Influence of acyl groups on glucopyranoside reactivity in Lewis acid promoted anomerisation

Article abstract of DOI:10.1016/j.tetlet.2018.05.076

Lewis acid promoted anomerisation has potential in O- or S-glycoside synthesis. Herein, the anomerisation kinetics of thirty-one β-D-glucopyranosides was determined to determine how particular acyl protecting groups and their location influence reactivity towards a Lewis acid promoted reaction. The replacement of acetyl groups with benzoyl groups led to reduced reactivity when located at O-3, O-4 and O-6. However a reactivity increase was observed when the acetyl group was replaced by a benzoyl group at O-2. The 2,3,4,6-tetra-O-(4-methoxy)benzoate had an ～2-fold increase in rate when compared to the tetrabenzoate.

Full text of DOI:10.1016/j.tetlet.2018.05.076

Accepted Manuscript
Influence of acyl groups on glucopyranoside reactivity in Lewis acid promoted
anomerisation
Mark P. Farrell, Lisa M. Doyle, Paul V. Murphy
PII:
S0040-4039(18)30701-9
https://doi.org/10.1016/j.tetlet.2018.05.076
TETL 50023
DOI:
Reference:
Tetrahedron Letters
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27 March 2018
23 May 2018
25 May 2018
Please cite this article as: Farrell, M.P., Doyle, L.M., Murphy, P.V., Influence of acyl groups on glucopyranoside
reactivity in Lewis acid promoted anomerisation, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.05.076
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Influence of acyl groups on glucopyranoside reactivity
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Increasing reactivity to SnCl4

1
Tetrahedron Letters
Influence of acyl groups on glucopyranoside reactivity in Lewis acid promoted
anomerisation
Mark P. Farrell, Lisa M. Doyle and Paul V. Murphy*
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland, H91 TK33
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Lewis acid promoted anomerisation has potential in O- or S-glycoside synthesis. Herein, the
anomerisation kinetics of thirty one -D-glucopyranosides was determined to determine how
particular acyl protecting groups and their location influence reactivity towards a Lewis acid
promoted reaction. The replacement of acetyl groups with benzoyl groups led to reduced
reactivity when located at O-3, O-4 and O-6. However a reactivity increase was observed when
Available online
the acetyl group was replaced by
methoxy)benzoate had an ~2 fold increase in rate when compared to the tetrabenzoate.
a benzoyl group at O-2. The 2,3,4,6-tetra-O-(4-
Keywords:
Carbohydrates
Anomerisation
Glycoside
2009 Elsevier Ltd. All rights reserved.
Lewis Acid
Protecting groups
Reactivity
———
* Corresponding author. e-mail: paul.v.murphy@nuigalway.ie

2
Tetrahedron Letters
1. Introduction
groups as well as partial oxidative cleavage of benzylidene
groups.
Reactions at the anomeric centre are influenced by a variety of
Next the benzylation of 4 (Scheme 3) under the biphasic alkali
factors. For instance, in glycosylation, protecting groups on
saccharide hydroxyl groups influence the stereochemical
outcome as well as the reaction rate.1 Differences in
glycosylation rate can be exploited in reactivity based
oligosaccharide synthesis in one pot.2 Acyl protecting groups are
considered ‘disarming’ in such glycosylation reactions when
compared with ether protecting groups, such as benzyl ethers.3
This is because the acyl group is more electron withdrawing than
the ether and reduces the stability of transition states leading to
cationic intermediates4 resulting from exocyclic cleavage in these
reactions.
conditions previously reported by Garegg and co-workers24 gave
a mixture of 8 and 9 which were isolated in 39% and 17% yields,
respectively. Benzoylation, followed by catalytic hydrogenolysis
and subsequent acetylation gave 10β and 11β in 73% and 66%
yields, respectively, over the three steps from 8 and 9.
Reactivity in Lewis acid promoted anomerisation5,6,7 is also
influenced by protecting groups,8,9 a reaction that is believed to
proceed via a cationic intermediate resulting from endocyclic
cleavage10,11 (Scheme 1). Acyl groups located on the saccharide
oxygen atoms reduce the rate of these reactions compared to
when ether groups are present.6,8 Furthermore, there are
differences between acyl groups. Tetra-O-benzoyl--D-
glucopyranoside 2 is more reactive than the corresponding
tetraacetate 1. Based on inductive effects the presence of
benzoyl groups would destabilize a cationic intermediate more
than acetyl groups. However, the use of benzoylated reactants has
been more successful, giving higher yields and shorter reaction
times in equatorial to axial anomerisation reactions compared to
reactions of the analogous acetylated reactants. This has been
demonstrated in glycosphingolipid synthesis achieved via Lewis
acid promoted anomerisation,12,13 and more recently in the
successful anomerisation of benzoylated glycosyl thiols.14
Scheme 2. Synthesis of 6 and 7
In this paper the influence of acyl groups on the reactivity of a
Lewis acid promoted anomerisation reaction of a series of O-
glucopyranosides is probed further with a view to identification
of protecting group strategies that would lead to wider
application of anomerisation.15,16,17,18,19,20,21,22 A variety of acyl
protected glucopyranosides are prepared and a structure reactivity
relationship is established. Here we report that the presence of
benzoyl groups at C-2 of the -glucopyranoside generally leads
to a rate enhancement in the anomerisation reaction, while
benzoyl groups at C-3, 4 or 6 lead to a rate reduction when
compared to the presence of acetyl groups at these positions.
However, the replacement of all four acetyl groups with benzoyl
groups gave the highest reactivity. Other tetra-O-acyl derivatives
with improved reactivity compared to tetra-O-benzoyl groups are
also reported.
Scheme 3. Synthesis of 10 and 11
Attention turned to the preparation of compounds with two or
three benzoate groups (Schemes 4-6). Partial oxidative cleavage
of 5 and subsequent benzoylation gave 12β (62%). Benzoylation
of 4 was followed by acid catalysed cleavage of the benzylidene
acetal in CH2Cl2-MeOH and acetylation to give 14β.
Scheme 1. Proposed mechanism for the Lewis acid promoted anomerisation
of glucopyranosides
2. Results and Discussion
2.1 Synthesis of compounds for study
The preparation of monobenzoylated compounds was first
investigated (Scheme 2). Thus Zemplén deacetylation of 1,
which has been described previously,7 gave 3. Reaction of 3 with
benzaldehyde dimethyl acetal in the presence of p-TsOH gave 4.
Acetylation gave 5. Oxidative cleavage of the benzylidene group
using NaBrO3-Na2S2O4 under bi-phasic conditions, followed by
acetylation, resulted in the formation of a separable mixture,
giving 6β (54%) and 7β (25%). The application of biphasic
NaBrO3-Na2S2O4, described by Adinolfi and co-workers,23 was
used frequently herein for the successful removal of benzyl
Scheme 4. Synthesis of 12 and 14

Acid catalysed cleavage of the benzylidene group from both 8
and 9 and their subsequent benzoylation gave 15 and 16.
Oxidative removal of the benzyl groups with NaBrO3-Na2S2O4
proceeded smoothly and subsequent acetylation gave 17 and
18.

3
With various reactants in hand, the Lewis acid catalysed
anomerisations were investigated.7 Reactions were carried out in
NMR tubes with CDCl3 as the solvent and using 1 equivalent of
SnCl4 as the promoter. Concentrations of reactant (-anomers in
Table 1) and the major product (-anomer) were monitored as a
function of time and were also measured at equilibrium (when no
further change in the concentration of reactant and products were
observed). The data obtained was used in equation (1) for
equilibrium kinetics:25
–
(1)
–
where [A]0 is the initial concentration of the β-anomer, [A]e is the
concentration of the β-anomer at equilibrium, [A]t is the
concentration of the β-anomer at a time (t), kf is the rate constant
of the forward reaction (β → α) and kr is the rate constant of the
reverse reaction (α → β). Each reaction was carried out in
triplicate and the data for all reactants in Table 1 gave linear plots
with r2 values of 0.97 or greater. The kf+kr value for each reactant
was the slope and these values are given in Table 1 along with
relative reactivities.
Scheme 5. Synthesis of 17 and 18
Partial oxidative cleavage of the benzylidene group of 13 gave
a mixture of 19 and 20. Subsequent acetylation gave 21β and
22β.
Scheme 6. Synthesis of 21 and 22
Intermediate 23, prepared from 9 (Scheme 7), was treated with
NaH and methyl iodide to give 24. The benzyl group of 24 was
then removed to give 25. Acylation of 25 gave 27-30. The
tetra-O-methyl derivative 26 was prepared as previously
described.8
Scheme 8. Synthesis of 33-36
Scheme 7. Synthesis of 27-30
Partial reductive cleavage of the benzylidene group of 13
using methanesulfonic acid (MSA) and NaBH3CN resulted in the
regioselective formation of 31. Benzoylation gave 32. Oxidative
removal of the 6-O-benzyl ether followed by acylation gave 33-
36 (Scheme 8) whereas various peracylated compounds 37-
46 were prepared by the peracylation of 32 in pyridine-DMAP
(Scheme 9).
Scheme 9. Synthesis of 37-46
In this kinetic study the SnCl4:reactant ratio used was 1:1. This
differed from the earlier study from our laboratory where a
SnCl4:reactant ratio of 0.5:1 was used.8 The 1:1 ratio was used to
reduce the overall reaction time so as to more rapidly obtain kf+kr
values. This explains differences in the kf+kr values reported for
1, 2 and 26 in this study with those reported previously. In
the previous study 2 was ~4 fold faster than 1 whereas it was
~2 fold faster using the current conditions. However, the trend in
kf+kr values was consistent with those published earlier, with
fully benzoylated reactant 2 being faster than the acetylated 1.
The fully methylated derivative 26 was more than two orders of
magnitude faster than both acylated compounds.
2.2 Reactivity study
On the basis of inductive effects (pKa benzoic acid = 4.20 vs pKa
acetic acid = 4.76) the anomerisation of benzoylated reactant 2
would be expected to be slower than 1.26 The presence of

4
Tetrahedron Letters
benzoyl groups at C-3, C-4 and C-6, instead of acetates, in
influenced by steric hindrance with more crowding in 2 than for
examples in entries 1 and 3-12 in Table 1. This crowding pushes
the 2-carbonyl group closer to the carbocation centre where it can
stabilize the forming cation.
various monobenzoylated, dibenzoylated and tribenzoylated
reactants, consistently led to a reduction in the rate of
anomerisation (compare each of entries 3-5, 7 and 9 with 1). In
contrast, the presence of a benzoyl group at C-2 generally led to
rate increases (compare entry 6 with 1; 8 with 5; 10 with 7 and 9
with 2). The replacement of the 2-O-acetate of 17 (Entry 9) to
give 2 led to the highest increase (four fold) in reactivity (Table
1, entries 1-12).
While this study has focused on anomerisation, a 2-O-benzoyl
group was shown to increase reactivity in a glycosylation
reaction,27 this being explained by the benzoyl group being
involved in neighboring group participation. However, a rate
enhancing effect for a 2-O-benzoate group may not be a general
phenomenon in glycosylation.1 In anomerisation involving a
cationic intermediate, the 2-O-benzoyl group could also
participate as a neighboring group. The degree of participation
could be increased, as mentioned, due to increased steric
hindrance. The presence of the phenyl group also enables a
resonance contribution from the 2-O-benzoyl group. This might
explain why 2 is faster than the sterically hindered tetra-O-
pivalylated derivative 39. The use of a more electron releasing
p-methoxybenzoyl group increased reactivity, which is consistent
with increased stabilization of carbocation formation in a rate
influencing step.28
The tetra-O-methylated 26 is over 600 times more reactive
than fully acylated 1 under these conditions. Replacement of the
2-O-methyl group with an acyl group led to a reduction in the
rate of anomerisation (Entries 13-17). However, the 2-O-
benzoate 28 (Entry 15) was 1.3 times more reactive than 2-
acetate 27 (Entry 14). The more electron withdrawing p-
fluorobenzoate 29 reduced the rate (Entry 16) whereas the 2-O-
pivalate 30 was most reactive of the 2-O-acyl-3,4,6-tri-O-
methyl--D-glucopyranosides 27-30.
The next series of compounds give insight into the effect of
substituents at C-6, chosen for investigation due to its proximity
to the proposed site of coordination to SnCl4 (Entries 18-21).
There was no clear trend apparent based on electronic properties,
although the p-methoxy derivative was the most
reactive.Finally, the study of homoacyl glucopyranosides
(Entries 22-31) revealed the most improvement in reactivity for
the 2,3,4,6-tetra-O-(4-methoxy)benzoate 42 (Entry 27), which is
associated with the greater electron releasing properties of the p-
methoxy benzoyl group, compared to the benzoyl group.
A
further study which has the aim to increase the
understanding of why benzoates are more reactive in
anomerisation reactions is in progress and this study will be
reported in due course.
Acknowledgments
This publication has partly emanated from research supported
by Science Foundation Ireland (SFI, grant number 12/IA/1398)
and is co-funded under the European Regional Development
Fund under Grant Number 14/SP/2710. The authors thank the
Irish Research Council and Roche Ireland Ltd for an Enterprise
Partnership postgraduate scholarship to MPF.
3. Summary and Conclusion
Relatively low reactivity differences (e.g. 2 fold) between
fully acetylated or fully benzoylated glycosides can influence
reaction progression and yields from anomerisation reactions.
This is more noticeable during the preparation of
glycosphingolipids, where the aglycon is more complex. Hence,
synthetic routes have been developed herein that have enabled
the regioselective acylation of glucopyranosides in order to gain
insight how the location of the acyl group influences reactivity.
The study showed that the placement of benzoyl groups at O-2
led to an increase in reactivity, but to reduction when placed
elsewhere, the exception being that the presence of four
benzoates gave the highest reactivity. The latter could be
Supplementary Material
Experimental section including analytical data for compounds
and selected NMR spectra.
Table 1. Reactivity of compounds in SnCl4 promoted anomerisationa
Entry Reactant (-anomer)
Major product (-anomer)
106(kf + kr) (s-1)
Relative Reactivity
1
Ratio : Yield of the
-anomer
(%)
1
7.6
9:1
64
2
3
4
15.7
6
2.07
0.79
0.93
95:5
72
92:8
81
76
7.1
89:11
5
6
7.2
8.6
0.95
1.13
93:7
9:1
73
61

5
7
4.6
0.61
92:8
84
8
9
8.5
3.7
1.12
0.49
88:12
9:1
61
54
10
11
6.2
6.6
0.82
0.87
91:9
9:1
67
83
12
13
5.6
0.74
615
89:11
96:4
70
72
4676
14
3088
406
92:8
74
15
16
4088
1854
538
244
95:5
95:5
71
52
17
4386
577
94:6
84

6
Tetrahedron
Table 1 (contd). Reactivity of compounds in SnCl4 promoted anomerisation
Entry
Reactant
106(kf + kr) (s-1)
Relative Reactivity
0.91
Ratio : Yield of -
anomer (%)
18
6.9
9:1
41
19
20
10.4
8.2
1.37
1.08
96:4
93:7
66
73
21
22
5.8
8.3
0.76
1.09
85:15
90:10
62
66
23
24
9.4
1.24
1.3
92:8
95:5
76
81
10.1
25
26
6.2
7.2
0.82
0.95
95:5
61
49
90:10
27
28
27.9
31.1
3.67
4.1
92:8
95:5
57
61
29
30
27.0
12.5
3.55
1.64
94:6
9:1
51
48
31
21.6
2.84
95:5
45
a
Isolated yield after chromatographic separation. PMBz = p-methoxybenzoyl; 2-Nap = 2-naphthyl; 1-Nap = 1-naphthyl; PTBBz = p-(tert-butyl)benzoyl; p-
MeBz = p-methylbenzoyl; PFBz = p-fluorobenzoyl; PCBz = p-chlorobenzoyl; Piv = trimethylacetyl or pivalate.
References and notes

7
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Highlights
1. Synthesis of regioselectively protected
glucopyranosides
2. Reactivity study involving 31 reactants
3. Providing insight into the influence of acyl
groups on a reaction at the anomeric centre