The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones

Article abstract of DOI:10.1002/anie.201902507

Uronic acids are important constituents of polysaccharides found on the cell membranes of different organisms. To prepare uronic-acid-containing oligosaccharides, uronic acid 6,3-lactones can be employed as they display a fixed conformation and a unique reactivity and stereoselectivity. Herein, we report a highly β-selective and efficient mannosyl donor based on C-4 acetyl mannuronic acid 6,3-lactone donors. The mechanism of glycosylation is established using a combination of techniques, including infrared ion spectroscopy combined with quantum-chemical calculations and variable-temperature nuclear magnetic resonance (VT NMR) spectroscopy. The role of these intermediates in glycosylation is assayed by varying the activation protocol and acceptor nucleophilicity. The observed trends are analogous to the well-studied 4,6-benzylidene glycosides and may be used to guide the development of next-generation stereoselective glycosyl donors.

Full text of DOI:10.1002/anie.201902507

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Accepted Article
Title: The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones
Authors: Hidde Elferink, Rens Mensink, Wilke Castelijns, Oscar
Jansen, Jeroen Bruekers, Jos Oomens, Jonathan Martens,
Anouk Rijs, and Thomas Boltje
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902507
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The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones
Hidde Elferink‡[a], Rens A. Mensink‡ [a], Wilke W.A. Castelijns[a], Oscar Jansen[a,b], Jeroen P.J.
Bruekers[a], Jonathan Martens[b], Jos Oomens[b], Anouk M. Rijs*[b], Thomas J. Boltje*[a]
and reaction parameters, the mechanism of glycosylation is best
Abstract: Uronic
acids
are
important
constituents
of
described as
a continuum between SN1-like and SN2-like
polysaccharides found on the cell membranes of different organisms.
To prepare uronic acid containing oligosaccharides, uronic acid 6,3-
lactones can be employed as they display a fixed conformation and
a unique reactivity and stereoselectivity. Herein we report a highly β-
selective and efficient mannosyl donor based on C-4 acetyl
mannuronic acid 6,3-lactone donors. The mechanism of
glycosylation is established using a combination of techniques
including IR ion spectroscopy combined with quantum-chemical
calculations and variable-temperature nuclear magnetic resonance
(VT NMR) spectroscopy. The role of these intermediates in
glycosylation is assayed by varying the activation protocol and
acceptor nucleophilicity. The observed trends show analogy to the
well-studied 4,6-benzylidene glycosides and may be used to guide
the development of next-generation stereoselective glycosyl donors.
reaction pathways.[2]
Stereocontrol in a glycosylation reaction is difficult to achieve
due to two main factors. First, SN1-like and SN2-like pathways
leading to opposing diastereomers may be simultaneously
operative. Secondly, the SN1-like pathway may not be
stereoselective. In order to obtain stereoselective glycosylations,
it is therefore essential to ensure that either the reaction takes
place via one stereoselective pathway (SN1-like or SN2-like), or
that both pathways lead to the same stereoisomer. In some
cases, this can be achieved by the introduction of a bicyclic
protecting group on the glycosyl donor.[3] Recently, we reported
the use of mannuronic acid 6,3-lactones as glycosyl donors (1)
and found them to be highly β-selective (Scheme 1).[4] The
lactone bridge presumably leads to a β-selective oxocarbenium
ion conformer 5, but also allows for remote participation of the
C-4 benzyl ether (4) as evidenced by the formation of a 1,4-
anhydrosugar byproduct (Scheme 1). These results contrast
those reported for galacturonic acid 6,3-lactone 3, which is
The main challenge in the chemical preparation of
oligosaccharides is the stereoselective synthesis of glycosidic
bonds, which can exist as α- or β-diastereomers.[1] The
glycosylation reaction is a nucleophilic substitution reaction
between an electrophilic glycosyl donor carrying an anomeric
leaving group and a glycosyl acceptor containing a nucleophilic
alcohol. Depending on the nature of the glycosyl donor, acceptor
highly α-selective.[5] In this case, reaction of
intermediate via an SN2-like pathway is presumably
responsible for the α-selectivity.
a β-triflate
6
Scheme 1: Proposed glycosylation intermediates of uronic acid 6,3-lactone glycosyl donors (1-3). LG: Leaving Group
[a]
Radboud University, Institute for Molecules and Materials Heyendaalseweg 135, 6525 AJ, Nijmegen, (The Netherlands) E-mail: t.boltje@science.ru.nl
Radboud University, Institute for Molecules and Materials, FELIX laboratory, Toernooiveld 7c, 6525 ED, Nijmegen (The Netherlands), Email:
a.rijs@science.ru.nl
[b]
‡
These authors contributed equally
Supporting information for this article is given via a link at the end of the document.
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OH
Herein, we report the development of a mannuronic acid 6,3-
lactone donor carrying a C-4 acyl group. This donor does not
suffer from byproduct formation, whilst still providing good β-
selectivity. A systematic study of the glycosylation mechanism of
uronic acid 6,3-lactones was performed to explain the difference
in stereoselectivity and reactivity between manno-, gluco- and
galacto-configured donors. To this end, reactive intermediates
were characterized using infrared (IR) ion spectroscopy, which
provided evidence for remote C-4 acyl participation in the gas
phase. Furthermore, glycosyl triflate intermediates were
characterized using variable temperature (VT) NMR
experiments. Finally, the reactivity of the intermediates was
profiled by varying acceptor nucleophilicity. Clear trends
emerged that are analogous to those found in other bicyclic
donor systems, such as 4,6-benzylidene protected manno- and
glucosides.[6] These findings may provide clear directions for
designing next-generation stereoselective glycosyl donors.
AcOH
H2O
OBn
O
OBn
Ph
O
O
HO
O
NapO
NapO
88%
SPh
SPh
14
15
TEMPO
BAIB
64%
O
Ac2O
Pyr
OBn
O
HOOC
HO
RO
O
SPh
OBn
O
87%
OAc
SPh
DDQ
DCM/H2O
70%
16: R = Nap
17: R = H
12
Scheme 2: Key steps in the C-4 acetyl 6,3-uronic acid lactone donor-
synthesis. Manno-type donor 4 is shown as an example.
equatorially and afforded the α-galactoside with excellent stereo-
selectivity (α/β = 20/1, Table 1, entry 5) in line with earlier
reports.[5, 7] Glycosylation of 9 using the N-iodosuccinimide (NIS)
/AgOTf promoter system under premix conditions led to an
Our previous studies utilized carboxybenzyl (CB) donors which
require pre-activation; therefore, we prepared thioglycoside
derivatives 9[3b]
,
10[7] and 11[8] to investigate whether
glycosylations under standard (premix) conditions would prevent
1,4-anhydrosugar formation. Glycosylation of 9-10 by pre-
activation with Ph2SO/Tf2O[9] followed by addition of glycosyl
acceptor 7 (Table 1, entry 1,3 and 5) mainly led to 1,4-
anhydrosugar as expected.[4, 10] Galactoside 11 does not suffer
from 1,4-anhydrosugar formation as the C-4 benzyl is positioned
improved yield of the β-disaccharide (22%), although
a
significant amount of 1,4-anhydro sugar was still formed (Table
1, entry 2).[11] In case of gluco-lactone 10, exclusive formation of
the 1,4-anhydrosugar was observed under the same conditions.
Galactoside 11 provided a much lower α-selectivity under pre-
mix conditions as the β-triflate intermediate was not pre-formed.
Table 2: Glycosylation of donors 9-13
To prevent 1,4-anhydrosugar formation while retaining the
stereo-directing capability of the C-4 substituent, we focused on
the introduction of a C-4 acetyl ester.[12] The synthesis of manno-
type C-4 acetyl donors 12 started from known 4,6-benzylidene
protected precursor 14 (Scheme 2).[13] Acidic hydrolysis of the
4,6-benzylidene and subsequent oxidation using TEMPO/BAIB[7,
14] afforded uronic acid 16 in good yield. DDQ oxidation of the 2-
methylnaphthyl (Nap) ether afforded the corresponding C-3
alcohol (17), which was lactonized using acetic anhydride.[15]
Under the same conditions, the C-4 alcohol was acetylated
affording the desired uronic acid 6,3-lactone donor 12 in good
yields. Gluco-type donor 13 was prepared using an analogous
procedure (see supporting information). Notably, the oxidation of
a 3,4,6-triol precursor to afford 6,3-uronic acid lactones directly
was also successfully explored based on Stahl’s procedure for
lactonization (see supporting information, scheme S2, S47).[3d, 16]
Though with a modest yield (19%), this procedure potentially
provides access to 12 and 13 and its 4-OH derivatives.
Next, the reactivity and stereoselectivity of donors 12 and 13
was explored (Table 1, entry 7-10). Activation was achieved
under premixed conditions with NIS/AgOTf at -10oC. With
acceptors 7-8, both donors gave the corresponding
disaccharides in a good yield using only a small excess of the
donors, showing that the introduction of the C-4 acetyl group
prevented byproduct formation as intended. Mannose donor 12
showed excellent β-selectivity (α/β = 1/20), whereas glucose
donor 13 formed mostly the β-product, albeit with modest
selectivity (α/β = 1/2.5).
[a]
[b]
Isolated yield of the disaccharide as a mixture of α/β anomers,
ratios were determined in the crude reaction mixture using key integrals
in 1H-NMR spectra. Protocols: Ph2SO, Tf2O, TTBP, DCM, -78oC then 7,
or 10/11, NIS, DCM AgOTf (cat), -10oC.
To obtain insight in the different stereochemical preference of
donors 12 and 13, we characterized the intermediates likely
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responsible for their SN2-like and SN1-like pathways. Solvent
separated ion pairs (SSIP) such as 4 and 5 are believed to
define the SN1-like pathway and are challenging to characterize
due to their intrinsic high reactivity, short life-times and
equilibrium with the glycosyl triflate 6. Recently, we reported the
use of collision-induced dissociation tandem mass spectrometry
(CID MS/MS) in combination with IR ion-spectroscopy to
characterize these elusive glycosyl cations.[17] Electrospray
ionization (ESI) of thioglycoside donors was employed to form
removing overlap in fragmentation pathways (Figure S7, B and
S9, B). Fragment ions of 18 and 20 were mass-isolated in a
quadrupole ion trap[19] and subsequently characterized by IR ion-
spectroscopy using the FELIX IR free electron laser (IR-FEL)
operating in the 700-2100 cm-1 region (for details see supporting
information S70).
The experimental IR spectra resulting from the cations of
lactones 18 and 20 show best agreement with the calculated
spectra of the oxocarbenium ions in the 4E conformation (Figure
the precursor ions, which were subsequently fragmented by CID, 1, A and B). Interestingly, in both cases the best-match structure
giving the desired glycosyl cations. Spectral assignments were
made by comparing the experimental IR spectra with theoretical
IR spectra obtained by high level ab initio calculations.[18] Using
this technique, glycosyl cations derived from glycosyl donors 9,
10, 12 and 13 were structurally characterized by IR ion
spectroscopy in the gas phase. To simplify the IR spectra, the
does not correspond with the lowest-energy structure, which
involves participation of the 4-OMe and is favored by 7.7 kJ/mol
and 16.7 kJ/mol in mannuronic acid lactone 19 and glucuronic
acid lactone 21, respectively. Nonetheless, the E conformation
4
places the C-4 substituent in pseudo-axial position enabling its
remote participation.
benzyl ethers were replaced by methyl ethers (18, 20, 22 and 24, In contrast, the IR spectra of lactones 22 and 24 can be
see SI p18-22 for preparation details).
assigned to conformers that result from C-4 acetyl participation,
which also represent the lowest-energy structures (Figure 1, C
and D). Characteristic bands in the measured spectrum of 23
and 25 at 1550 and 1430 cm-1 are in good agreement with the
calculated O–C═O+ stretch of the dioxolenium ion and the C4-H4
bending mode, respectively (filled). In addition, the presence of
only one C=O stretch mode at 1846 cm-1 (23) and 1851 cm-1
(25), respectively, rules out the oxocarbenium ion and supports
the involvement of the 4-OAc. For the methylated as well as for
the acetylated species, no clear differences between mannose
The desired fragment cations at m/z 187 were formed from
protonated methyl ether analogues of lactones 12 and 13 via
tandem mass spectrometry. Upon close inspection, a fragment
resulting from another fragmentation pathway appeared in the
same m/z 187 mass channel. (see Figure S7, A and S9, A). To
favor oxocarbenium ion formation, the anomeric thioglycosides
were oxidized to sulfoxides 18 and 20. Additionally, the oxidation
induced an m/z difference of 16 in the parent ion, thereby
Figure 1: Comparison of the calculated spectra (filled) with the measured spectra of generated 6,3-uronic acid lactone cations 19 (A), 21 (B), 23 (C) and 25 (D). Energies
in A and B are relative to the 0.0 kJ/mol structure as reported in figure S8 and S10, respectively.
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Table 3: Key-glycosylations to elucidate the mechanism driving the
stereoselectivity in 6,3-uronic acid lactone donors 4 and 5
and glucose are observed in the structures of the glycosyl
cations formed.
This may suggest that their SN1-like pathways are likely very
similar and that both the manno- and gluco-type 6,3-uronic acid
lactones to be intrinsically β-selective in SN1-like pathways. It
should be noted however, that the structure of the glycosyl
cations 19, 21, 23 and 25 were determined in the gas phase and
may differ from those formed in solution.
Next, we set out to characterize the contact-ion pair
intermediates in solution by VT-NMR[20]. To this end, we
prepared glycosyl sulfoxides 26 and 27 by oxidation of donors
12 and 13 with m-CPBA. 26 and 27 were activated at low
temperature (-78oC) with Tf2O in presence of TTBP in CD2Cl2
and characterized by VT-NMR. Interestingly, in both cases, the
formation of the β-triflate (28 and 29) as the major species was
observed and confirmed by 2D-HOESY NMR (Figure 2). Both
samples were allowed to warm up and showed disappearance
of the triflate at -10oC (Figure S2) and -4oC (Figure S4) for
mannose 28 and glucose 29, respectively. No α-triflate was
observed during the experiments. The stability of the β-triflates
may result from the electron withdrawing effect of the C-4 acetyl
[a]
[b]
Isolated yield of the disaccharide as a mixture of α/β anomers, ratios
were determined in the crude reaction mixture using key integrals in 1H-
NMR spectra. Protocols: Ph2SO, Tf2O, TTBP, DCM, -78oC then 7/allylTMS,
or 10/11, NIS, DCM AgOTf (cat), -10oC.
as well as the constrained 6,3-lactone bridge[21]
. A VT-
experiment to trap the participating acyl group[22] using a C-4
Boc derivative of 12 showed initial β-triflate formation leading to
a complex mixture which upon work-up converted to the 1,4-
anhydro-byproduct instead of the expected cyclic carbonate (see
supporting information, fig. S5-S7).
determine the difference in reactivity, a number of glycosylations
were performed thereby varying the activation protocol and
acceptor nucleophilicity[23] (See Table 2). First, donors 12 and 13
were pre-activated with Ph2SO and Tf2O at -60oC to allow for β-
triflate formation. After full activation, acceptor 7 was added and
the mixtures were allowed to slowly warm up. Mannosyl donor
12 retained almost full β-selectivity (Table 2, entry 2) indicating
that the glycosylation does not take place via SN2-like
displacement of the β-triflate, but rather via an alternative
pathway. In contrast, glycosylation of glucosyl donor 13 under
pre-activation conditions showed good α-selectivity (Table 2,
entry 5) suggesting significant reaction via the β-triflate
intermediate similar to galactosyl donor 11 (Table 1, entry 5).To
confirm the latter result, glycosylations with allyl-TMS as a
nucleophile under pre-activation conditions were performed.
Glycosylations with allyl-TMS are irreversible, their steric effects
are minimized and its weaker nucleophilicity minimizes reaction
via an SN2-like pathway[24]. In these cases, both mannosyl and
glucosyl donors displayed high β-selectivity, indicating that their
SN1-like pathways lead to the same diastereomer (Table 2, entry
3 and 6 respectively). Apart from the C-2 stereochemistry,
mannosyl and glucosyl donor 12 and 13 also differ in the
stereochemistry of the leaving group. We synthesized the α-SPh
glucosyl donor 30 to explore the impact of leaving group
orientation (see SI). Glycosylation under premix conditions gave
a good yield and showed slight α-selectivity (Table 2, entry 7).
We hypothesize that activation of the α-leaving group may lead
to more rapid β-triflate formation, which can be displaced by the
acceptor.
As both mannoside 12 and glucoside 13 give rise to the same
reactive intermediates for the SN1-like and SN2-like pathways,
the observed difference in stereoselectivity is likely a result of
different reactivities of the respective intermediates. To
Figure 2: Characterization of glycosyl triflates 28 and 29 at -60 oC in CD2Cl2
by VT-NMR.
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involved in the SN1-like pathways and were characterized using
IR ion spectroscopy in the gas phase. Glycosyl triflate
intermediates likely involved in the SN2-like pathways were
characterized using VT-NMR. The involvement of these
intermediates in glycosylation was assayed by varying the
activation protocol and acceptor nucleophilicity. The observed
trends showed analogy to the well-studied 4,6-benzylidene
glycosides and we believe that these guidelines will enable the
design of the next generation of stereoselective glycosyl donors.
Acknowledgements
We would like to acknowledge dr. P.B. White for his help with
the VT-NMR experiments and dr. G. Berden for his support with
the IRMPD experiments. We gratefully acknowledge the
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
(NWO) for the support of the FELIX Laboratory. Calculations
were carried out at the SurfSARA Cartesius cluster under NWO
Rekentijd contract 16327. This work was supported by a ERC-
STG (758913) grant awarded to TJB.
Figure 3: Observed trends in fixed bicyclic glycosyl donor systems. 7 is used
as example for ROH. Selected examples in case of the 4,6-benzylidene
glycosides for ROH and allyl-TMS are reffered to accordingly.
Keywords: Glycosylation • Uronic acids • IR ion spectroscopy •
Oxocarbenium ion •
Overall, these results indicate that the reaction intermediates of
both the SN-1 and SN-2-like pathways for 12 and 13 are
expected to lead to opposing diastereomers (α- and β-
glycosides, respectively). However, the relative reactivity of the
reaction intermediates differs and results in contrasting overall
stereo-selectivity. In this respect, glycosylations with uronic acid
6,3-lactones 12 and 13 show a profound analogy with β-
selective mannosylations utilizing 4,6-benzylidene mannosyl
donors, developed by Crich and coworkers (Figure 3).[6, 25] Both
are bicyclic systems that stabilize the formation of glycosyl
triflates[26] as well as defined glycosyl cation intermediates.[27]
SN2-like pathways are expected to occur via glycosyl triflates 28,
29, 31[26] and 33[28] and SN1-like reactions are likely to proceed
via glycosyl cations 23, 25, 32[27] and 34.[27, 29] The axial triflates
of both systems show a comparable trend in reactivity and can
be related to the orientation of the C-2 substituent. Both
mannoside 31 and glucoside 28 have a ∆-2 effect[30] caused by a
neighboring axial C-2 substituent. Both triflate species are
reactive in SN2-like pathways and yield β- and α-glycosides with
strong nucleophiles, respectively. Counterparts 33 and 28
lacking a ∆-2 effect both lead to triflate species that do not
participate in the glycosylation event and selectivity likely arises
from alternative pathways. SN1-like reactions via glycosyl cations
34[29] and 23 would be expected to lead to the observed α- and
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established using a combination of analytical techniques and
glycosylation experiments. Glycosyl cation intermediates likely
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10.1002/anie.201902507
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
A
new
type
of
β-selective
Hidde Elferink, Rens A. Mensink, Wilke
W.A. Castelijns, Oscar Jansen, Jeroen
P.J. Bruekers, Jonathan Martens, Jos
Oomens, Anouk M. Rijs*, Thomas J.
Boltje*
mannosylation donors was developed
and its glycosylation mechanism was
elucidated
approach
using
an
integrated
IR ion
combining
spectroscopy and VT NMR.
Page No. – Page No.
The Glycosylation Mechanisms of
6,3-Uronic Acid Lactones
This article is protected by copyright. All rights reserved.