Direct Experimental Characterization of Glycosyl Cations by Infrared Ion Spectroscopy

Article abstract of DOI:10.1021/jacs.8b01236

Glycosyl cations are crucial intermediates formed during enzymatic and chemical glycosylation. The intrinsic high reactivity and short lifetime of these reaction intermediates make them very challenging to characterize using spectroscopic techniques. Here

Full text of DOI:10.1021/jacs.8b01236

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Direct Experimental Characterization of
Glycosyl Cations by Infrared Ion Spectroscopy
Hidde Elferink, Marion E. Severijnen, Jonathan Martens, Rens A. Mensink, Giel
Berden, Jos Oomens, Floris P.J.T. Rutjes, Anouk M. Rijs, and Thomas J. Boltje
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01236 • Publication Date (Web): 14 Apr 2018
Downloaded from http://pubs.acs.org on April 14, 2018
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Direct Experimental Characterization of Glycosyl Cations by Infrared
Ion Spectroscopy.
Hidde Elferink,‡,a Marion E. Severijnen,‡,b Jonathan Martens,b Rens A. Mensinka, Giel Berden,b
Jos Oomens,b Floris P. J. T. Rutjes,a Anouk M. Rijs,*,b and Thomas J. Boltje*,a
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aRadboud University, Institute for Molecules and Materials, Synthetic Organic Chemistry, Heyendaalseweg 135,
6525 AJ, Nijmegen, The Netherlands.
bRadboud University, Institute for Molecules and Materials, FELIX laboratory, Toernooiveld 7c, 6525 ED, Nijmegen,
The Netherlands.
Supporting Information Placeholder
the solvent separated ion pair, also known as the oxocarbe-
ABSTRACT: Glycosyl cations are crucial intermediates
nium ion. Hence, to fully understand the mechanistic path-
ways of glycosylation reactions, it is crucial to elucidate the
structure of its intermediates such as glycosyl oxocarbenium
ions. However, glycosyl oxocarbenium ions are very challeng-
ing to characterize due to their intrinsic high reactivity, short
life-times and equilibrium with the corresponding contact
ion pair. Very recently, NMR spectroscopy of glycosyl oxo-
carbenium ions was reported in super acid solution.9 Howev-
er, the harsh conditions to generate the oxocarbenium ions
are not compatible with all types of protecting groups com-
monly used in oligosaccharide synthesis. Tandem mass spec-
trometry (MS/MS) can be employed to generate glycosyl
cations in complete isolation and their gas-phase fragmenta-
tion has been extensively studied.10-14 Recently, the use of MS
in combination with infrared (IR) ion spectroscopy has
formed during enzymatic and chemical glycosylation. The
intrinsic high reactivity and short life-time of these reaction
intermediates makes them very challenging to characterize
using spectroscopic techniques. Herein, we report the use of
collision induced dissociation tandem mass spectrometry to
generate glycosyl cations in the gas phase followed by infra-
red ion spectroscopy using the FELIX infrared free electron
laser. The experimentally observed IR spectra were compared
to DFT calculated spectra enabling the detailed structural
elucidation of elusive glycosyl oxocarbenium and dioxoleni-
um ions.
The principle challenge in chemical oligosaccharide synthe-
sis is the stereoselective synthesis of glycosidic bonds.1 Glyco-
sidic bonds connecting monosaccharides can exist as α- or β-
diastereomers. The most common approach to chemically
prepare glycosidic bonds is a nucleophilic substitution reac-
tion between a glycosyl donor carrying an anomeric leaving
group, and a glycosyl acceptor containing a nucleophilic al-
cohol. Depending on the nature of the glycosyl donor, accep-
tor and reaction parameters, the mechanism of a glycosyla-
tion is best described as a continuum between SN1-like and
SN2-like reaction pathways (Scheme 1).2
emerged as a powerful method to determine the gas-phase
15-20
structures of molecular ions in MS/MS
can structure 21-26
and to probe gly-
.
Herein we report the use of collisional dissociation to gener-
ate glycosyl cations followed by characterization using infra-
red (IR) ion spectroscopy. Electrospray ionization (ESI) of
four glycosyl donors was employed to form a parent ion
which was fragmented using collision induced dissociation
(CID) affording the desired glycosyl cations. Crucially, the
absence of a counter ion and solvent led to “naked” cations
that could be characterized using IR ion spectroscopy. The IR
spectra showed specific diagnostic vibrational bands ena-
bling the assignment of oxocarbenium and dioxolenium ions.
In addition, a mixture of two dioxolenium ion isomers could
be resolved thereby providing insight into the dynamics of
these elusive intermediates.
Scheme 1: Reactive intermediates in glycosylation reactions
and their respective reaction pathways
We synthesized mannosyl donors 1-4 as substrates and the
commonly used benzyl ethers were replaced by methyl
ethers in order to eliminate IR signals resulting from the
aromatic system (Scheme 2). Thioglycosides were selected as
they are frequently used glycosyl donors and have been used
to study the formation and fragmentation of glycosyl cations
using CID.27-29
Stereoselective glycosylation can be achieved by the SN2-like
displacement of a contact ion pair or covalent intermediate
such as glycosyl triflates3, sulfonium ions4,5 and dioxolenium
ions6 (Scheme 1). Reactions via this pathway are well studied
as the reaction intermediates can be characterized by low
temperature NMR spectroscopy.3,7,8 Loss of stereoselectivity
during the displacement of the contact ion pair intermedi-
ates is often attributed to an alternative reaction pathway via
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Scheme 2: Structures of the mannosyl donors used in this
study
In our spectral assessment, peak positions (cm-1) are most
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important since peak intensities in the calculated spectrum
are based on linear IR absorption, whereas the measured
spectra rely on multiple-photon absorption.Initial optimiza-
tion indicated that DFT calculations at the B3LYP/6-31++G(d,
p) level, with relative energies determined using MP2/6-
311++G(2d, 2p), proved to provide the most representative
spectra (Fig. S3). It is well established that acetyl protected
donors produce dioxolenium ions via neighboring group
participation.32 The experimental IR spectrum was compared
with the calculated IR spectra of the lowest energy isomers of
four different structural families with m/z=331. Participation
of the C-2, C-3, C-4 or C-6 acetyl ester was considered to-
gether with the unstabilized oxocarbenium ion (Fig. S4). The
lowest energy structure resulted from C-2 acetyl participa-
tion followed by C-3 participation (+5.8 kJ/mol), whilst C-
4/C-6 participation or no participation display significant
higher energies (+34.2-40.3 kJ/mol). Based on the energies
themselves, the latter three structures are unlikely to be pre-
sent. This is further supported by comparing the calculated
and experimental IR spectra. The calculated C=O+ stretch of
the oxocarbenium ion would appear at 1616 cm-1 (Fig. S4),
however, this signal is absent in the measured spectrum. The
participation of acetyl esters can be assigned by the calculat-
ed O-C=O+ stretch (~1540 cm-1), and the C-C stretch (~1495
cm-1) modes of the dioxolenium ion, whereas the C=O stretch
vibration of the non-participating acetyl esters are found at
1725-1800 cm-1. The C-6 acetyl C=O stretch (1725 cm-1) is dis-
tinct from the other esters and clearly visible in the meas-
ured IR spectrum. Calculations show that this signature is
lost upon C-6 acetyl participation thereby excluding it (Fig.
S4). Dioxolenium ions resulting from either C-2 (1a) or C-3
(1b) ester participation both produce low energy structures
(Fig. 1). However, when comparing the calculated peaks orig-
inating from the O-C=O+ stretch and C-C stretch vibrations
of the dioxolenium ion (1538 and 1496 cm-1), it is clear that C-
2 participation is in much better agreement with the experi-
mentally observed spectrum (1a, Fig 1A) than C-3 participa-
tion (1b, Fig 1B). Finally, the assignment that the activation of
1 leads to a C-2-dioxolenium ion is consistent with previous
NMR studies.32 Hence, isobaric glycosyl cation fragments can
be distinguished on the basis of their IR spectrum using DFT
calculations.
OAc
OAc
O
OMe
OMe
O
AcO
AcO
MeO
MeO
1
SPh
2
SPh
OMe
O
OMe
O
MeOOC
MeO
MeO
MeOOC
AcO
MeO
SPh
SPh
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Ionization of mannosyl donor 1 was achieved using ESI re-
sulting in the parent ion [M+NH4]+ with a m/z ratio of 458.
Subsequent isolation and CID led to the formation of various
fragment ions, most notably the mannosyl cation with m/z
ratio of 331 (Fig. S1). This fragment ion was isolated in a
quadrupole ion trap30 and subsequently characterized by IR
ion spectroscopy using the FELIX laser operating in the 700-
1850 cm-1 region (for details see SI). The mannosyl cation
derived from 1, produced an IR spectrum containing a wealth
of well-resolved and diagnostic peaks (Fig. 1, black line). To
explore the generality of this approach, gluco- and galacto-
side were also prepared, fragmented and characterized by IR
ion spectroscopy producing similar, yet distinct IR spectra
(Fig. S2).
To obtain structural information on the formed ions, infrared
ion spectroscopy is combined with high level ab initio calcu-
lations.31 Calculated IR spectra from selected low energy
structures were compared with the experimental IR spectra
for structural assignments.
Next, we investigated the characterization of the more chal-
lenging oxocarbenium ion using permethylated mannosyl
donor 2 to limit the possibilities for neighboring group par-
ticipation. ESI of 2 followed by CID resulted in the desired
fragment ion with m/z = 219 (Fig. S5). Subsequent IR ion
spectroscopy yielded an IR spectrum rich in diagnostic peaks
for structural characterization (Fig. 2, black line). DFT calcu-
lations for oxocarbenium ions resulting from 2 yielded two
main structural families which differ in energy by ~13 kJ/mol
(2a and 2b, Fig. 2, color fill). Both structures are oxocarbeni-
um ions, but differ in the conformation of the pyranose ring,
3E (2a) and 4H3 (2b). Most notably, the calculated C=O+
stretch, in 2a and 2b, corresponding to the C-1 oxocarbenium
ion (1609 cm-1) was indeed observed in the measured spec-
trum at 1585 cm-1 (Fig. 2A,B). The lowest energy structure,
Figure 1: Comparison of the calculated spectra (filled) of 2-O-
acetyl- (1a) or 3-O-acetyl- (1b) participation with the meas-
ured IR ion spectrum of mannosyl cation derived from 1
(black line in both panels).
3
the E envelope, displayed the best fit with the observed
spectrum Previous calculations by Whitfield suggested a two
4
3
conformer hypothesis with H3 and E conformations as the
3
lowest energy states.33 The calculated spectra of the E (2a)
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and H3 (2b) conformers are very similar but the additional
peak at 1058 cm-1 (C-3-C-4 and C-2–O-2 stretch) predicted for
Ionization and fragmentation resulted in the corresponding
mannuronyl cations (Fig. S7). Well resolved IR spectra were
obtained displaying distinct diagnostic peaks for permethyl-
ated mannuronic acid 3 (Fig. 3A, black line). DFT-
calculations indicated that participation of the C-6 ester pro-
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3
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the H3 conformer is absent in the measured spectrum (Fig.
2B). In the calculated 3E conformation, the same C-3-C-4 and
C-2–O-2 interactions are calculated at slightly lower wave-
numbers (991 cm-1) and are in better agreement with the
measured spectrum. Together with the fact that the 4H3 has a
vided the lowest energy structure 3a (Fig. 3A, color fill).
3
higher energy, this suggests the E is the preferred conform-
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er. These data indicate that elusive oxocarbenium ions can
be generated and characterized at a highly detailed level us-
ing diagnostic peaks indicative of pyranose conformation.
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The conformational flexibility of glycosyl oxocarbenium ions
is an important factor determining the stereochemical out-
come of a glycosylation reaction. Much effort has been di-
rected to the creation of oxocarbenium ions that display a
well-defined conformation to induce stereoselectivity via the
preferential attack on one diastereotopic face.34 A prime ex-
ample are oxocarbenium ions derived from mannuronic acid
3
esters 3 and 4 which are expected to favor the H4 confor-
mation due to stabilization of the oxocarbenium ion by the
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pseudo axial C-6 carboxylate ester.34-37
.
Subsequent
pseudo axial attack is favorable as it directly leads to the β-
product in the chair conformation. In addition, it is also
known that the α-triflate intermediate contact ion pair is
formed in reactions with 3, leading to the β-product via SN2-
like displacement.39 Hence, to elucidate the solvent separat-
ed ion pair side of this continuum we characterized cations
resulting from the fragmentation of 3 and 4.
Figure 2: Comparison of the calculated spectra (filled) of the
Figure 3: Comparison of calculated spectra (filled) with the
measured IR ion spectra (black line) of mannuronic acids 3a,
4a, 4b (A-C) and a mixture of isomers 4a and 4b (D).
4
3E (2a) or H3 (2b) oxocarbenium ion conformer with the
measured IR ion spectrum of the m/z=219 CID fragment of 2
(black line in both panels). Energies are relative to the 0.0
kJ/mol structure as reported in Fig. S6.
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The measured spectrum is in good agreement with the calcu-
well as additional ESI and CID spectra and DFT calculations
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3
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lated spectrum of this structure. The peak observed at 1637
cm-1 corresponds well with the calculated peak at 1644 cm-1
describing the diagnostic O-C=O+ stretch vibration. The CH
bend modes of the methyl ester located at ~1409-1487 cm-1 in
the stabilized oxocarbenium ion also have clear overlap (3a,
Fig. 3A). Furthermore, the various CH bending modes be-
longing to the methoxy and ring hydrogens were identified
in the calculated spectrum and showed clear overlap with
peaks in the measured spectrum. Isomers in which the C-6
ester does not participate were also considered, however as
the characteristic calculated C=O stretch vibration at ~1800
cm-1 is not observed in the experimental IR spectrum, we can
discard these structures (Fig. S8). Hence, these data strongly
suggest C-6 ester participation upon activation of 3.
in PDF format.
AUTHOR INFORMATION
Corresponding Author
* Dr. A.M. Rijs, a.rijs@science.ru.nl and Dr. T.J. Boltje,
t.boltje@science.ru.nl.
Author Contributions
9
‡HE and MS contributed equally.
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Finally, mannuronic acid ester donor 4 containing a C-4 ester
was investigated. In this case, ester participation from both
diastereotopic faces of the oxocarbenium ion should be pos-
sible. The IR spectra of the isolated ions of 4 were obtained
and yield a well resolved spectrum (Fig. 3B-D, black line).
Initial DFT calculations pointed towards structure 4a result-
ing from C-6 ester participation as observed with 3 (Fig. 3B).
All major calculated peaks such as CH bending, C-6 O-C=O+
stretch and 4-Ac C=O stretch could be assigned and showed
excellent agreement between the experimental- and theoret-
ical IR spectrum (Fig. 3B). However, distinct peaks in the
measured spectrum observed at 1557 cm-1 and 1267 cm-1 were
not accounted for by the calculation. However, the comput-
ed spectrum of isomer 4b with C-4 acetyl participation shows
clear activity at these vibrational frequencies (Fig. 3C). The
most characteristic peak calculated at 1554 cm-1 (4-Ac, O-
C=O+ stretch) is highly diagnostic for C-4 acetyl participation
whereas the peak at 1261 cm-1 (C-6-OMe stretch) belongs to
the non-participating methyl ester. Mixing of the two calcu-
lated spectra belonging to both participation modes (4a and
4b) led to an excellent fit of the observed spectrum (Fig. 3D).
This result highlights the possibility to characterize a mix-
ture of isomers using IR ion spectroscopy thereby providing
crucial insight in the dynamics of glycosyl cations.
This work was supported by an NWO VENI and ERC-Stg
grant awarded to TB and an NWO VICI grant awarded to JO.
Calculations were carried out at the SurfSARA Cartesius clus-
ter under NWO Rekentijd contract 16327. We gratefully
acknowledge the Nederlandse Organisatie voor Weten-
schappelijk Onderzoek (NWO) for the support of the FELIX
Laboratory.
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