10.1002/ejoc.201601439
European Journal of Organic Chemistry
COMMUNICATION
by estimating the molecular weight using DOSY NMR.17 To
study this in more detail, the β-TCA 3 was synthesized and its
activation with BF3∙OEt2 followed by VT-NMR at 218 K. The
fluorides 9 and 10 were formed, but in an almost 1:1 ratio and
hence without stereospecificity. This substantial difference in
selectivity, between the anomeric set of donors, is surprising as
the β-TCA 3 would give the thermodynamically more stable α-
fluoride 10 directly if the reaction was stereospecific. This is
however clearly not the case and hence there is not a common
intermediate, starting from the two TCA-anomers, and therefore
two different mechanistic pathways.
The α-TCA is the thermodynamically more stable anomer, due
to the anomeric effect. Its complex formation with BF3∙OEt2 is
therefore having a longer life time and enough time to transfer a
fluoride ion from the β-side, i.e. not through the formation of an
oxocarbenium ion intermediate, which would give unspecific
formation of glycosyl fluorides. The increased stability of the α-
In conclusion, glycosyl fluorides have been shown to be an
important intermediate in the BF3∙OEt2 activated glycosylations
with trichloroacetimidate donors. The stability and hence
detectability of these intermediates is strongly dependent on the
inherent reactivity of the donor. Conformationally restricted
donors, such as the benzylidene protected donors in this study,
are prone to give the fluorides, but other donors do also yield
detectable amounts. From low temperature NMR it was found
that the α-TCA donor mainly gave the β-fluoride, whereas the β-
TCA gave mixtures. In time the thermodynamically more stable
α-fluoride was the main anomer observed. This clearly indicates
at least two different activation pathways, with different reactive
intermediates, which is contrary to the commonly accepted
oxocarbenium ion mechanism, but very important for improving
glycosylations.
trichloroacetimidate might require participation from
a
Acknowledgements
nucleophile to be expelled.18 The β-TCA on the other hand is
less stable and interaction with the catalyst results in leaving
group departure, without a concerted transfer of the fluoride. The
attack of the fluoride from the α-side might also be hampered by
repulsion due to the restricted conformational freedom of the
donor enforced by the 4,6-O-benzylidene.
We thank CHEM, UCPH for funding.
Keywords: Glycosylation • Mechanism • VT-NMR • Glycosyl
fluorides • Trichloroacetimidates
From the results presented glycosyl fluorides seems to be
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R.R. Schmidt, J. Michel Angew. Chem. Int. Ed. 1980, 19, 731-732
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in
glycosylations
using
trichloroacetimidates and BF3-OEt2. In most cases the fluorides
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the BF3∙OEt2 promoted reaction conditions19 and hence
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When the donor is less reactive or do not benefit from any
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have a sufficient life time to be detected and in some cases
isolated.
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[12] M. D’Alarcao, V. Azev, S. Suzuki WO 2008/080064 A1 2008
[13] Small amounts of glycosyl fluoride formation (~5%) has been observed
in boron fluoride catalyzed glucosylations using a trichloroacetimidate
donor: A. Kumar, V. Kumar, R.T. Dere, R.R. Schmidt Org. Lett. 2011,
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[14] D. Crich, M. Smith, Q. Yao, J. Picione Synthesis 2001, 323-326
[15] The composition of the actual catalyst is presumably more complex as
several Lewis and Brønsted acids are formed when the acceptor and
BF3∙OEt2 react.
[16] T.G. Frihed, M. Bols, C.M. Pedersen Chem. Rev. 2015, 115, 4963-
5013
[17] The stereospecific formation of glycosyl fluoride has recently been
studied by low temp. NMR: Y. Qiao, W. Ge, L. Jia, X. Hou, Y. Wang, C.
M. Pedersen Chem. Commun. 2016 (DOI: 10.1039/C6CC05272J)
[18] A similar mechanism for the activation of -trichloroacetimidates by
PhBF2, but not BF3∙OEt2, has been proposed by Schmidt and
coworkers. See ref. 13 and A. Kumar, R. R. Schmidt Eur. J. Org. Chem.
2012, 2715-2719
Figure 2. Suggested reaction paths and reactive intermediates from activation
of the anomeric set of donors, prone to give glycosyl fluorides (2 and 3), based
on VT-NMR experiments. The commonly proposed activation mechanism of
trichloroacetimidate donors is shown below.
[19] When the β-fluoride 9 was submitted to a cat. amount of BF3∙OEt2 it
was instantaneously consumed at rt and hence these intermediates are
Conclusions
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