Structural and Computational Analysis of 2-Halogeno-Glycosyl Cations in the Presence of a Superacid: An Expansive Platform

Article abstract of DOI:10.1002/anie.201907001

An expansive NMR-based structural analysis of elusive glycosyl cations derived from natural and non-natural monosaccharides in superacids is disclosed. For the first time, it has been possible to explore the consequence of deoxygenation and halogen substitution at the C2 position in a series of 2-halogenoglucosyl, galactosyl, and mannosyl donors in the condensed phase. These cationic intermediates were characterized using low-temperature in situ NMR experiments supported by DFT calculations. The 2-bromo derivatives display intramolecular stabilization of the glycosyl cations. Introducing a strongly electron-withdrawing fluorine atom at C2 exerts considerable influence on the oxocarbenium ion reactivity. In a superacid, these oxocarbenium ions are quenched by weakly coordinating SbF₆^? anions, thereby demonstrating their highly electrophilic character and their propensity to interact with poor nucleophiles.

Full text of DOI:10.1002/anie.201907001

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Structural and Computational Analysis of 2-Halogeno-Glycosyl
Cations in Superacid: An extansive Platform
Authors: Ludivine Lebedel, Ana Arda, Amélie Martin, Jérome Désiré,
Agnès Mingot, Marialuisa Aufiero, Nuria Aiguabella font, Ryan
Gilmour, Jesus Jimenez-Barbero, yves bleriot, and Sebastien
Thibaudeau
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907001
Angew. Chem. 10.1002/ange.201907001
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Angewandte Chemie International Edition
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COMMUNICATION
Structural and Computational Analysis of 2-Halogeno-Glycosyl
Cations in Superacid: An Expansive Platform
[
a]
[b]
[a]
[a]
[a]
Ludivine Lebedel, Ana Ardá, Amélie Martin, Jérôme Désiré, Agnès Mingot, Marialuisa
Aufiero, Nuria Aiguabella Font, Ryan Gilmour, Jesus Jiménez-Barbero,* Yves Blériot* [a] and
[
c]
[c]
[c]
[b]
Sébastien Thibaudeau* [a]
Abstract: An expansive NMR–based structural analysis of elusive
glycosyl cations derived from natural and non-natural
monosaccharides in superacids is disclosed. For the first time, it has
been possible to explore the consequence of deoxygenation and
comparable stability to benzylic ions,[9] the environment of the
pyranose ring, containing multiple C-O bonds, reduces the
stability and lifetime of these ionic species.[10,11] The synergistic
electron withdrawing effect of an halogen atom at C-2 likely
enhances this global effect by rendering the anomeric carbon
atom even more electron deficient. Accordingly, while the direct
observation of glycosyl cations in the gas phase by
complementary spectroscopic methods[12,13] and indirect
observation[14,15] has been reported, their direct characterization in
the condensed phase has failed despite a number of very elegant
attempts.[16] Strongly inspired by the work of Olah and Prakash,
who unlocked large areas of carbocation chemistry exploiting non
halogen substitution at the C-2 position in
a series of 2-
halogenoglucosyl, galactosyl and mannosyl donors in the condensed
phase. These cationic intermediates were characterized using low
temperature in situ NMR experiments supported by DFT calculations.
The 2-bromo derivatives display intramolecular stabilization of the
glycosyl cations. Introducing a strongly electron withdrawing fluorine
atom at C-2 exerts considerable influence on the oxocarbenium ion
reactivity. In superacid, these oxocarbenium ions are quenched by
–
nucleophilic superacid conditions,[17] using HF/SbF
both reagent and solvent, we recently generated and
weakly coordinating SbF
6
anions, thereby demonstrating their highly
5
superacid as
electrophilic character and their propensity to interact with poor
nucleophiles.
a
[
18]
characterized glucosyl cations in a condensed phase. However,
this proof of concept study has been limited to glycosyl cations
bearing only equatorial substituents. To address the urgent need
for general strategies to enable the direct characterization of
glycosyl cations, the impact of halogens at C-2 on the superacid-
mediated transient and key glucosyl, galactosyl and mannosyl
cation formation, structure and stability is presented (Fig. 1).
2-Deoxyhalogenated glycosyl donor derivatives are versatile
building blocks for preparative glycochemistry. Inclusion of a
functional handle at C-2 allows glycosylation to be influenced in a
traceless fashion, rendering them ideal to access 2-
deoxyglycosides.[1] This important class of carbohydrates
appears frequently in bioactive natural products[2] but
stereocontrolled glycosidic bond formation remains challenging.[3]
Deoxyfluorinated glycosyl donors are a particularly prominent
class of halo-sugars and have found widespread application in
mechanistic enzymology.[4] These structures are also pivotal for
the generation of glycoproteins containing the 19F NMR active
probe, promising candidates for carbohydrate vaccines[5] and in
radiopharmaceutical chemistry.[6] The fluorine substituent has
Figure 1. Superacid-mediated glycosyl cations generation and study.
The 2-deoxygalactopyranosyl donor 1 was first studied to
evaluate the effect of an axial electron withdrawing substituent at
C-4, as this subtle change has been shown to favor a through
space stabilization of the transient glycosyl cation.[19], [20] Donor 1
also been strategically employed to direct glycosylation selectivity,
particularly when matched with protecting group electronics.[7]
Chemical glycosylation is a mechanistic continuum that includes
dissociative extreme featuring putative oxocarbenium ion
intermediates.[ Unlike simple oxocarbenium ions that are of
8]
5
was submitted to HF/SbF conditions and cleanly furnished a
polycationic species, which was analyzed by NMR, following our
previously described protocol.[
18a]
Detailed NMR analysis of this
[
a]
L. Lebedel, Dr. A. Martin, Dr. J. Désiré, Dr. A. Mingot, Prof. Y.
Blériot, Prof. S. Thibaudeau
IC2MP UMR CNRS 7285, Equipe “Synthèse Organique”,
Université de Poitiers
species was in excellent agreement with the 2-deoxy-
galactopyranosyl cation 2 (anomeric proton at 9.18 ppm and
anomeric carbon at 228.5 ppm). The quality of the recorded NMR
spectra allowed for the complete analysis of the homonuclear
NMR coupling constants, which assisted by computational
4
rue Michel Brunet 86073 Poitiers cedex 9, France
E-mail: sebastien.thibaudeau@univ-poitiers.fr; yves.bleriot@univ-
poitiers.fr
Dr. A. Ardá, Prof. J. Jiménez-Barbero
CIC bioGUNE, Parque technologico de Bizkaia, Edif. 801A-1°,
Derio-Bizkaia 48160, and Ikerbasque, Basque Foundation for
Science, Maria Lopez de Haro 3, 48013 Bilbao, Spain.
E-mail: jjbarbero@cicbiogune.es
Dr. Marialuisa Aufiero, Dr. Nuria Aiguabella Font, Prof. R. Gilmour
Organisch Chemisches Institut
4
analysis, permitted to infer the major contribution of a E envelope
[
[
b]
c]
conformation to ion 2 (Fig. 2). Interestingly, this conformation was
also assigned to the 2-deoxyglucosyl cation,[ in which the three
sugar ring substituents adopted a pseudoequatorial orientation to
minimize charge repulsion. Here,the acetate at C-4 remains axial.
While neighboring group participation of the 2-OAc group was
clearly operative, leading to the dioxalenium ion 4 when studying
peracetylated D-galactosyl donor 3 (Fig. 2b), (see SI) potential
participation of the 4-OAc of the 2-deoxy donor 1 was not
observed in superacid.
18a]
Westfälische Wilhelms Universität Münster
Corrensstrasse 40, 48149 Münster, Germany.
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
Intuitively, inserting an electronegative substituent at C-2 is
expected to increase the electrophilicity of the glycosyl
oxocarbenium ion, thus favoring potential remote axial acetate
participation to stabilize this species. Therefore, the behavior of
the 2-bromo-2-deoxygalactosyl fluoride 5 in superacid was
examined.
donor 3. The high electrophilic character of the postulated
transient mannosyl cation,[21] illustrated by the trapping of silver
perchlorate by peracetylated mannopyranosyl chloride,[22] and the
challenge associated with its generation in solution led us to
investigate this unique glycosyl donor. Peracetylated-β-D-
mannopyranose 7 and its 2-bromo-2-deoxy fluoride counterpart
8[23]
5
were both treated with HF/SbF superacid. Interestingly, while
peracetylated gluco- and galactopyranose previously furnished
the corresponding dioxalenium ions as single species, the
a)
mannosyl donor
dioxalenium ion 9 observed as a distorted C
7
furnished
a
mixture of the expected
4E conformation
4
1
conformer (see SI)
along with some unreacted mannosyl donor in its polyprotonated
form 10, emphasizing the singular reactivity of this unique
stereoisomer. Gratifyingly, the 2-bromo 2-deoxymannosyl donor
8 furnished an ionic species whose NMR signals were in good
b)
agreement with
a 2-bromomannosyl oxocarbenium ion 11
Distorted 4C
conformation
(anomeric proton at  = 8.50 ppm and anomeric carbon at  =
1
4
195.4 ppm). Flattening of the sugar ring adopting a
H
3
Figure 2. Generation of a) ion 2 after reaction of 2-deoxygalactopyranosyl donor
in HF/SbF (conformation in solution); b) dioxalenium ion 4 after reaction of
peracetylated D-galactosyl donor 3 in HF/SbF (conformation in solution).
conformation was evidenced by J-coupling constant analysis.
Again, this conformation places the bromine atom in a pseudo-
axial orientation allowing stabilization of the positive charge
developed at the anomeric center by bromine (Fig. 4).
1
5
5
Under HF/SbF
5
conditions, the corresponding 2-deoxy-2-bromo-
galactosyl cation 6 was produced according to the NMR data (Fig.
3
). The signal for the anomeric carbon for ion 6 was not detected
by 3C NMR that can be attributed to the scalar relaxation effect
1
a)
of the quadrupolar bromine nucleus that causes severe line
broadening effect on C-1. This effect, also operative in the 2-
bromoglucose case (see SI), is
a
clear experimental
demonstration of the existence of a stabilizing orbital overlap
4
between Br and C-1. A H
5
conformation, placing the bromine in
a pseudo-axial orientation, was attributed to the 2-bromo-2-
deoxygalactosyl cation 6 by comparing the experimental and
DFT-calculated coupling constants and 13C chemical shifts for its
optimized structure (see SI). This conformation allows the above-
mentioned stabilization of the galactosyl cation by electron
donation from the bromine lone pairs to the electron deficient
antibonding orbital of O5-C1, as revealed by Natural Bond Order
analysis.
b)
4
H3 conformation
4H
conformation
5
Figure 4. a) Generation of mannosyl ions
peracetylated-β-mannopyranose 7 in HF/SbF
NMR spectra of 2-bromomannosyl oxocarbenium ion 11 in HF/SbF
conformation in solution).
9
and 10 after reaction of
at -40 °C; b) Generation and
at -40 °C
5
5
(
Figure 3. Generation and 1H NMR spectrum of 2-bromogalactosyl
oxocarbenium ion 6 in HF/SbF at -40°C (conformation in solution).
5
Having demonstrated the through space stabilization of the
glycosyl cation exerted by the bromine at C-2 whatever the
glycosyl donor stereochemistry, in superacid, we switched to
Regarding remote anchimeric assistance, introduction of the
bromine at C-2 failed to trigger 4-OAc participation, suggesting a
instantaneous protonation of this ester in superacid that precludes
its anchimeric assistance, unlike with the 2-OAc in the galactosyl
2
-fluoro derivatives that was expected to behave differently. Due
to its unique properties,[ the “magic fluorine” atom has attracted
24]
considerable attention in recent years and has been implicated in
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Angewandte Chemie International Edition
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COMMUNICATION
the discovery of new chemical entities possessing unique
physicochemical properties.[25] Glycoscience is no exception and
examined. Its activation under optimized superacid conditions led
to a cationic species whose anomeric NMR shifts (δH1 = 4.55
ppm; δC1 = 101.3 ppm) (Fig. 5b) did not match those of the
the incorporation of fluorine atoms into carbohydrates is well
documented.[
26]
The 1-acetyl-2-fluoro tetrahydropyran 12 was
calculated 2-fluoroglucosyl cation 16 (see SI). Indeed, the NMR
4
selected as a 2-fluoro glycosyl donor model and yielded the
data strongly support a α-configured species 15 adopting a C
1
corresponding cyclic oxocarbenium ion 13 upon treatment with
conformation resulting from cation stabilization by SbF -
6
HF/SbF
5
(δH1 = 8.79 ppm; δC1 = 227.3 ppm, 2JC-F = 35 Hz; see
counterion. This species perfectly illustrates the dramatic
difference in reactivity between a simple tetrahydropyranyl
oxocarbenium ion and a glycosyl cation bearing several electron-
withdrawing C-O substituents. We were particularly puzzled by
the unusual broad signal in the 13C NMR spectrum recorded at -
SI). This result confirmed that unstable and highly intriguing α-
fluorinated cyclic carboxonium ions,[27-29] can be observed by low-
temperature NMR spectroscopy in superacid solutions (Fig. 5a).
4
0 °C exhibited by the anomeric carbon of 15 (Fig. 6b) and by the
absence of NMR coupling constants of H-1 and C-1 with the F of
the SbF -. In order to corroborate the structure of 15, its 13C NMR
a)
6
spectrum was recorded at higher temperatures (up to 10°C).
Fittingly, a sharper doublet peak with a large coupling (24Hz) was
obtained for C-1, in agreement with an unconventional
coordination phenomenon triggered by the “non-coordinating”
SbF -
anion (Fig. 6b).[32]
6
4
C1 conformation
4
E conformation
a)
+10ꢀC
b)
0
ꢀC
-
-
10ꢀC
b)
20ꢀC
-
40ꢀC
C)
Figure 6. a) Formation and observed privileged conformation of ion 15 in
superacid HF/SbF solution; deuteration and calculated privileged conformation
5
of the postulated SSIP fluorinated glucosyl cation analogue 16; b) Sharpening
of the anomeric carbon signal of ion 15 with increasing temperature; c)
Formation of mannose-derived ionic species 19, observed by low-temperature
NMR in superacid HF/SbF solution and deuteration of its postulated SSIP
5
fluorinated mannosyl cation analogue 20.
Collectively, these data suggest that, unlike in the 2-Br case, the
media counter anions interact with the “superelectrophilic”[33] 2-
fluoro glucosyl cation leading to a fast equilibrium between an
observed contact ion pair 15 and a transient solvent separated ion
Figure 5. a) Generation and NMR spectra of 2-fluorotetrahydropyranyl ion 13 in
HF/SbF at -40 °C; b) Generation and NMR spectra of ion 15 resulting from
5
5
reaction of 1,2-difluorinated glucosyl donor 14 with HF/SbF at -40 °C and
calculated 2-fluoroglucosyl oxocarbenium ion 16.
4
pair 16 found to adopt a E conformation by calculations (see SI)
The absence of large 3JH-F NMR coupling constants suggests a
flattened conformation in solution, with the H-C-C-F dihedral
angle close to 90°C,[30] in line with the idea that an electronegative
substituent located in the vicinity of the cyclic oxocarbenium ion
must strongly influence its ground state conformation.[7,31] The
reactivity of the 1,2-difluorinated glucosyl donor 14 was next
that could not be observed on the NMR time scale. This
hypothesis was indeed supported by the observation of at least
two major coordinated species when the reaction was performed
in magic acid (HSO
of fluoro-fluorosulfato (SbF6 n(SO
3
F/SbF
5
), a solution known to contain mixtures
-
F) -
5n+1-)
3
n
) and fluoro (Sb
n
F
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COMMUNICATION
antimonates (see SI).[34,35] Thus, in the absence of nucleophile in
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5
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[4]
[5]
[6]
2
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1
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
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superacids and NMR analysis provides an expansive platform to
explore glycosyl cations in the condensed phase. The initial
generation of D-gluco-configured glycosyl cations in
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natural and non-natural sugars that are biologically relevant. For
the first time, galactose and mannose-derived systems could be
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halogens at C-2. A combined experimental and computational
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can have on conformation: a seemingly subtle switch from C2-F
to C2-Br causes very different conformational behavior. Whilst
analysis of the 2-bromo derivatives indicate a through space
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stereochemistry, investigation of the 2-fluoro glycosyl donors
suggests that intermolecular stabilization of the transient glycosyl
cation by poorly nucleophilic fluoroantimonate species is
operational. It is evident that for these fluorinated species, even
in a “non-nucleophilic” environment, counter ion matters. This
result may pave the way for glycosylation reactions with
unprecedented weak nucleophiles.
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LL and AM thank the Agence Nationale de la Recherche (ANRs
SweetCat and Oxycarb) for PhD grants. ST and YB acknowledge
the European Union (ERDF), Région Nouvelle Aquitaine and the
University of Poitiers for financial support. RG and JJB
acknowledge the European Research Council for generous
support (ERC-2013-StG Starting Grant to RG - Project number
[
[
[
3
7
36376-ChMiFluorS and ERC-2017-AdG to JJB - Project number
88143-RECGLYCANMR). AA and JJB thank Agencia Estatal de
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Investigación (Spain) for grants CTQ2015-64597-C2-1-P and
Severo Ochoa Excellence Accreditation SEV‐2016‐0644. We
thank Dr. Gonzalo Jiménez-Osés and Dr. Tammo Diercks (CIC
1
Albrecht, R. Gilmour, ACS Chem. Neurosci. 2018, 9, 1159.
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Keywords: glycosylation
superelectrophile • reaction mechanisms
•
oxocarbenium
•
fluorine
•
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Low-temperature
NMR analysis
DFT calculations
Halogen substitution effect on
Ludivine Lebedel, Ana Arda, Amélie
Martin, Jérôme Désiré, Agnès Mingot,
Marialuisa Aufiero, Nuria Aiguabella
Font, Ryan Gilmour, Jesus Jiménez-
Barbero,* Yves Blériot,* Sébastien
Thibaudeau*
superacid-generated glucosyl,
galactosyl and mannosyl cations
conformation was explored by low
temperature in situ NMR experiments
and supported by DFT calculations.
4E
Page No. – Page No.
Structural and Computational
Analysis of 2-Halogeno-Glycosyl
Cations in Superacid: An Expansive
Platform
4C1
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This article is protected by copyright. All rights reserved.