Gem-difluorocarbadisaccharides: Restoring the exo-anomeric effect

Article abstract of DOI:10.1002/anie.201405008

Molecular mimicry is an essential part of the development of drugs and molecular probes. In the chemical glycobiology field, although many glycomimetics have been developed in the past years, it has been considered that many failures in their use are related to the lack of the anomeric effects in these analogues. Additionally, the origin of the anomeric effects is still the subject of virulent scientific debates. Herein, by combining chemical synthesis, NMR methods, and theoretical calculations, we show that it is possible to restore the anomeric effect for an acetal when replacing one of the oxygen atoms by a CF₂ group. This result provides key findings in chemical sciences. On the one hand, it strongly suggests the key relevance of the stereoelectronic component of the anomeric effect. On the other hand, the CF₂ analogue adopts the natural glycoside conformation, which might provide new avenues for sugar-based drug design. Taking effect: The combination of chemical synthesis, NMR methods, and calculations show that it is possible to restore the anomeric effect for an acetal when replacing one of the oxygen atoms by a CF₂ group. This result provides key findings as it strongly suggests the importance of the stereoelectronic component for the anomeric effect, and may open new avenues for sugar-based drug design.

Full text of DOI:10.1002/anie.201405008

Angewandte
Chemie
DOI: 10.1002/anie.201405008
Glycosides
gem-Difluorocarbadisaccharides: Restoring the exo-Anomeric
Effect**
Bixue Xu, Luca Unione, Joao Sardinha, Shaoping Wu, Mꢀlanie Ethꢁve-Quelquejeu,
Amelia Pilar Rauter, Yves Blꢀriot, Yongmin Zhang, Sonsoles Martꢂn-Santamarꢂa, Dolores Dꢂaz,
Jesus Jimꢀnez-Barbero,* and Matthieu Sollogoub*
Dedicated to Max Malacria on the occasion of his 65th birthday
Abstract: Molecular mimicry is an essential part of the
development of drugs and molecular probes. In the chemical
glycobiology field, although many glycomimetics have been
developed in the past years, it has been considered that many
failures in their use are related to the lack of the anomeric
effects in these analogues. Additionally, the origin of the
anomeric effects is still the subject of virulent scientific debates.
Herein, by combining chemical synthesis, NMR methods, and
theoretical calculations, we show that it is possible to restore the
anomeric effect for an acetal when replacing one of the oxygen
atoms by a CF2 group. This result provides key findings in
chemical sciences. On the one hand, it strongly suggests the key
relevance of the stereoelectronic component of the anomeric
effect. On the other hand, the CF2 analogue adopts the natural
glycoside conformation, which might provide new avenues for
sugar-based drug design.
mainly carbon, nitrogen, or sulphur.[3] Those modifications
induce a change in the stability, polarity, charge, conforma-
tion, ring flexibility, or hydrogen-bonding pattern to improve
their affinity for the target protein.[4] The precise under-
standing of the parameters governing those changes is
therefore essential to the design of new and more efficient
therapeutic molecules. More specifically, the replacement of
the exocyclic anomeric oxygen atom by a carbon atom leads
to C-glycosides[5] while replacement of the endocyclic one
produces carbasugars.[6] In both cases, when the aglycone is
another glycoside, this transformation leads to non-hydro-
lysable disaccharide analogues: C-disaccharides and carbadi-
saccharides (Figure 1).
C
arbohydrates play a pivotal role in multiple biological
processes which are initiated upon specific molecular recog-
nition of sugar ligands by cellular receptors.[1] Therefore,
sugar mimicry is an essential part of the development of
carbohydrate-based therapeutics, an area which already
proved successful with molecules such as Miglustat, Acar-
bose, or Voglibose.[2] The mimics are sugar scaffolds bearing
a relatively minimal modification which changes its properties
while still resembling the sugar. Hence, modifications of the
sugar moiety largely concentrate on the replacement of one or
both the acetal oxygen atoms by another atom, which is
Figure 1. Schematic perspective of the different glycomimetics men-
tioned in the text.
[*] B. Xu,[+] Dr. J. Sardinha, S. Wu, Prof. M. Ethꢀve-Quelquejeu,
Prof. Y. Blꢁriot, Dr. Y. Zhang, Prof. M. Sollogoub
Sorbonne Universitꢁs, UPMC Univ Paris 06
Institut Universitaire de France, UMR CNRS 8232, IPCM
4, place Jussieu, 75005 Paris (France)
Dr. S. Martꢂn-Santamarꢂa
Faculty of Pharmacy
Universidad CEU San Pablo, 28668-Madrid (Spain)
[+] These authors contributed equally to this work.
[**] The group in Paris thank the China Scholarship Council for Ph.D.
fellowships to B.X. and S.W., and Fundażo para a CiÞncia
e Tecnologia for a research grant (J.S.). The groups in Madrid thank
COSTactions BM1103 and CM1102, the MINECO grants CTQ2012-
32025 and CTQ2011-22724, and the European Commission
DYNANO and GLYCOPHARM ITN-projects. We also thank the CAI-
NMR of University Complutense for NMR spectrometer time and
CESGA (USC) for supercomputing time.
E-mail: matthieu.sollogoub@upmc.fr
L. Unione,[+] Dr. S. Martꢂn-Santamarꢂa, Dr. D. Dꢂaz,
Prof. J. Jimꢁnez-Barbero
Chemical and Physical Biology, CIB-CSIC
Ramiro de Maeztu 9, 28040 Madrid (Spain)
E-mail: jjbarbero@cib.csic.es
Dr. J. Sardinha, Prof. A. Pilar Rauter
Centro de Quꢂmica e Bioquꢂmica, Faculdade de CiÞncias da
Universidade de Lisboa, Lisboa (Portugal)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405008.
Prof. Y. Blꢁriot
Universitꢁ de Poitiers, UMR CNRS 7285, IC2MP
4, avenue Michel Brunet, 86022 Poitiers Cedex (France)
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Also, in both cases the conformational behavior of those
molecules drastically changes: more flexibility in the inter-
glycosidic linkage as well as the population of unnatural
conformations are observed.[7] These changes are often
detrimental to the efficient interaction of such molecules
with target proteins, mainly because of the entropic penalty it
induces. This phenomenon has been tentatively attributed to
the absence of the anomeric effects, especially the exo-
anomeric one.[8] The anomeric effects are still subject to
virulent scientific debate,[9–11] but the exo-anomeric effect
plausibly finds its origin in the favorable interaction between
a lone pair of electrons on the exocyclic anomeric oxygen
atom with the parallel s* orbital of the adjacent C1–O5 bond.
More precisely, it is the fact that this interaction is more
favorable than the interaction of a lone pair orbital of the
same oxygen atom with the s*C1-C2. This difference can be
a simple methyl a-d-glucopyranoside (1) and its CH2 (2) and
CF2 (3) counterparts. Solvent effects are included using the
polarizable continuum model (PCM) representing water. The
obtained geometries were then submitted to natural bond
orbital[15–17] (NBO) analysis investigating how the endo- and
exo-anomeric effects were affected by these structural
modifications, since NBO analysis allows the elucidation of
the role of intramolecular orbital interactions. The protocol
considers all possible interactions between the filled donors
and empty acceptors and estimates their energetic importance
using second-order perturbation theory. For each donor NBO
(i) and acceptor NBO (j), the stabilization energy E(2),
associated with the corresponding electron delocalization, is
estimated as:
2
Eð2Þ ¼ qi ðFi,jÞ =ejꢀei
ꢀ
attributed to the different polarization between the C1 O5
ꢀ
and C1 C2 bonds, thus producing a larger s* orbital centered
Where qi is the orbital occupancy, ei and ej are the diagonal
elements (orbital energies), and Fi,j is the off-diagonal NBO
Fock matrix element. Table 1 lists the calculated stabilization
energies corresponding to the anomeric effects. As expected
on the less electronegative atom of the polarized bond
(Figure 2). Therefore, the search for closer stereoelectronic
Table 1: Second-order interaction energy (E2, kcalmolꢀ1) between donor
and acceptor orbitals in a natural sugar (1) and analogous carbasugars
(2; CH2, and 3; CF2).
Molecule
Stabilization Energy
(E2) kcalmolꢀ1
exo-anomeric effect
endo-anomeric effect
nOexo!s*C1-Oendo
nOendo!s*C1-Oexo
17.39
10.66
Figure 2. Schematic representation of the lone pair–s* interactions
responsible for the exo-anomeric effect. The exo-anomeric conformers
are represented in the top row. For the regular glycoside (left), a good
overlapping between the s* and the lone pair is possible. The
possibility of restoration of the exo-anomeric effect in gem-difluoro-
carbadisaccharides is presented at the right-hand side. The non-exo-
anomeric geometries are depicted in the bottom row. In this case, no
proper overlapping between the s* and the lone pair is possible for
any molecule.
nOexo!s*C1-C5a
N.P.
0.84
nOexo!s*C1-C5a
NFax(LP)!s*C1-Oexo
9.24
1.33
mimics, retaining this feature, is essential. According to the
previous statement, replacement of the endocyclic oxygen
atom by a CF2 group instead of a CH2 should induce
they coexist in the natural glycoside 1, but disappear in the
analogous CH2 carbasugar 2. However, and much to our
delight the exo-anomeric effect reappears in the gem-difluor-
ocarbaglycoside 3. Interestingly, a small but unexpected
interaction between a lone pair of electrons on the axial
fluorine atom and the s*C1-O1 is observed to mimick the endo-
anomeric effect.
ꢀ
a polarization of the C1 CF2 bond and restore the exo-
anomeric effect (Figure 2). A contrario, when the exocyclic
oxygen atom is replaced by a CF2 rather than a CH2 it
populates the unnatural non-exo conformation as a result of
ꢀ
ꢀ
hyperconjugation of the C1 H1 and C1 C2 bonds with the
The energy contribution to the exo-anomeric effect in the
natural sugar compared to the one in the corresponding CH2
and CF2 carbasugars clearly suggests that the fluorine atoms,
because of their high electronegativity, favor the recovery of
[12,13]
ꢀ
C F bonds.
Interestingly, while many C-disaccharides
and carbasugars, and some CF2 C-disaccharides have been
prepared, there is no report of the synthesis of any gem-
difluorocarbadisaccharide.[14] We therefore embarked on the
synthesis and study of such a molecule to explore the
possibility of restoring the exo-anomeric effect in a carbonated
sugar mimic.
ꢀ
the exo-anomeric effect through polarization of the C1 CF2
bond. The optimized structural parameters of the studied
molecules obtained at the DFT (B3LYP/6-31 ++ G PCM)
level[18] of theory are given in Table S1 in the Supporting
Information. The calculated bond lengths for 2 and 3 in the
anomeric region, compared to those of 1, are in agreement
First, we tested our hypothesis in silico. Hence, we
performed density functional theory (DFT) calculations on
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with the presence of an exo-anomeric effect in 3 (Table S1).
According to the calculated molecular orbital diagrams (see
Figure S1 in the Supporting Information), the uneven elec-
88% yield as a mixture of two inseparable diastereomers. The
second fluorination was achieved slightly differently through
treatment of 6 with Selectfluor in the presence of DAST,
followed by the addition of triethylamine to give the desired
difluorosulfide 7 in 61% yield together with monofluorosulf-
oxides (22%). Further oxidation of 7 with mCPBA produced
the sulfoxides 8 in 90% yield as an inseparable mixture of two
diastereomers. Their thermolysis with Bn3N in Ph2O at 1908C
under air for 120 hours gave the difluoroalkene 9 in 65%
yield. Treatment of 9 with TIBAL gave the desired carbocycle
as a mixture of diastereomeric alcohols, which were oxidized
into a single ketone (10) with Dess–Martin periodinane. The
synthesis of the diol 11 was achieved by hydroxymethylation
with Fleming–Tamao oxidation procedure from 10. Reaction
of 10 with freshly prepared Tamaoꢀs reagent provided b-
hydroxysilanes, which was subjected without purification to
ꢀ
tron density distribution in the C1 X5a s-bonding orbitals for
3 and 1, compared to those of 2, translates to a better orbital
overlap between the (n) lone pair molecular orbital of the
exocyclic oxygen atom and the unoccupied antibonding (s*)
molecular orbital of C1. Moreover, the inductive effect of the
electron-withdrawing fluorine atoms at C5a also contributes
to the preservation of a large stereoelectronic exo-anomeric
contribution in 3.
Encouraged by this preliminary work, and to experimen-
tally validate this concept, we synthesized a gem-difluorocar-
badisaccharide (Scheme 1). We have previously synthesized
gem-difluorocarbasugars[19] using an O!C 1,3-rearrange-
ment[20] applied to C-glycosides.[21] This strategy produced
a free pseudoanomeric hydroxy group which was ready for
further functionalization. However, despite numerous
attempts, this OH could neither be alkylated nor substituted.
In parallel, we have also shown that disaccharides could
undergo the O!C 1,3-rearrangement directly, thus producing
carbadisaccharides.[22] We therefore turned our attention
towards this strategy for the present work. However, the
challenge here was the synthesis of a gem-difluorinated exo-
glycal. After several attempts, the successful route was
inspired by the work of McCarthy and Prakash on nucleo-
sides,[23] and involved a Pummerer reaction. The starting
alcohol 4 was produced from maltose using a known route.[22]
Sulfidation of 4 was then achieved by treatment with bis(4-
methoxyphenyl) disulfide and tributylphosphine in DMF to
afford the sulfide 5 in 92% yield. Fluorination of 5 was
performed using a modified Pummerer reaction with DAST
in the presence of NIS to give the monofluorosulfides 6 in
ꢀ
oxidative cleavage of the Si C bond by basic hydrogen
peroxide to give 11. Final deprotection of 11 using palladium
on charcoal (Pd/C) as a catalyst in methanol proceeded
smoothly to give the target molecule 12 in quantitative yield
(Scheme 1).
Thus, the conformation of 12 was investigated by a combi-
nation of NMR spectroscopy and molecular modeling meth-
ods, and compared to that of the carbasugar analogue 13
(Scheme 1), where fluorine atoms are replaced by hydrogen
atoms, to probe the stereoelectronic effect of the CF2 group.
The synthesis of 13 is given in the Supporting Information and
uses the same last steps as those used for 12 from a known
intermediate.[24] We first performed molecular mechanics
calculations (MM3*)[25] and found that for both 12 and 13
there were three more stable conformations around the F/Y
glycosidic linkages, which were the exo-F/syn-Y (F/Y ca.
ꢀ40/ꢀ20), exo-F/anti-Y (F/Y ca. ꢀ40/180), and non-exo-F/
Scheme 1. Reagents and conditions: a) Bis(4-methoxyphenyl) disulfide (1.5 equiv), nBu3P, DMF, RT, overnight, 92%; b) DAST (5 equiv), N-iodo-
succinimide (NIS, 2.1 equiv), CH2Cl2, ꢀ408C to RT, overnight, 88%; c) Selectfluor (1.25 equiv), DAST (0.18 equiv), CH3CN, RT, 45 min; then
anhydrous triethylamine (1.5 equiv), RT, 45 min, 61%; d) mCPBA (1.1 equiv), CH2Cl2, ꢀ208C to RT, overnight, 90%; e) Bn3N (3 equiv) Ph2O,
1908C, 120 h, 65%; f) TIBAL (12 equiv), toluene, 508C, 30 min, 29%; g) Dess–Martin periodinane (3.7 equiv), CH2Cl2, RT, 1 h; h) [(isopropoxy-
dimethylsilyl)methyl]magnesium chloride, 4 ꢃ M.S., THF, 08C, 1 h; i) TBAF (4 equiv), KHCO3 (8 equiv), H2O2 (20 equiv), THF/MeOH (1:1, V/V),
08C, 1 h, 13% over three steps; j) H2, 10% Pd/C, MeOH, RT, 15 h, quant. DAST=diethylaminosulfurtrifluoride, DMF=N,N-dimethylformamide,
mCPBA=n-chloroperbenzoic acid, TBAF=tetra-n-butylammonium fluoride, THF=tetrahydrofuran, TIBAL=triisobutylaluminum.
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Figure 3. Ball and stick representations and relative steric energy
values of the major conformers of 12 and 13 according to MM3*
calculations.
syn-Y (F/Y ca. 40/0) conformations (see the Supporting
Information for details). The calculated conformers are
represented in Figure 3 together with the steric energy
values provided by MM3*.[25] Other force fields (AMBER*,
OPLS) provided similar geometries and relative steric energy
values.
1H-1H NOESY and/or 1H-19F HOESY NMR experiments
were carried out on both 12 and 13. As shown on Figure 4 the
pattern of correlations for H1’ is strikingly different between
12 and 13. While the only inter-residue correlation of H1’ is
with H4 for 12, H1’ correlates with H3, H4, H5, and H6 in the
case of 13 (Figure 4A,B). Both the Feq in 12 and and H5aeq
(further referred to as Heq) in 13 correlate with H4 and a H6
(Figure 4C,D).
We next estimated the interatomic distances using the
calculated structures (Figure 3) as well as the experimental
proton–proton and proton–fluorine distances from the inte-
gration of the observed NOE crosspeaks using the isolated
spin pair approximation (ISPA).[26] The results are reported in
Table S3 of the Supporting Information and illustrated on the
different conformers in Figure 5. For 12 the exo-F/anti-Y
conformer can be easily dismissed because no correlations are
observed between H1’ and H5, nor between Feq and H3. The
fact that H1’ only correlates with H4 cannot discriminate
between the exo-F/syn-Y and the non-exo-F/syn-Y con-
formers, but the presence of a Feq–H4 correlation together
with the absence of the H1’–H6 correlation allows the clear
discrimination between both geometries exclusively in favor
of the exo-F/syn-Y conformer. In striking contrast, the
simultaneous presence of Heq–H4, Heq–H6, H1’–H3, H1’–
H4, H1’–H5, and H1’–H6 correlations for 13 clearly indicate
a conformational equilibrium between the three conformers
depicted in Figure 3. In particular, the presence of the Heq–H4
NOE can only be explained by the exo-F/syn-Y geometry.
The presence of the Heq–H6S NOE and H1’–H6R NOE can
only be satisfied by the alternative non-exo-F/syn-Y confor-
mer. The observation of the H1’–H3 and H1’–H5 NOE is only
compatible with the presence of the third exo-F/anti-Y
Figure 4. (Upper) Strips of two-dimensional NOESY spectra (700 ms
mixing time) of 12 (A) and 13 (B) taken at frequency of H1’. (Lower)
Strips of 2D 1H-19F HOESY (500 ms mixing time) of 12 (C) and 1H-1H
NOESY (700 ms mixing time) for 13 (D). Key NOEs are highlighted.
No other inter-residue NOE interactions are observed above the noise
level.
conformation. (Figure 5) Therefore, the three conformations
indeed exist in solution. The possibility of establishing an
intra-residue OH5···Oexo hydrogen bond was also scrutinized
because it could stabilize one or the other conformation.
According to the calculations, this possibility would exist for
both exo- and non-exo conformers. However, since the
experiments have been performed in water (D2O), given the
massive presence of water molecules, the importance of any
intraresidue OH···O interaction should be at a minimum and
not influence the conformational behavior. Nevertheless, its
4
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Received: May 6, 2014
Revised: June 6, 2014
Published online: && &&, &&&&
Keywords: anomeric effect · conformation analysis · fluorine ·
.
glycosides · NMR spectroscopy
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Angewandte
Communications
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6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Glycosides
B. Xu, L. Unione, J. Sardinha, S. Wu,
M. Ethꢁve-Quelquejeu, A. Pilar Rauter,
Y. Blꢂriot, Y. Zhang, S. Martꢃn-Santamarꢃa,
D. Dꢃaz, J. Jimꢂnez-Barbero,*
M. Sollogoub*
&&&& — &&&&
gem-Difluorocarbadisaccharides:
Restoring the exo-Anomeric Effect
Taking effect: The combination of chem-
ical synthesis, NMR methods, and cal-
culations show that it is possible to
restore the anomeric effect for an acetal
when replacing one of the oxygen atoms
by a CF2 group. This result provides key
findings as it strongly suggests the
importance of the stereoelectronic com-
ponent for the anomeric effect, and may
open new avenues for sugar-based drug
design.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!