rela-
tive to CD were possible. The examined glycoconjugate hence faced
the primary and the secondary rim of macrocycle with adamantane
and with mannose subunit, respectively. The 1:1 inclusion com-
plexes and host molecules were further optimized according to
method described in the chapter Computational details.
The geometry of CD was optimized starting from the X-ray de-
termined structure, with water molecules excluded according to
the procedure described in the literature.17,22,34 The obtained
structure (H2) is shown in Fig. 7. The other, energetically more
favourable conformer, (H1) is the result of conformational analysis.
The notably smaller energy of the conformer H1 with respect to H2
can be attributed to formation of favourable hydrogen bonds be-
tween the facing C6 hydroxyl groups at the primary rim. As a con-
sequence of realized hydrogen bonds the structure of cyclodextrin
and corresponding cross section of its cavity changed from rounded
(H2) to more elliptical shape (H1).
The main goal of the performed computational studies was to
obtain an insight in the possible structures of the complexes be-
tween the examined guest molecules and b-CD. Namely, the ma-
jority of the literature data suggest the formation of complexes
with deeply embedded adamantyl moiety, usually protruding out
of the wider secondary rim of CD. This experimental finding is
usually explained by the truncated cone shape of the macrocycle,
which prevents the deep inclusion of adamantane in primary
complexes. However, quite recently, primary complexes of anilines
with a deeply embedded adamantane subunit were reported.33 The
mentioned result suggests that the structure of the complexes
between adamantane-based compounds and cyclodextrin could be
strongly influenced by the substituents on the AMA subunit.
Moreover, it indicates that the larger stability of the majority of
secondary with respect to corresponding primary complexes can-
not be solely explained by the truncated cone shape of the mac-
rocycle. The crystal structure of the host and recent all atom
The structures of the selected 10b$CD complexes (M1eM5),
molecular dynamics (MD) simulations of
b-CD in explicit water
formed out of one guest (10 ) and one host molecule (CD), and the
b
supported this conclusion, since no considerable difference in the
diameters of primary and secondary rim was observed in either
case.34,35
In the present paper the 1:1 inclusion complexes 10b$CD were
formed by translation of the guest molecule through the CD cavity,
entering via the secondary and primary rim, respectively (Fig. 6).
corresponding relative energies can be seen in Figs. 8 and 9. The
energetically most favourable complex M1 is of slightly bent
structure with adamantyl subunit situated within the cavity and
the chiral linker passing through the primary rim of CD (i.e., pri-
mary complex). The complexes M2eM5 with guest molecule
Fig. 6. The relative position of the guest (10b) and the host (CD) molecule in 10b$CD complexes.

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
8057
Fig. 7. B3LYP/6-31G(d) in water (PCM) optimized geometries of host (H) molecules. Relative energies of the selected CD are written in italic.
Fig. 8. Side view of B3LYP/6-31G(d) in water (PCM) optimized geometries of 10b$CD inclusion complexes (M1, M3 and M5). Relative energies of the complexes are written in italic.
protruding out of the secondary rim of CD are energetically less
favourable.
According to the obtained results, the formation of hydrogen
bonds between the guest molecules and CD significantly contrib-
utes to the overall stabilization of the inclusion complexes. This is
most evident from the structures of the secondary complexes, M3
and M5. As can be seen in Fig. 8, the pre-defined entrance orien-
tation of the mannose conjugate is largely preserved in M5,
resulting in weak participation of the sugar subunit in the com-
plexation process. On the other hand, due to a slightly bent

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
Fig. 9. Side and top view of B3LYP/6-31G(d) in water (PCM) optimized geometries of 10
b$CD inclusion complexes (M2 and M4). Relative energies of the complexes are written
in italic.
structure of the guest, the multiple hydrogen bonds of the hydro-
philic part of the guest molecule and CD are realized in the con-
former M3.
primary and the secondary rim is rather small. It is worth em-
phasizing that the energy of the conformer M4 is quite similar to
M3, even though the geometry of the complexes is quite different.
The guest molecule in M4 is not bent as in the case of M3, but rather
tilted from the predefined entrance line. This, in turn, resulted in
partial inclusion of the adamantyl subunit and only peripheral in-
teractions of hydrophilic part of guest molecule with secondary
eOH groups of CD.
Further reorganization of the CD structure from rounded (M4) to
elliptical shape (M2) exposes the adamantyl subunit even more to
the outer region. The lower energy of M2 in comparison to M4 is
mostly the outcome of hydrogen bonds formation between the
facing C6eOH groups at the primary rim of CD. The relative energy
difference of H2 and H1 (54 kJ molꢃ1) is almost identical to the
corresponding difference of M4 and M2 complexes.
The appropriate modelling of solvent effects in the system
studied is obviously very important. While favourable hydrogen
bonds of the guest could be explicitly modelled with eOH groups of
CD, the similar approach in modelling of water molecules is not
possible due to their number. Therefore, a polarizable continuum
model of the solvent (PCM) is usually used as the acceptable
compromise between expensive computational time and adequate
treatment of solvent effects. Another drawback of the implicit
solvent model, in spite of its robustness, is inadequate treatment of
the water molecules inside the cavity of CD.
Despite the fact that the computational findings are not in ac-
cord with experimental results, they do provide deeper insight into
the complexation process. They indicate that the favourable sol-
vation of hydrophilic part of the guest molecule might be signifi-
cantly more pronounced in secondary complexes where the sugar
part is positioned farther from the cavity of CD, due to the existence
In order to explain the differences in the stability of the primary
and secondary complexes, the hydrogen bond patterns in M1 and
M3 (Fig. 10) were studied in detail by using Bader’s atoms-in-
molecules (AIM) theory,36 which was reported as useful in the
analysis of these interactions.37,38 These two complexes were
chosen for comparison due to the relatively similar conformation of
the guest molecule. In the complex M1 hydrogen bonding occurs at
both rims of CD. At the primary rim of the macrocycle hydrogen
bond donors and acceptors of guest molecule (eNH and C]O from
chiral spacer and mannose eOH groups) form a ring with primary
eOH groups of CD (eight hydrogen bonds in total). At the secondary
rim seven OeH/O interactions between C2 and C3 hydroxyl
groups of adjacent glucose units form a ring of hydrogen bonds. By
contrast, the hydrogen bonds between the host and guest mole-
cules in the M3 complex are predominantly formed at the sec-
ondary rim. The hydrogen bonding pattern is comprised of seven
OeH/O interactions between C2 and C3 hydroxyl groups. In this
case, only mannose eOH groups, and not eHN and C]O groups of
chiral linker, act as additional hydrogen bond donors and acceptors
in interaction with secondary rim eOH groups. It should be noted
that all hydrogen bonds occurring in the complexes M1 and M3
were verified using the AIM method according to Koch and Pope-
lier formalism.37,38
Interestingly, the cross section of CD cavity is rather similar in
M1 and M3 complexes. It resembles the rounded shape of H2
conformer of the host. The computational investigations are hence
in accord with the earlier investigations of the host structure,34,35
which suggest that the difference between the diameters of the

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
8059
Fig. 10. Hydrogen bonds pattern at the primary and the secondary rim of B3LYP/6-31G(d) in water (PCM) optimized 10b$CD inclusion complexes M1 and M3.
of short secondary eOH, and not lengthy and more flexible primary
eCH2OH groups. Consequently, the deep embedding of the AMA
subunit with the hydrophilic part protruding out of the primary rim
might require extensive dehydration of the hydrophilic part of the
guest molecule than the formation of corresponding secondary
complex. The majority of the literature data suggest that the for-
mation of the secondary complexes is favoured due to the fact that
the adamantane subunit does not fit into the primary rim of cy-
clodextrin. Our results indicate that this factor is perhaps less im-
portant for the explanation of the larger stability of secondary
complexes with respect to the primary ones. As mentioned earlier,
the formation of the primary complexes of AMA containing
derivatives with cyclodextrin33 and the crystal structure34 of the
macrocycle as well as MD simulations in explicit water35 support
these findings.
3. Conclusion
Comprehensive structural, thermodynamic and computational
studies were undertaken in order to get a detailed insight into the
binding of adamantyl glycoconjugates with b-CD. The experimental
investigations included two series of glycosides, one with mannose
and one with galactose sugar subunit. The synthesis of the latter
series was reported here for the first time.

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
On the basis of the results of spectroscopic and microcalorimetric
investigations it was concluded that 1:1 secondary complexes of the
examined guests with -CD are being formed, primarily as a result of
adamantane inclusion into the hydrophobic cavity of the macro-
cycle. The NMR studies of adducts formed revealed the inclusion of
adamantane subunit within the macrocycle and relatively weak
involvement of the hydrophilic part of the guest molecules in the
hosting process. The notably favourable complexation of the ex-
under N2 and BF3$Et2O was added (277.5
mL, 2.19 mmol, 1 equiv).
Benzylated -galactopyranosyltrichloroacetimidate (1.5 g,
a,b-D
b
2.19 mmol) suspended in dry DCM (2 mL) was then added dropwise
within 15 min after which the reaction mixture was stirred for the
additional 2.5 h and monitored by TLC (diethyl ether/petroleum
ether 1:1). Iced 1 M NaHCO3 was added and the resulting mixture
was extracted with diethyl ether. Organic layers were washed with
water and dried over Na2SO4. After filtration, the organic layer was
concentrated in vacuo and the residue was purified by column
chromatography on silica gel (diethyl ether/petroleum ether 1:1).
The products were isolated as anomeric pale yellow oil mixtures
amined adamantyl glycosides (log K ꢅ4.5) with
b-CD is by large
enthalpically controlled. The contribution of the standard reaction
entropy to the binding energetics was favourable, but relatively
small in the case of all investigated guests. The thermodynamically
favourable hosting of examined ligands can be adequatelyexplained
by the hydrophobic hydration of the host cavityand the adamantane
group on one hand and by the extensive hydration of both the linker
functional groups and the sugar subunits covalently attached to the
adamantane subunit on the other.
(1a,b, 856 mg, 61%) and (2a,b, 912 mg, 65%). The anomeric mixtures
were then rechromatographed to isolate the pure anomers of each
ester derivative.
4.2.1. Methyl
(2R)-(2,3,4,6-tetra-O-benzyl-
a
-
D
-galactopyranosy
loxy)-2-methylpropionate (1
a
). Yellow oil; [
a
]
D
þ30.9 (c 0.56,
The computational studies support this conclusiondthe notable
preference for the formation of complexes and extensive hydrogen
bonding between the host and the hydrophilic part of the guest
molecule was noticed in the implicitly modelled water (PCM).
According to those findings the reason for the difference in the
stability of secondary and primary complexes could be dehydration
of the hydrophilic subunit realized upon the complete inclusion of
adamantane inside the cavity. The reason for this behaviour might
be the fact that the presence of methylene groups at the primary rim
pre-supposes more pronounced dehydration of the hydrophilic
subunit of the guest than in the case of secondary complexes. Pro-
vided that the hydrophilic part of the guest experiences strong hy-
dration (and hence remains largely solvated upon the adamantane
inclusion) this could, at least partially, explain the experimentally
observed larger stability of the secondary with respect to primary
complexes of AMA based guests in water. The other reason might be
the computationally observed difference in the hydrogen bonding
pattern at the primary and the secondary rim of macrocycle. How-
ever, one should keep in mind that the applied theoretical model
may exaggerate the tendency for the formation of hydrogen bonds
between the primary hydroxyl groups.
CHCl3); Rf (diethyl ether/petroleum ether 1:1)¼0.39; 1H NMR
(300 MHz, CDCl3)
d: 7.39e7.26 (m, 20H, HeAr), 4.95 (d,
Jgem¼11.5 Hz, 1H, CH2Ph), 4.87 (d, J1,2¼3.5 Hz, 1H, H-1), 4.86e4.64
(m, 4H, 2 CH2Ph), 4.58 (d, Jgem¼11.5 Hz, 1H, CH2Ph), 4.51e4.39 (m,
2H, CH2Ph), 4.04 (dd, J1,2¼3.8 Hz, J2,3¼10.13 Hz, 1H, H-2), 3.98e3.89
(m, 3H, H-3, H-4, H-5), 3.68e3.64 (m, 2H, H-6a, H-6b), 3.62 (s, 3H,
OCH3), 3.53 (d, J¼6.4 Hz, 2H, OCH2), 2.89e2.78 (m, 1H, CH), 1.19 (d,
J¼7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 174.91 (C]O),
138.91,138.82,138.76,138.13 (CeAr),128.37e127.33 (CHeAr), 98.05
(C1), 78.87, 76.65, 75.23, 70.02 (C2eC5), 74.76, 73.47, 73.16, 72.86
(4CH2Ph), 69.63 (C6), 69.06 (OCH2), 51.59 (OCH3), 39.95 (CH), 14.13
(CH3). Anal. Calcd for C39H44O8: C, 73.10; H, 6.92. Found: C, 73.02; H,
6.88.
4.2.2. Methyl
(2R)-(2,3,4,6-tetra-O-benzyl-b-D-galactopyranosylo
xy)-2-methylpropionate (1
b
). Yellow oil; [
a
]
D ꢃ13.7 (c 0.42, CHCl3);
Rf (diethyl ether/petroleum ether 1:1)¼0.32; 1H NMR (300 MHz,
CDCl3)
d
: 7.37e7.25 (m, 20H, HeAr), 4.93 (d, Jgem¼11.7 Hz, 1H,
CH2Ph), 4.88e4.69 (m, 4H, 2CH2Ph), 4.62 (d, Jgem¼11.7 Hz, 1H,
CH2Ph), 4.45e4.40 (m, 2H, CH2Ph), 4.35 (d, J1,2¼7.7 Hz, 1H, H-1),
4.15e4.13 (m, 1H, H-3), 3.88 (d, J4,5¼2.6 Hz, 1H, H-4), 3.80 (dd,
J1,2¼7.7 Hz, J2,3¼9.7 Hz, 1H, H-2), 3.61 (s, 3H, OCH3), 3.60e3.50 (m,
5H, H-6a, H-6b, H-5, OCH2), 2.83e2.77 (m, 1H, CH), 1.24 (d, J¼7.1 Hz,
4. Experimental
3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 174.76 (C]O), 138.68, 138.57,
4.1. General methods for the synthesis of AMA
galactoconjugates
138.47, 137.89 (CeAr), 128.50e127.40 (CHeAr), 104.14 (C1), 82.13,
79.30, 73.44, 73.44 (C2eC5), 75.07, 74.51, 73.52, 73.07 (CH2Ph),
71.22 (C6), 68.74 (OCH2), 51.69 (OCH3), 40.04 (CH),14.15 (CH3). Anal.
Calcd for C39H44O8: C, 73.10; H, 6.92. Found: C, 72.88; H, 6.89.
Starting compound 2,3,4,6-tetra-O-benzyl-
D-galactopyranosyl
trichloroacetimidate was prepared according to the published
procedure.26 Linkers methyl (R)- and (S)-3-hydroxy-2-
methylpropionates were purchased from Aldrich Corp. The other
reagents used in syntheses were obtained from Aldrich Corp. and
Fluka. All solvents were purified using the standard procedures.
Column chromatography (solvents and proportions are given in
text) was performed on Merck silica gel 60 (size 70e230 mesh
ASTM) and TLC monitoring on Fluka silica gel (60F 254) plates
(0.25 mm). Visualization was mostly achieved by the use of UV light
and/or by charring with H2SO4. Optical rotations were measured at
room temperature using the SchmidtþHaenschPolartronic NH8. 1H
and 13C NMR spectra were recorded using Bruker Avance spec-
trometer with TMS as an internal standard. C, H and N analyses
were provided by the Analytical Services Laboratory of
4.2.3. Methyl
(2S)-(2,3,4,6-tetra-O-benzyl-a-D-galactopyranosylo
xy)-2-methylpropionate (2
a
). Yellow oil; [
a
]
D þ24.2 (c 0.41, CHCl3);
Rf (diethyl ether/petroleum ether 1:1)¼0.34; 1H NMR (300 MHz,
CDCl3)
d
: 7.36e7.25 (m, 20H, HeAr), 4.95 (d, Jgem¼11.44 Hz, 1H,
CH2Ph), 4.82 (d, J1,2¼3.8 Hz, 1H, H-1), 4.80e4.63 (m, 4H, 2 CH2Ph),
4.56 (d, Jgem¼11.4 Hz, 1H, CH2Ph), 4.51e4.40 (m, 2H, CH2Ph), 4.03
(dd, J1,2¼3.6 Hz, J2,3¼10.0 Hz, 1H, H-2), 4.00e3.85 (m, 4H, H-3, H-4,
H-5, H-6a), 3.61 (s, 3H, OCH3), 3.53 (d, J¼6.5 Hz, 2H, OCH2), 3.40 (dd,
J6a,5¼5.9 Hz, J6a,6b¼9.6 Hz, 1H, H-6b), 2.89e2.75 (m, 1H, CH), 1.18 (d,
J¼7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 175.02 (C]O),
138.83, 138.73, 138.70, 138.09 (CeAr), 128.40e127.32 (CHeAr),
97.84 (C1), 78.82, 76.54, 75.01, 69.36 (C2eC5), 74.74, 73.35, 73.06,
73.06 (CH2Ph), 69.81 (C6), 68.83 (OCH2), 51.62 (OCH3), 39.79 (CH),
14.22 (CH3). Anal. Calcd for C39H44O8: C, 73.10; H, 6.92. Found: C,
73.01; H, 6.90.
ꢀ
ꢁ
RuCerBoskovic Institute, Zagreb.
4.2. Glycosylation of methyl (R)- and (S)-3-hydroxy-2-
methylpropionates
4.2.4. Methyl
(2S)-(2,3,4,6-tetra-O-benzyl-b-D-galactopyranosylo
xy)-2-methylpropionate (2
b
). Yellow oil; [
a
]
D ꢃ20.1 (c 0.30, CHCl3);
Methyl (R)- or (S)-3-hydroxy-2-methylpropionate (151.1
mL,
Rf (diethyl ether/petroleum ether 1:1)¼0.31; 1H NMR (300 MHz,
1.37 mmol, 1.6 equiv) was suspended in dry DCM (2 mL) at 0 ꢀC
CDCl3)
d
: 7.38e7.25 (m, 20H, HeAr), 4.92 (d, Jgem¼11.6 Hz, 1H,

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
8061
CH2Ph), 4.88e4.66 (m, 4H, 2 CH2Ph), 4.61 (d, Jgem¼11.7 Hz, 1H,
CH2Ph), 4.47e4.38 (m, 2H, CH2Ph), 4.35 (d, J1,2¼7.7 Hz, 1H, H-1),
3.94e3.87 (m, 2H, H-3, H-4), 3.81e3.70 (m, 2H, H-2, H-5), 3.59 (s,
3H, OCH3), 3.61e3.47 (m, 4H, OCH2, H-6a, H-6b), 2.87e2.75 (m, 1H,
69.63 (C6), 68.87 (OCH2), 39.47 (CH), 13.72 (CH3). Anal. Calcd for
C38H42O8: C, 72.82; H, 6.75. Found: C, 72.59; H, 6.67.
4.3.4. (2S)-(2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyloxy)-2-
CH), 1.16 (d, J¼7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 175.27
methylpropionic acid (4
b
). Pale yellow oil (80.2 mg, 82%); [
a
]
D ꢃ4.5
(C]O), 138.71, 138.56, 138.49, 137.88 (CeAr), 128.44e127.40
(CHeAr), 104.03 (C1), 82.05, 79.25, 73.46, 73.39 (C2eC5), 74.90,
74.50, 73.51, 73.10 (4CH2Ph), 71.39 (C6), 68.77 (OCH2), 51.71 (OCH3),
40.25 (CH), 14.09 (CH3). Anal. Calcd for C39H44O8: C, 73.10; H, 6.92.
Found: C, 72.90; H, 6.86.
(c 0.76, CHCl3); Rf (CHCl3/CH3OH 9:1)¼0.59; 1H NMR (300 MHz,
CDCl3)
d
: 7.33e7.21 (m, 20H, HeAr), 4.89 (d, Jgem¼11.7 Hz, 1H,
CH2Ph), 4.86e4.62 (m, 4H, 2CH2Ph), 4.57 (d, Jgem¼11.7 Hz, 1H,
CH2Ph), 4.49e4.42 (m, 2H, CH2Ph), 4.37 (d, J1,2¼7.8 Hz, 1H, H-1),
3.95e3.90 (m, 1H, H-3), 3.80e3.70 (m, 3H, H-2, H-4, H-5),
3.60e3.46 (m, 4H, OCH2, H-6a, H-6b), 2.85e2.74 (m, 1H, CH),1.17 (d,
4.3. General procedure for methyl ester hydrolysis
J¼7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 178.51 (C]O),
138.55, 138.42, 138.39, 137.68 (CeAr), 128.46e127.41 (CHeAr),
104.04 (C1), 82.03, 79.23, 73.45, 73.30 (C2eC5), 75.11, 74.45, 73.52,
73.04 (CH2Ph), 71.37 (C6), 68.86 (OCH2), 40.08 (CH), 13.78 (CH3).
Anal. Calcd for C38H42O8: C, 72.82; H, 6.75. Found: C, 72.65; H, 6.62.
To a solution of pure anomer of each ester derivative 1
a, 1b, 2a
and 2 (100 mg, 0.16 mmol) in dioxane (1 mL) 10 equiv of 1 M NaOH
b
was added and the reaction mixture was stirred for 24 h at 40 ꢀC
and monitored by TLC (C6H6/EtOAc 2:1). Reaction mixtures were
then treated with 0.5 M HCl (pH 3.5) and saturated brine was
added. Mixtures were extracted with diethyl ether and organic
layers dried over Na2SO4. After filtration, the organic layer was
concentrated in vacuo and the residues purified by column chro-
matography on silica gel (CHCl3/MeOH 9:1) and corresponding
acids were isolated.
4.4. General procedure for the synthesis of AMA
glycoconjugates
To a solution of pure anomer of each carboxylic acid derivative
3
a
, 3
(25.4 mg, 0.21 mmol, 1.3 equiv) previously mixed with Et3N
(28.8 L) was added. The mixtures were then stirred for 0.5 h at the
b, 4a and 4b
(100 mg, 0.16 mmol) in dry DCM at 0 ꢀC, EDC$HCl
m
4.3.1. (2R)-(2,3,4,6-Tetra-O-benzyl-
a
-
D
-galactopyranosyloxy)-2-
same temperature. HOBt$H2O (21.6 mg, 0.16 mmol, 1 equiv) was
added next and the mixtures were left stirring for additional 2 h.
During that time the reaction mixture was allowed to gradually
reach the room temperature. AMA$HCl (150.1 mg, 0.8 mmol) pre-
methylpropionicacid(3
a
). Pale yellow oil (80.2 mg, 82%); [
a
]D þ15.6
(c 0.42, CHCl3); Rf (CHCl3/CH3OH 9:1)¼0.66; 1H NMR (300 MHz,
CDCl3)
d
: 7.35e7.25 (m, 20H, HeAr), 4.92 (d, Jgem¼11.5 Hz, 1H,
CH2Ph), 4.81 (d, J1,2¼3.9 Hz, 1H, H-1), 4.78e4.64 (m, 4H, 2CH2Ph),
4.55 (d, Jgem¼11.5 Hz, 1H, CH2Ph), 4.49e4.37 (m, 2H, CH2Ph), 4.03
(dd, J1,2¼3.7 Hz, J2,3¼9.9 Hz, 1H, H-2), 3.94e3.87 (m, 3H, H-3, H-4,
H-5), 3.69 (dd, J6a,5¼5.8 Hz, J6a,6b¼9.9 Hz, 1H, H-6a), 3.63e3.50 (m,
3H, H-6b, OCH2), 2.85e2.74 (m, 1H, CH), 1.17 (d, J¼7.1 Hz, 3H, CH3);
viously mixed with Et3N (110.9 mL) was then added and the reaction
mixtures were left stirring overnight. After treatment with 0.5 M
HCl (pH 3.5) the mixtures were extracted with DCM, the combined
organic layers were washed with saturated NaHCO3 and dried over
Na2SO4. After the filtration, the organic layers were concentrated in
vacuo and the residues purified by column chromatography on
silica gel (C6H6/EtOAc 2:1) followed by the isolation of AMA
glycoconjugates.
13C NMR (75 MHz, CDCl3)
d: 177.89 (C]O), 138.65, 138.51, 138.37,
137.82 (CeAr), 128.45e127.38 (CHeAr), 98.46 (C1), 78.86, 76.11,
74.84, 69.76 (C2eC5), 74.71, 73.50, 73.28, 73.10 (CH2Ph), 70.02 (C6),
69.07 (OCH2), 39.45 (CH), 13.59 (CH3). Anal. Calcd for C38H42O8: C,
72.82; H, 6.75. Found: C, 72.60; H, 6.65.
4.4.1. (2R)-N-(Adamant-1-yl)-3-(2,3,4,6-tetra-O-benzyl-a-D-galacto
pyranosyloxy)-2-methylpropanamide (5a). Pale yellow oil (68.1 mg,
4.3.2. (2R)-(2,3,4,6-Tetra-O-benzyl-
b
-
D
-galactopyranosyloxy)-2-
56%); [
a
]
D þ10.6 (c 0.72, CHCl3); Rf (C6H6/EtOAc 2:1)¼0.64; 1H NMR
methylpropionic acid (3
b
). Pale yellow oil (77.2 mg, 79%); [
a
]
D ꢃ15.5
(300 MHz, CDCl3) d: 7.39e7.25 (m, 20H, HeAr), 5.96 (s, 1H, NeH),
(c 0.46, CHCl3); Rf (CHCl3/CH3OH 9:1)¼0.53; 1H NMR (300 MHz,
4.96 (d, Jgem¼11.1 Hz, 1H, CH2Ph), 4.84 (d, J1,2¼3.7 Hz, 1H, H-1),
4.81e4.66 (m, 4H, 2CH2Ph), 4.58 (d, Jgem¼11.5 Hz, 1H, CH2Ph),
4.51e4.37 (m, 2H, CH2Ph), 4.04 (dd, J1,2¼3.6 Hz, J2,3¼9.9 Hz, 1H, H-
2), 3.97 (app t, J¼6.4 Hz, J¼6.5 Hz, 1H, H-5), 3.93e3.87 (m, 2H, H-3,
H-4), 3.68e3.44 (m, 4H, H-6a, H-6b, OCH2), 2.54e2.43 (m, 1H, CH),
CDCl3)
d
: 7.36e7.22 (m, 20H, HeAr), 4.89 (d, Jgem¼11.5 Hz, 1H,
CH2Ph), 4.84e4.62 (m, 4H, 2CH2Ph), 4.57 (d, Jgem¼11.7 Hz, 1H,
CH2Ph), 4.49e4.39 (m, 2H, CH2Ph), 4.36 (d, J1,2¼7.7 Hz, 1H, H-1),
4.14e4.09 (m, 1H, H-3), 3.78 (dd, J1,2¼7.9 Hz, J2,3¼9.8 Hz, 1H, H-2),
3.74 (d, J4,5¼2.7 Hz, 1H, H-4), 3.68e3.45 (m, 5H, OCH2, H-6a, H-6b,
H-5), 2.84e2.72 (m, 1H, CH), 1.24 (d, J¼7.2 Hz, 3H, CH3); 13C NMR
1.96 (s, 3H, 3HbeAMA), 1.89 (s, 6H, 3HaeAMA), 1.59 (s, 6H,
3H
g
eAMA), 1.06 (d, J¼7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d:
(75 MHz, CDCl3)
d
: 178.64 (C]O), 138.60, 138.43, 138.43, 137.62
173.47 (C]O), 138.70, 138.56, 138.54, 137.76 (CeAr), 128.35e127.38
(CHeAr), 98.78 (C1), 79.02, 76.43, 75.19, 69.70 (C2eC5), 74.71,
73.60, 73.22, 73.18 (CH2Ph), 71.46 (C6), 69.44 (OCH2), 51.48 (CeN),
(CeAr), 128.43e127.38 (CHeAr), 104.06 (C1), 82.11, 79.34, 73.42,
73.15 (C2eC5), 75.19, 74.38, 73.50, 72.97 (CH2Ph), 71.03 (C6), 68.98
(OCH2), 39.83 (CH), 13.80 (CH3). Anal. Calcd for C38H42O8: C, 72.82;
H 6.75. Found: C, 72.64; H, 6.60.
41.73 (CH), 41.49 (CaeAMA), 36.34 (CgeAMA), 29.38 (CbeAMA),
14.33 (CH3). Anal. Calcd for C48H57NO7: C, 75.86; H, 7.56; N, 1.84.
Found: C, 75.69; H, 7.60; N, 1.89.
4.3.3. (2S)-(2,3,4,6-Tetra-O-benzyl-a-D-galactopyranosyloxy)-2-met
hylpropionic acid (4
a
). Pale yellow oil (82.1 mg, 84%); [
a
]
D þ34.5 (c
4.4.2. (2R)-N-(Adamant-1-yl)-3-(2,3,4,6-tetra-O-benzyl-b-D-galactopyr-
0.82, CHCl3); Rf (CHCl3/CH3OH 9:1)¼0.70; 1H NMR (300 MHz,
anosyloxy)-2-methylpropanamide (5b). Pale yellow oil (67.0 mg,
CDCl3)
d
: 7.38e7.24 (m, 20H, HeAr), 4.91 (d, Jgem¼11.4 Hz, 1H,
55%); [
a
]
D ꢃ7.3 (c 0.66, CHCl3); Rf (C6H6/EtOAc 2:1)¼0.53; 1H NMR
CH2Ph), 4.79 (d, J1,2¼3.4 Hz, 1H, H-1), 4.77e4.64 (m, 4H, 2 CH2Ph),
4.54 (d, Jgem¼11.4 Hz, 1H, CH2Ph), 4.50e4.37 (m, 2H, CH2Ph), 4.04
(dd, J1,2¼3.6 Hz, J2,3¼9.9 Hz, 1H, H-2), 3.97e3.80 (m, 4H, H-3, H-4,
H-5, H-6a), 3.51 (d, J¼6.1 Hz, 2H, OCH2), 3.46 (dd, J6b,5¼5.4 Hz,
J6a,6b¼10.1 Hz, 1H, H-6b), 2.81e2.70 (m, 1H, CH), 1.17 (d, J¼7.1 Hz,
(300 MHz, CDCl3) d: 7.36e7.25 (m, 20H, HeAr), 5.76 (br s, 1H, NeH),
4.94 (d, Jgem¼11.6 Hz, 1H, CH2Ph), 4.90e4.73 (m, 4H, 2 CH2Ph), 4.58
(d, Jgem¼11.6 Hz, 1H, CH2Ph), 4.48e4.39 (m, 2H, CH2Ph), 4.35 (d,
J1,2¼7.6 Hz,1H, H-1), 4.00e3.94 (m,1H, H-3), 3.90 (d, J4,5¼2.8 Hz,1H,
H-4), 3.78 (dd, J1,2¼7.7 Hz, J2,3¼9.7 Hz, 1H, H-2), 3.60e3.48 (m, 5H,
H-5, H-6a, H-6b, OCH2), 2.50e2.39 (m, 1H, CH), 1.96 (s, 3H,
3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 178.00 (C]O),138.60,138.52,
138.23, 137.87 (CeAr), 128.48e127.34 (CHeAr), 97.96 (C1), 78.85,
76.25, 74.83, 69.60 (C2eC5), 74.73, 73.52, 73.37, 72.96 (CH2Ph),
3Hb
eAMA), 1.92 (s, 6H, 3H
a
eAMA), 1.60 (s, 6H, 3H
g
eAMA), 1.12 (d,
J¼7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 173.08 (C]O),

ꢀ
8062
Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
138.70, 138.63, 138.37, 137.77 (CeAr), 128.44e127.46 (CHeAr),
103.44 (C1), 82.17, 79.42, 73.56, 73.39 (C2eC5), 75.18, 74.59, 73.58,
72.95 (CH2Ph), 71.64 (C6), 68.59 (OCH2), 51.59 (CeN), 41.45
(c 0.62, CH3OH); Rf (CH3CN/H2O 5:1)¼0.54; 1H NMR (300 MHz,
CD3OD)
d
: 7.23 (br s, 1H, NeH), 4.23 (d, J1,2¼7.06 Hz, 1H, H-1),
3.98e3.92 (m, 1H, H-3), 3.83 (d, J4,5¼2.8 Hz, 1H, H-4), 3.80e3.68 (m,
(CaeAMA), 41.42 (CH), 36.38 (CgeAMA), 29.39 (CbeAMA), 14.06
2H, H-2, H-5), 3.52e3.45 (m, 4H, H-6a, H-6b, OCH2), 2.67e2.55 (m,
(CH3). Anal. Calcd for C48H57NO7: C, 75.86; H, 7.56; N,1.84. Found: C,
75.72; H, 7.57; N, 1.92.
1H, CH), 2.03 (s, 9H, 3HbeAMA, 3HaeAMA), 1.71 (s, 6H,
3Hg
eAMA), 1.07 (d, J¼7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CD3OD)
d: 176.72 (C]O), 104.84 (C1), 76.72, 75.02, 72.40, 70.41 (C2eC5),
4.4.3. (2S)-N-(Adamant-1-yl)-3-(2,3,4,6-tetra-O-benzyl-
a-
D-galacto
72.57 (C6), 62.57 (OCH2), 52.90 (CeN), 42.54 (CH), 42.37 (C
aeAMA),
pyranosyloxy)-2-methylpropanamide (6
a
). Pale yellow oil (80.2 mg,
37.55 (C eAMA), 30.94 (C eAMA), 14.73 (CH3). Anal. Calcd for
C20H33NO7: C, 60.13; H, 8.33; N, 3.51. Found: C, 60.07; H, 8.22; N,
3.29.
g
b
66%); [
a
]
D þ31.8 (c 0.40, CHCl3); Rf (C6H6/EtOAc 2:1)¼0.53; 1H NMR
(300 MHz, CDCl3) d: 7.37e7.25 (m, 20H, HeAr), 6.09 (s, 1H, NeH),
4.94 (d, Jgem¼11.4 Hz, 1H, CH2Ph), 4.73 (d, J1,2¼3.4 Hz, 1H, H-1),
4.81e4.65 (m, 4H, 2CH2Ph), 4.58 (d, Jgem¼11.4 Hz, 1H, CH2Ph),
4.53e4.39 (m, 2H, CH2Ph), 4.05 (dd, J1,2¼3.5 Hz, J2,3¼10.1 Hz, 1H, H-
2), 4.00e3.89 (m, 3H, H-3, H-4, H-5), 3.74e3.37 (m, 4H, H-6a, H-6b,
4.5.3. (2S)-N-(Adamant-1-yl)-3-a-D-galactopyranosyloxy-2-methylp
ropanamide (8a). Pale yellow crude foam (49.0 mg, 93%); [a]
D
þ131.8 (c 0.44, CH3OH); Rf (CH3CN/H2O5:1)¼0.56; 1H NMR
OCH2), 2.45e2.38 (m, 1H, CH), 1.96 (s, 3H, 3H
b
eAMA), 1.89 (s, 6H,
(300 MHz, CD3OD)
d
: 7.32 (br s, 1H, NeH), 4.77 (d, J1,2¼3.3 Hz, 1H,
3Ha
eAMA), 1.59 (s, 6H, 3H
g
eAMA), 1.05 (d, J¼7.0 Hz, 3H, CH3); 13
C
H-1), 3.85e3.83 (m, 1H, H-2), 3.80e3.64 (m, 6H, H-3, H-4, H-5, H-
6a, OCH2), 3.25 (dd, J6a,5¼4.6 Hz, J6a,6b¼9.2 Hz, 1H, H-6b), 2.69e2.56
NMR (75 MHz, CDCl3)
d: 173.57 (C]O),138.61,138.61,138.29,138.03
(CeAr), 128.39e127.25 (CHeAr), 97.85 (C1), 79.28, 76.40, 74.88,
69.38 (C2eC5), 74.85, 73.88, 73.32, 72.92 (CH2Ph), 70.60 (C6), 68.54
(m, 1H, CH), 2.08 (br s, 9H, 3HbeAMA, 3HaeAMA), 1.70 (s, 6H,
3H
g
eAMA), 1.02 (d, J¼7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CD3OD)
(OCH2), 51.55 (CeN), 41.51 (C
a
eAMA), 41.07 (CH), 36.36 (C
geAMA),
d: 176.82 (C]O), 100.08 (C1), 72.14, 71.67, 71.07, 70.17 (C2eC5),
29.39 (C eAMA),13.67 (CH3). Anal. Calcd for C48H57NO7: C, 75.86; H,
b
71.04 (C6), 62.74 (OCH2), 52.87 (CeN), 42.50 (CaeAMA), 42.40 (CH),
7.56; N, 1.84. Found: C, 75.68; H, 7.62; N, 1.93.
37.54 (C eAMA), 30.95 (CHeAMA), 14.33 (CH3). Anal. Calcd for
g
C20H33NO7: C, 60.13; H, 8.33; N, 3.51. Found: C, 60.02; H, 8.30; N,
3.35.
4.4.4. (2S)-N-(Adamant-1-yl)-3-(2,3,4,6-tetra-O-benzyl-b-D-gal-
actopyranosyloxy)-2-methylpropanamide (6
(73.0 mg, 60%); [
D þ16.3 (c 0.82, CHCl3); Rf (C6H6/EtOAc 2:1)¼0.45;
1H NMR (300 MHz, CDCl3)
: 7.37e7.25 (m, 20H, HeAr), 5.90 (br s,1H,
NeH), 4.94 (d, Jgem¼11.5 Hz, 1H, CH2Ph), 4.90e4.69 (m, 4H, 2CH2Ph),
4.57 (d, Jgem¼11.6 Hz, 1H, CH2Ph), 4.44 (br s, 2H, CH2Ph), 4.37 (d,
J1,2¼6.6 Hz,1H, H-1), 3.88e3.69 (m, 4H, H-2, H-3, H-4, H-5), 3.61e3.49
(m, 4H, OCH2, H-6a, H-6b), 2.58e2.48 (m, 1H, CH), 1.98 (s, 3H,
b). Pale yellow oil
a]
4.5.4. (2S)-N-(Adamant-1-yl)-3-b-D-galactopyranosyloxy-2-methyl-
d
propanamide (8b). Pale yellow crude foam (48.0 mg, 91%); [a]
D
þ24.4 (c 0.57, CH3OH); Rf (CH3CN/H2O 5:1)¼0.55; 1H NMR
(300 MHz, CD3OD)
3.82e3.68 (m, 5H, H-2, H-3, H-4, H-5, H-6a), 3.52e3.45 (m, 3H, H-
d
: 4.84 (s,1H, NeH), 4.21 (d, J1,2¼7.5 Hz,1H, H-1),
6b, OCH2), 2.66e2.61 (m, 1H, CH), 2.04 (s, 9H, 3HbeAMA,
3H
b
eAMA), 1.91 (s, 6H, 3H
a
eAMA), 1.57 (s, 6H, 3H
g
eAMA), 1.05 (d,
3H
a
eAMA), 1.71 (s, 6H, 3H
g
eAMA), 1.03 (d, J¼7.0 Hz, 3H, CH3); 13
C
J¼6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 173.77 (C]O),138.62,
NMR (75 MHz, CD3OD) d: 176.81 (C]O), 105.59 (C1), 76.80, 74.96,
138.58, 138.40, 137.68 (CeAr), 128.52e127.46 (CHeAr), 104.76 (C1),
81.97, 79.43, 73.73, 73.36 (C2eC5), 75.14, 74.65, 73.58, 73.10 (CH2Ph),
72.64, 70.31 (C2eC5), 73.48 (C6), 62.58 (OCH2), 52.85 (CeN), 42.97
(CH), 42.35 (C eAMA), 37.58 (C eAMA), 30.98 (C eAMA), 14.59
a
g
b
73.00 (C6), 68.82 (OCH2), 51.60 (CeN), 42.19 (CH), 41.47 (C
a
eAMA),
(CH3). Anal. Calcd for C20H33NO7: C, 60.13; H, 8.33; N, 3.51. Found: C,
59.98; H, 8.26; N, 3.30.
36.37 (C eAMA), 29.36 (C eAMA), 13.89 (CH3). Anal. Calcd for
g
b
C48H57NO7: C, 75.86; H, 7.56; N,1.84. Found: C, 75.70; H, 7.59; N,1.90.
4.6. NMR investigations
4.5. General procedure for debenzylation of AMA conjugates
The 1H NMR investigations of the hosting process were per-
formed by means of Bruker Avance (600 MHz) spectrometer at
25 ꢀC. For that purpose solutions containing pure and mixed re-
actants were prepared in 99.96% D2O. The corresponding spectra
were recorded and the chemical shifts of the reaction participants
To a solution of pure anomer of each AMA conjugate 5
a, 5b, 6a
and 6 (100 mg, 0.13 mmol) in DCM (5 mL) 50 mg of 10% Pd/C and
b
20 mL of CH3OH was added. The mixtures were subjected to hy-
drogen atmosphere under 4 bar at room temperature while being
stirred for 24 h. The mixtures were then filtered over a Celite bed
and the obtained filtrates were concentrated in vacuo. The residues
were purified by column chromatography on silica gel (CH3CN/H2O
5:1) and deprotected compounds were obtained.
were referenced to internal D2O (
d
¼4.80 ppm). 1H NMR titration of
11
b
with cyclodextrin was performed by adding aliquots of the
stock host solution to the guest solutions up to 1:2 guest to host
molar ratio. The guest concentration (c¼1 mM) was kept constant
in all cases and the concentration of macrocycle was varied.
For all the other examined galactose and mannose conjugates
only the 1H NMR spectra of the solution at the 1:2 guest to host
molar ratio were collected. For that purpose, the host solution
(c¼20 M) was added to the guest solution (c¼5 mM). The ROESY
spectra of the reaction mixtures at 1:1 guest to host molar ratio
4.5.1. (2R)-N-(Adamant-1-yl)-3-a-D-galactopyranosyloxy-2-
methylpropanamide (7a). Pale yellow crude foam (50.1 mg, 95%);
[
a
]
þ54.2 (c 0.50, CH3OH); Rf (CH3CN/H2O 5:1)¼0.56; 1H NMR
D
(300 MHz, CD3OD)
d
: 4.87 (s, 1H, NeH), 4.81 (d, J1,2¼3.2 Hz, 1H, H-
1), 3.87e3.65 (m, 6H, H-2, H-3, H-4, H-5, H-6a, H-6b), 3.61 (d,
J¼6.8 Hz, 2H, OCH2), 2.71e2.60 (m, 1H, CH), 2.04 (br s, 9H,
were recorded in the case of 10a and 10b derivatives.
3H
b
eAMA, 3H
a
eAMA), 1.70 (s, 6H, 3H
g
eAMA), 1.05 (d, J¼7.0 Hz,
3H, CH3); 13C NMR (75 MHz, CD3OD)
72.58, 71.74, 71.15, 70.38 (C2eC5), 72.20 (C6), 62.90 (OCH2), 52.88
(CeN), 42.78 (CH), 42.36 (C eAMA), 37.54 (C eAMA), 30.95
(C eAMA),14.87 (CH3). Anal. Calcd for C20H33NO7: C, 60.13; H, 8.33;
N, 3.51. Found: C, 60.01; H, 8.25; N, 3.32.
d
: 176.76 (C]O), 101.21 (C1),
4.7. Microcalorimetry
a
g
Microcalorimetric experiments were performed by means of an
isothermal titration calorimeter VP Itc, Microcal at 25.0 ꢀC. The
calorimeter reaction cell was filled with adamantyl glycoside so-
lution (V0¼1.42 cm3; c0z5ꢂ10ꢃ4 mol dmꢃ3) in water. The enthalpy
changes were recorded upon stepwise additions (5 min intervals)
of cyclodextrin aqueous solution (c¼5ꢂ10ꢃ3 mol dmꢃ3). Blank
b
4.5.2. (2R)-N-(Adamant-1-yl)-3-
b
-D-galactopyranosyloxy-2-methylp
ropanamide (7 ). Pale yellow crude foam (49.6 mg, 94%); [a]
b
D ꢃ18.1

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Z. Car et al. / Tetrahedron 69 (2013) 8051e8063
8063
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4.8. Computational details
Since the size of the molecular systems modelled in this research
(consisting up to 350 atoms) limited the use of the computationally
demanding quantum-mechanical methods for conformational
search, the combination of molecular mechanics and density func-
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was limited to one mannose derivative,
b anomer, namely 10b with
(S)-absolute configuration of the chiral linker. The initial geometries
were built in Chem3D (CambridgeSoft, Cambridge, MA) program
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Acknowledgements
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This research was supported by the Ministry of Science, Edu-
cation and Sports of the Republic of Croatia (grants No. 119-
1191344-3121, No. 119-1191342-2961 and No. 119-1191342-1339).
Computational resources provided by Isabella cluster (isa-
bella.srce.hr) at Zagreb University Computing Centre (SRCE) were
used for this research.
€
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