Glycosylation intermediates studied using low temperature 1H- and 19F-DOSY NMR: New insight into the activation of trichloroacetimidates

Article abstract of DOI:10.1039/c6cc05272j

Low temperature ¹H- and ¹⁹F-DOSY have been used for analyzing reactive intermediates in glycosylation reactions, where a glycosyl trichloroacetimidate donor has been activated using different catalysts. The DOSY protocols have been optimized for low temperature experiments and provided new insight into acid catalyzed glycosylation chemistry. From the study a new glycosylation intermediate was characterized.

Full text of DOI:10.1039/c6cc05272j

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Glycosylation intermediates studied using low
1
19
temperature H- and F-DOSY NMR: new insight
Cite this:DOI: 10.1039/c6cc05272j
into the activation of trichloroacetimidates†
Received 4th July 2016,
Accepted 23rd August 2016
Yan Qiao,ab Wenzhi Ge,a Lingyu Jia,b Xianglin Hou,b Yingxiong Wang*b and
Christian M. Pedersen*c
DOI: 10.1039/c6cc05272j
www.rsc.org/chemcomm
Low temperature 1H- and 19F-DOSY have been used for analyzing about the intermediates formed and to separate them in order
reactive intermediates in glycosylation reactions, where a glycosyl to analyze and to get information about both the relative
trichloroacetimidate donor has been activated using different catalysts. amount and the number of intermediates we have studied
The DOSY protocols have been optimized for low temperature experi- the use of 1H- and 19F diffusion ordered NMR spectroscopy
ments and provided new insight into acid catalyzed glycosylation (DOSY) at low temperature.
chemistry. From the study a new glycosylation intermediate was
characterized.
Measurements of molecular diffusion by NMR have been
carried out since the eighties, but only in recent years has it been
part of the routine experiments provided by NMR-manufacturers.
The mechanism of the glycosylation reaction is central to The diffusion is dependent on the molecular size, shape and
carbohydrate chemistry.1 As the reactions often are complex whether the molecule is non-covalently interacting with other
mixtures containing excess amounts of promoters and additives, species.6 The relationship between molecular size and diffusion
such as acid scavengers, drying agents and acceptors, intermediates coefficient has been used by several groups to estimate the
are notoriously difficult to analyze and impossible to isolate.2 molecular weights of intermediates7 and complexes8 by the use
Half a century ago NMR spectroscopy became available and was of internal reference compounds. This approach has been applied
1
immediately applied to study carbohydrates and soon also mainly to H-DOSY, but also 19F-DOSY studying Brønsted acid–
reactive intermediates at low temperature.3 The study of glyco- base complexes.9 We envisaged that a combination of 1H- and
sylation reactions with low temperature NMR has recently 19F-DOSY could provide information about the intermediates
experienced a renaissance, where especially the Crich group formed under the catalytic activation of trichloroacetimidate
has used it extensively to study reactive intermediates, such (TCA) donors. The most used catalysts, i.e. trimethylsilyl trifluoro-
as glycosyl triflates, and on this basis suggested mechanisms sulfonate (TMSOTf) or BF3ÁOEt2, contain fluorine, whereas the TCA
e.g. for b-mannosylation.4 The work by Crich and others3 in donors do normally not. By using this double determination,
combination with better hardware and software has made this i.e. 1H- and 19F-DOSY, it should be possible to distinguish between
technology accessible and doable for most research groups. The intermediates having the catalyst bound or not.
culmination of this development has recently led to the first
Trichloroacetimidates (TCAs) are one of the most commonly
observation of a carbohydrate oxocarbenium ion by NMR.5 used glycosyl donor types due to its simplicity and catalytic
Despite the advances in NMR resolution one major obstacle activation.10 It has therefore been studied using VT-NMR to
remains, i.e. the highly complex spectra contain several carbo- elaborate the influence of additive,11 intermolecular participation12
hydrate derived compounds and it is therefore tedious if not and it has been used as a source of glycosyl triflates (as B in Fig. 1)13
impossible to analyze the data fully. To get more information by using TMSOTf or similar reagents in equivalent amounts.
Despite its excessive use, the mechanism of the activation of TCA
has only been sparsely investigated and only little is known
about the reaction mechanism. It has commonly been illustrated
that the Lewis (or Bronsted) acid reacts with the nitrogen atom in
the trichloroacetimidate (like A in Fig. 1). This activates the TCA
group and results in the formation of an oxocarbenium ion
intermediate (C in Fig. 1) followed by the attack by the nucleo-
phile (acceptor); commonly a hydroxyl group, i.e. an SN1 type of
reaction. (Fig. 1, C).14 Recent studies by Peng and Schmidt have
a Analytical Instrumentation Center & State Key Laboratory of Coal Conversion,
Institute of Coal Chemistry, Chinese Academy of Sciences,
27 South Taoyuan Road, Taiyuan 030001, People’s Republic of China
b Shanxi Engineering Research Center of Biorefinery, Institute of Coal Chemistry,
Chinese Academy of Sciences, 27 South Taoyuan Road, Taiyuan 030001,
People’s Republic of China
c Department of Chemistry, University of Copenhagen, Universitetsparken 5,
DK-2100 Copenhagen, Denmark. E-mail: cmp@chem.ku.dk
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6cc05272j
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formed as expected from the examples in the literature
(Scheme 1).13 The stereochemistry was confirmed by the small
3J1–2 (3 Hz) coupling constant, which is unambiguous for
4
a-D-glucosides in the C1 conformation. When using 0.3 equiv.
TMSOTf it was found that the donor reacted in a 1 : 1 ratio
and hence did not undergo a catalytic transformation in the
absence of an acceptor (see the ESI†). Due to the equal size of
the donor and the product, these could not be clearly separated
1
by DOSY, but from the comparison of H- and 19F-DOSY it was
clear that the triflate group indeed was attached to the sugar
moiety (19F-DOSY), whereas the TMS group was not (1H-DOSY).
This confirms the formation of glucosyl triflate 2. Upon addi-
tion of equivalent amounts or excess of the catalyst full trans-
formation to the a-triflate was observed. In time an additional
product was formed under the reaction conditions at À55 1C.
This product was assigned to be the corresponding trichloro-
acetamide 3. The ratio between triflate 2 and amide 3 remained
stable until À5 1C. Between À5 1C and 5 1C the signals
corresponding to the a-triflate disappeared completely. When
a sub-stoichiometric amount (B50%) of BF3ÁOEt2 was added to
model donor 1 in CD2Cl2, the TCA was only consumed according
to the amount of catalyst added (approx. 40%) and hence there
was no catalytic transformation. Two new products appeared with
anomeric signals between 5 and 6 ppm. From the unusual
coupling pattern it could be confirmed that the a- and b-glucosyl
fluorides 4ab had been formed.21 19F-NMR gave rise to three new
major peaks, where 19F-DOSY confirmed that two of them had
similar diffusion coefficients and were connected to the sugar
moiety (similar diffusion coefficients based on 1H-DOSY and
Fig. 1 Activation of the TCA donor with an electrophilic catalyst. Three
different modes of activation. (A) Direct activation forming an activated
donor, without departure of the acetimidate (not observed). (B) Exchange
of the activated TCA by the counter ion (observed by NMR). (C) Formation
of an oxacarbenium ion (not observed).
shown that such deduction might not always be the scenario,
and that the catalyst in some cases could be activated by forming
a nucleophile–catalyst complex (similar to A in Fig. 1).15
As a model donor for our NMR study, 2-O-benzyl-3,4,6-tri-O-
acetyl a-D-glucopyranosyl trichloroacetimidate 116 was chosen.
It has a commonly used protective group pattern consisting of
benzyl and acetyl groups. The 2-O-benzyl group was required in
order to avoid neighboring group participation, which would
give a dioxolonium ion, which is well known and has been
thoroughly studied for 2-O-acetyl groups.17 The remaining
hydroxyl groups are acetylated, which reduces the donor reactivity
and could thereby increase the lifetime of the glycosylation
intermediate (not an oxocarbenium ion).18 Glycosylation reactions
with trichloroacetimidates are most often catalyzed by TMSOTf
or BF3ÁOEt2 and these catalysts were therefore the starting point
for the study.19
As a standardized condition the donor was dissolved in
CD2Cl2 (conc.: 0.04 M20) together with Tris-(trifluoromethyl)-
benzene as the internal 19F-reference compound. In the initial
studies the decomposition temperature, i.e. when the reactive
intermediates disappeared to give a stable product, was deter-
mined using the different catalysts. On this basis it was decided
to initiate the reactions at À55 1C using different amounts of the
catalyst first in sub-stoichiometric amounts, then in equivalent
and finally in excess. The different conditions were analyzed using
low temperature NMR. The catalysts were additionally analyzed
under the same conditions but independently, i.e. without donor
presence, to give reference spectra and to check whether they
aggregated at low temperature.
1
hence similar size). The H-DOSY confirms the existence of two
new sugar species with very similar diffusion coefficients and
that the signals of diethyl ether (from BF3ÁOEt2) are not
associated with the sugar. Adding additionally 0.7 equiv. of
BF3ÁOEt2 resulted in approx. 65% conversion of the TCA, which
remained a stable ratio – the donor is not fully consumed even
after adding more than 1 equiv. catalyst. The resulting mixture
of glucosyl fluorides 4ab and donor 1 remained stable for 47 h
at À55 1C. Increasing the temperature stepwise (10 1C steps)
resulted in a slow disappearance of the b-fluoride and at À15 1C
mainly the a-anomer could be observed. Re-cooling did not
change the composition of the sample.
From the results using TMSOTf or BF3ÁOEt2, it was clear that
the activation mode of the trichloroacetimidate depends on the
catalyst and in particular its counter ion. When this is a triflate
ion a clean conversion to the a-glucosyl triflate 2 was observed;
but what if the counter ion is less nucleophilic? Would it then
be possible to avoid substitution of the activated trichloroace-
The first activation of the TCA-donor using TMSOTf was
carried out, and a-triflate 2 was found to be the main product
timidate and instead observe an activated complex? To study this
22,23
hypothesis TMSNTf2
as a catalyst was investigated, since it
has been found to be more Lewis acidic than TMSOTf,24 but with
a less nucleophilic counter ion.25 To our surprise the NMR, of
the catalyst alone at À55 1C revealed 2 peaks in 1H- and 19F-NMR
and therefore the existence of 2 compounds (Scheme 2). Upon
increasing the temperature to 20 1C one broad signal was
observed and hence the compounds are in a slow equilibrium;
presumable as the mono- and dimer. This was further supported
Scheme 1 Activation of the TCA donor using TMSOTf or BF3ÁOEt2.
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(3J are large (B9 Hz), COSY, HSQC, NOESY). Two different
TMS signals were observed – one attached to the sugar (DOSY)
and one from TMS2O (from the side reaction with trace amounts
of water). 19F-NMR showed 3 peaks, which were significantly
different from the ones observed for the catalyst alone and its
reaction with methanol, i.e. suggesting some interaction with the
sugar, however not tightly associated (DOSY), but rather as an ion
pair. TMS-activated TCA donor 6 was found to be more labile that
the corresponding triflate 2 and even at À55 1C a slow degrada-
tion took place. Upon increasing the temperature to À20 1C
resulted in full conversion into the Friedel–Crafts product 7
(determined from the crude NMR and confirmed by HRMS),
but not trichloroacetamide 3, which is in contrast to when using
TMSOTf. As far as it comes to our knowledge this is the first
example of observing the activated complex of a trichloro-
acetimidate donor.26 The formation of this intermediate, when
having a less nucleophile catalyst counter ion support that
the triflate ion can act as a nucleophilic catalyst, whereas the
triflylimide cannot to the same extent.28
The diffusion coefficients obtained are related to the size
and shape of the molecules6 and as all compounds share the
sugar moiety it was assumed that the main difference would be
related to the molecular weight (MW) of the glycosyl donor and
the intermediates. An estimation of MW by DOSY27 could shine
light on the composition of the intermediates and other active
species in the reaction mixture. Several methods have been
developed for the determination of MW by DOSY. Normally
these involve the use of a set of internal reference compounds.
Due to the complexity and number of signals a recent published
procedure involving external calibration curves and only one
internal reference caught our interest.29 As the compounds in
our study are larger and the solvent is CD2Cl2 a new calibration
curve was prepared. A number of reference compounds with a
similar three-dimensional structure were chosen and their diffu-
sion coefficients determined in the presence of one internal
reference – 1,3,5-tris(trifluoromethyl)benzene, which can be used
as a reference in both 1H- and 19F-DOSY. For the 1H-DOSY
calibration curve, carbohydrate based structures were preferred,
and masses in the range from 74 to 1226 were included
(6 compounds, see the ESI† for details). For 19F-DOSY the avail-
able carbohydrate based compounds were limited and only one,
i.e. 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl fluoride, was part of
the calibration curve (see the ESI† for details). With the calibration
curves in hand the DOSY experiments were repeated to estimate
the MW of the formed intermediates. Excess of the catalysts were
used in order to ensure the formation of mainly one compound
and the temperature was kept at À55 1C.
Scheme 2 Reaction of Tf2NTMS with a model acceptor – MeOH. When
present in sub-stoichiometric amounts different complexes are formed.
by increasing the concentration of the catalyst by a factor 5,
which increases the amount of the proposed dimer in the
sample (Scheme 2). Adding a sub-stoichiometric amount of
MeOH (model acceptor) to the catalyst at À55 1C immediately
resulted in the disappearance of the peak from the dimer
1
(in H- and 19F-NMR) and the formation of a new peak assigned
to [MeOH–TMS]+ appeared. The addition of more MeOH resulted
in full conversion (Scheme 2). MeOH seems to catalyze the
monomerization.
When TMSNTf2 was added (0.3 equiv.) to model donor 1 at
À55 1C no dimer was detected and the signal from trichloro-
acetimidate 1 disappeared rapidly (Scheme 3), which is in
contrast to the same conditions using TMSOTf as the catalyst,
where a one to one reaction took place. 1H-NMR showed a
mixture of at least two compounds and 19F-NMR showed three
1
peaks. H-DOSY of the mixture confirmed the presence of two
sugar based compounds with a small difference in diffusion
1
coefficient and hence size. From H-DOSY it is, however, clear
that the TMS group from the catalyst is covalently attached to
the sugar in contrast to when using TMSOTf. 19F-DOSY does
not indicate that the sugar and ÀNTf2 are closely associated and
a covalent bond between them can therefore be excluded. Upon
the addition of equivalent amounts or excess of the catalyst the
donor was immediately transformed and 4 broad peaks, between
1
5.5 and 6.5 ppm, appeared in H-NMR (presumable N-H). After
10 min, the mixture equilibrated into mainly one compound with
1
no visible N-H signals. This compound was analyzed by H, 19F,
COSY, HSQC Ed, 1H-DOSY, 19F-DOSY, NOESY and N-H-HSQC.
The signals from the sugar-part could all be assigned and a chair
conformation with an equatorial C1-substituent confirmed
From the initial NMR studies and DOSY experiments good
evidence for the structures of the intermediates formed had
been obtained and hence their molecular weights (MW) could
be predicted and compared with calculated values based on the
calibration curve and the internal reference compound (Table 1).
Estimation of MWs from the calibration curves gave a good
estimation for the intermediates formed when using BF3ÁOEt2
and Tf2NTMS as the catalysts. The deviation is within 10%
and the predicted MW is in-between the results from the two
Scheme 3 Activation of TCA donor 1 with Tf2NTMS. The counter ion
Tf2NÀ is not nucleophilic enough to substitute the activated TCA, which
instead anomerizes in time and eventually decompose to 7.
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Table 1 MW determination by 1H- and 19F-DOSY measurements
9 H. Subramanian, C. P. Jasperse and M. P. Sibi, Org. Lett., 2015, 17, 1429.
10 (a) R. R. Schmidt and J. Michel, Angew. Chem., Int. Ed., 1980, 19,
731–733; (b) Reviewed in: X. Zhu and R. R. Schmidt, in Handbook of
Chemical Glycosylation, ed. A. V. Demchenko, Wiley-VCH, Weinheim,
2008, pp. 143–185.
b
MW [g molÀ1
]
DMW [%]
cal
a
Catalysts MW
[g molÀ1 1H-DOSY 19F-DOSY 1H-DOSY 19F-DOSY
]
pre
11 (a) S. R. Lu, Y. H. Lai, J. H. Chen, C. Y. Liu and K. K. T. Mong, Angew.
Chem., Int. Ed., 2011, 50, 7315; (b) Y. H. Lin, B. Ghosh and
K. K. T. Mong, Chem. Commun., 2012, 48, 10910; (c) A. B. Ingle,
C. S. Chao, W. C. Hung and K. K. T. Mong, Org. Lett., 2013, 15, 5290.
12 (a) J. H. Kim, H. Yang, J. Park and G. J. Boons, J. Am. Chem. Soc.,
2005, 127, 12090; (b) T. J. Boltje, J. H. Kim, J. Park and G. J. Boons,
Org. Lett., 2011, 13, 284; (c) T. Fang, K. F. Mo and G. J. Boons, J. Am.
Chem. Soc., 2012, 134, 7545; (d) D. J. Cox, G. P. Singh, A. J. A. Watson
and A. J. Fairbanks, Eur. J. Org. Chem., 2014, 4624.
13 (a) J. Y. Baek, B. Y. Lee, M. G. Jo and K. S. Kim, J. Am. Chem. Soc.,
2009, 131, 17705; (b) A. Rencurosi, L. Lay, G. Russo, E. Caneva and
L. Poletti, Carbohydr. Res., 2006, 341, 903; (c) J. Park, S. Kawatkar,
J. H. Kim and G. J. Boons, Org. Lett., 2007, 9, 1959.
14 See for an example: G.-J. Boons and K. J. Hale, Organic Synthesis with
Carbohydrates, Sheffield Academic Press Ltc, 2000, p. 108.
15 P. Peng and R. R. Schmidt, J. Am. Chem. Soc., 2015, 137, 12653.
16 (a) N. J. Davis and S. L. Flitsch, J. Chem. Soc., Perkin Trans. 1, 1994,
359–368; (b) N. C. R. van Straten, G. A. van der Marel and J. H. van
Boom, Tetrahedron, 1997, 53, 6523.
17 (a) Generally: S. Winstein and R. E. Buckles, J. Am. Chem. Soc., 1942,
64, 2780; (b) Early examples in carbohydrate chemistry have been
summarized in: R. U. Lemieux, Adv. Carbohydr. Chem., 1954, 9, 1.
18 (a) M. N. Kamat and A. V. Demchenko, Org. Lett., 2005, 7, 3215;
A 2-O-acetyl can, besides controlling the selectivity also increase the
reactivity, when anchimeric assistance is possible: (b) D. Crich and
M. Li, Org. Lett., 2007, 9, 4115; (c) M. Heuckendorff, C. M. Pedersen
and M. Bols, Org. Lett., 2011, 13, 5956.
19 (a) R. R. Schmidt and K.-H. Jung, in Preparative Carbohydrate Chemistry,
ed. S. Hanessian, Marcel Dekker, New York, 1997, pp. 283–312;
(b) X. Zhu and R. R. Schmidt, in Handbook of Chemical Glycosylation,
ed. A. V. Demchenko, Wiley VCH, Weinheim, 2008, p. 143.
20 The concentration was optimized for the DOSY experiments.
21 Glycosyl fluorides have earlier been observed in glycosylations using
trichloroacetimidate donors in combination with BF3ÁOEt2. See:
H. M. Christensen, S. Oscarson and H. H. Jensen, Carbohydr. Res.,
2015, 408, 51.
22 TMSNTf2 has been used to catalyze the glycosylation using per-
methacrylated O-glycosyl trichloroacetimidates with simple acceptors.
The yields were however low (up to 40%) and the selectivity controlled
by neighboring group participation. See: C. Zandanel, L. Dehuyser,
A. Wagner and R. Baati, Tetrahedron, 2010, 66, 3365.
23 (a) Tf2NTMS has previously been used for: Friedel-Craft alkylations
e.g. A. Isgii, O. Kotera, T. Saeki and K. Mikami, Synlett, 1997, 1145;
(b) b-allylation of enones: N. Kuhnert, J. Peverly and J. Robertson,
Tetrahedron Lett., 1998, 39, 3215; (c) Mukayama aldol reaction:
K. Ishihara, Y. Hiraiwa and H. Yamamoto, Synlett, 2001, 1851;
(d) Silylations: G. Simchen and S. Jonas, J. Prakt. Chem., 1998,
340, 506; (e) See also M. B. Boxer in e-EROS Encyclopedia of
Reagents for Organic Synthesis, 2008 (1,1,1-trifluoro-N-[(trifluoro-
methyl)sulfonyl]-N-(trimethylsilyl)methanesulfonamide).
BF3OEt2 609
TMSOTf 528
TMSNTf2 894
627
565
911
561
658
868
À3
À7
À2
8
À25
3
a
b
Predicted MW of the intermediates. MW calculated by the MW
calibration curves. See the ESI for details.
calibration curves. Both methods do however estimate larger
MWs for the activation with TMSOTf and the 19F-DOSY deviates
by 25%. One reason for the less precise MW prediction of this
compound could be that the calibration curve is based on mainly
non-carbohydrate based compounds, which have different three
dimensional structures and hence a slightly different relation
1
between diffusion constants and MWs. Generally the H-DOSY
calibration curve, which is based on carbohydrate derivatives,
gives the best correlation and hence the most accurate estimate.
Most importantly the double determination of MWs of the new
donor system using Tf2NTMS agrees with the predicted MWs and
thereby strongly support that intermediate 6 containing the
silylated trichloroacetimidate has been formed, which is a new
activation pathway and could be a new way to improve the yield
and selectivity in catalytic glycosylations.
In conclusion, we have used DOSY NMR for the first time to
investigate a glycosylation reaction at low temperature. The inter-
action between three different catalysts with a glucosyl trichloro-
acetimidate was studied, and it was found that the reaction
pathways and intermediates are different. The two common
catalysts, BF3ÁOEt2 and TMSOTf, give glucosyl-fluorides and
triflates, respectively, as intermediates. The donor is not transformed
catalytically under these conditions, where an acceptor is not
present. From this insight a new catalyst, Tf2NTMS was suggested
and found to activate the trichloroacetimidate catalytically, but
without cleavage of the glycosidic bond. The counter ion is not
nucleophilic enough to substitute the leaving group and this is a
novel promising concept for catalytic stereospecific glycosylations.
CMP acknowledges the CAS President’s International Fellow-
ship Initiative (2015VMB052).
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´
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´
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