Mapping the Relationship between Glycosyl Acceptor Reactivity and Glycosylation Stereoselectivity

Article abstract of DOI:10.1002/anie.201802899

The reactivity of both coupling partners—the glycosyl donor and acceptor—is decisive for the outcome of a glycosylation reaction, in terms of both yield and stereoselectivity. Where the reactivity of glycosyl donors is well understood and can be controlled through manipulation of the functional/protecting-group pattern, the reactivity of glycosyl acceptor alcohols is poorly understood. We here present an operationally simple system to gauge glycosyl acceptor reactivity, which employs two conformationally locked donors with stereoselectivity that critically depends on the reactivity of the nucleophile. A wide array of acceptors was screened and their structure–reactivity/stereoselectivity relationships established. By systematically varying the protecting groups, the reactivity of glycosyl acceptors can be adjusted to attain stereoselective cis-glucosylations.

Full text of DOI:10.1002/anie.201802899

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Accepted Article
Title: Mapping Glycosyl Acceptor Reactivity - Glycosylation
Stereoselectivity Relationships
Authors: Stefan van der Vorm, Jacob M. A. van Hengst, Marloes
Bakker, Herman S. Overkleeft, Gijsbert A. van der Marel, and
Jeroen Codée
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802899
Angew. Chem. 10.1002/ange.201802899
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10.1002/anie.201802899
Angewandte Chemie International Edition
COMMUNICATION
Mapping Glycosyl Acceptor Reactivity - Glycosylation
Stereoselectivity Relationships
Stefan van der Vorm, Jacob M. A. van Hengst, Marloes Bakker, Herman S. Overkleeft, Gijsbert A. van
der Marel, and Jeroen D. C. Codée*[a]
Abstract: The reactivity of both coupling partners -the glycosyl donor
and acceptor- is decisive for the outcome of a glycosylation reaction,
both in terms of yield and stereoselectivity. Where the reactivity of
glycosyl donors is well understood and can be controlled through the
manipulation of the functional/protecting group pattern, the reactivity
of glycosyl acceptor alcohols is ill-understood. We here present an
operationally simple system to gauge glycosyl acceptor reactivity,
which employs two conformationally locked donors whose
stereoselectivity critically depends on the reactivity of the nucleophile.
A wide array of acceptors was screened and their structure-reactivity-
stereoselectivity relationships established. By systematically varying
protecting groups it is shown how the reactivity of glycosyl acceptors
can be adjusted to attain stereoselective cis-glucosylations.
than reactive acceptors which can engage more readily in an SN2-
type displacement reaction (Scheme 1).[9] The stereochemical
outcome of glycosylation reactions of 4,6-O-benzylidene
protected glucose (A, Figure 1) and glucosazide (B, Figure 1)
donors turned out to be especially sensitive to the reactivity of the
nucleophile. A gradual change in stereoselectivity was observed
for these donors going from near complete -selectivity for the
most reactive acceptor (ethanol) to complete -selectivity for the
weakest nucleophiles (trifluoroethanol, hexafluoro-iso-propanol,
see Table 1, Entries 1-4). The corollary of this established
relationship is that the stereoselectivity of a glycosylation between
a benzylidene glucose donor and a given acceptor provides a
direct indication of the reactivity of the acceptor alcohol at hand.
We therefore reasoned that the benzylidene glucose/glucosazide
glycosylation system would be ideal to “measure” the reactivity of
acceptor alcohols in a glycosylation reaction setting. Here we
conceptualize this hypothesis and we use the system to
systematically map the reactivity of a panel of carbohydrate
acceptors to show how functional and protecting groups influence
the nucleophilicity of the alcohols to provide a scale of relative
acceptor reactivities to which any desired acceptor can be set
against and reveal its potential stereoselectivity in glycosylations.
The union of two carbohydrates to generate larger
oligosaccharides is arguably one of the most important reactions
in glycochemistry.[1] Although the glycosylation reaction has been
actively studied for more than half a century, many aspects that
affect this reaction, both in terms of yield and stereoselectivity,
remain enigmatic.[2] The reactivity of the carbohydrate building
blocks is one of the most important determinants that influence
the outcome of a glycosylation reaction.[3] The reactivity of donor
glycosides has been very well documented: the relative reactivity
value (RRV) of hundreds of thioglycosides has been established
and hundreds of anomeric triflates and other covalent reactive
species, key reactive intermediates formed in situ during the
reaction, have been characterized.[4] The reactivity of acceptor
glycosides is less well understood and systematic studies
investigating this important reaction parameter are extremely
scarce.[5] At the same time, it is common practice to change
protecting groups on the acceptor building block to influence the
yield or change the stereoselectivity of a glycosylation reaction.[6]
Often this is done in a time consuming, trial-and-error manner as
well defined guidelines how to tune the reactivity of an acceptor
and how this effects the glycosylation reaction are absent.[7]
Recently we have shown that the reactivity of the acceptor can
have a profound influence on the stereoselective outcome of a
glycosylation reaction.[8] Through the use of a panel of partially
fluorinated ethanols (ethanol, mono-, di- and trifluoro ethanol)[5c]
we revealed how the stereochemical outcome of a glycosylation
depends on acceptor nucleophilicity as a result of a shift in
continuum of mechanisms, with weaker nucleophiles requiring a
more dissociative reaction mechanism (with more SN1 character)
Scheme 1. General glycosylation mechanism, showing the equilibrium of
reactive species. Pg = protecting group.
To probe the effect of different functional and protecting groups
on the reactivity of a carbohydrate acceptor alcohol we used two
thioglycoside donors, benzylidene glucose A and benzylidene
glucosazide B, in combination with a preactivation procedure,[10]
in which the donor glycoside is activated prior to the addition of
the acceptor. This allows for a simpler reaction mechanism
manifold than an in situ activation protocol, which makes it easier
to analyze the effects of changing reactivity of the building blocks
used. For both donors we previously established a strong
relationship between acceptor reactivity and glycosylation
stereoselectivity and across the board, glycosylations of donor B
provided more -product than the glycosylations of donor A.[8a,b]
This effect was accounted for by the greater tendency of donor B
to partake in SN2-type reactions as a result of the electron-
[a]
S. van der Vorm, M. Bakker, J.M.A. van Hengst, prof.dr. H.S.
Overkleeft, prof. dr.G.A. van der Marel, dr. J.D.C. Codée
Bio-organic synthesis department
Leiden Institute of Chemistry, Leiden University
Einsteinweg 55, 2333 CC Leiden, The Netherlands
E-mail: jcodee@chem.leidenuniv.nl
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201802899
Angewandte Chemie International Edition
COMMUNICATION
withdrawing effect of the C-2-azide and the greater stability of the
the electron-withdrawing tendency of the protecting/functional
anomeric triflate that is formed as a reactive intermediate. In effect, group at the C-6 position, arises. The uronic acid 4, featuring a
the combination of the two donor systems should allow for
mapping the reactivity of acceptors of widely varying reactivity. As
a first objective we focused on mapping the stereoselectivity -
reactivity relationship for a diverse set of C-4-OH glucosyl
acceptors (Figure 1, 1-20). To keep steric and other structural
effects to a minimum we compared the effect of O-benzyl or O-
benzoyl groups as these groups are of a similar size, but differ
significantly in electronic properties. We investigated all possible
positional benzyl/benzoyl permutations. We also probed the effect
of different chemical functionalities at the C-6 position, where we
installed -besides the benzyl and benzoyl protected primary
alcohol functionalities - a 6-deoxy and carboxylic acid ester
functionality. Also the effect of the anomeric configuration was
analyzed.[11]
strongly electron-withdrawing carbonyl group in close proximity to
the acceptor’s nucleophilic center, provides most -product,
indicating that this is the least reactive of the four acceptors
studied.[12] It is also clearly apparent that the C-6-O-benzoyl has
a disarming effect on the reactivity of the acceptor as glucoside 3
is more -selective than its C-6-O-benzyl counterpart 1. The
configuration at the anomeric center does not affect the
Table 1. Glycosylations with model acceptors and 2,3-di-O-benzyl acceptors
1-4.[a]
Donor A
Donor B
Donor A
Donor B
Acceptor
 : 
 : 
Acceptor
 : 
 : 
(yield)
(yield)
(yield)
(yield)
1 : 10
(68%)
<1 : 20
(83%)
1
1A
1 : 1
(82%)
1B
1 : 7
(88%)
1 : 2.8
(70%)
1 : 6.7
(90%)
2
3
4
2A
2 : 1
(85%)
2B
1 : 5
(69%)
5 : 1
(70%)
2.9 : 1
(64%)
3A
4 : 1
(92%)
3B
1 : 1.1
(67%)
>20 : 1
(64%)
>20 : 1
(94%)
4A
5 : 1
(90%)
4B
1.1 : 1
(93%)
Figure 1. Donors A and B and C-4-OH glucosyl acceptors 1-20.
[a] Data for acceptor 1 and 4, and the four ethanols has been published in
In Table 1 the results of the glycosylation reactions of donors A
and B, previously obtained with the fluorinated model alcohols,
are listed alongside the reactions of acceptors of 2,3-di-O-benzyl
acceptors 1-4. A clear transition from - to -selectivity, following
reference 8a and 8b.
Table 2. Glycosylation results of -glucoside acceptors 17-20, 2-O-benzoyl acceptors 5-8, 3-O-benzoyl acceptors 9-10 and 2,3-di-O-benzoyl acceptors 13-16.
Donor A
Donor B
Donor A
Donor B
Donor A
Donor B
Donor A
Donor B
Acceptor
functional
group C6
Acceptor
(2,3-OBn,
-OMe)
 : 
(yield)
 : 
(yield)
Acceptor
(2-OBz,
3-OBn)
 : 
(yield)
 : 
(yield)
Acceptor
(2-OBn,
3-OBz)
 : 
(yield)
 : 
(yield)
 : 
(yield)
 : 
(yield)
Acceptor
(2,3-OBz)
(6-OBn)
17
18
19
20
17A
1 : 1
(79%)
17B
1 : 7
(80%)
5
6
7
8
5A
1 : 1.1
(81%)
5B
1 : 6
(88%)
9
9A
>20 : 1
(95%)
9B
6.7 : 1
(77%)
13
14
15
16
13A
>20 : 1
(90%)
13B
10 : 1
(93%)
(6-deoxy)
(6-OBz)
18A
1.1 : 1
(87%)
18B
1 : 5.6
(86%)
6A
1.1 : 1
(86%)
6B
1 : 5
(88%)
10
11
12
10A
>20 : 1
(93%)
10B
14 : 1
(81%)
14A
>20 : 1
(83%)
14B
20 : 1
(96%)
19A
3.3 : 1
(73%)
19B
1 : 1.2
(70%)
7A
3.5 : 1
(88%)
7B
1.3 : 1
(87%)
11A
>20 : 1
(95%)
11B
>20 : 1
(85%)
15A
>20 : 1
(91%)
15B
>20 : 1
(69%)
(5-CO2Me)
20A
20B
8A
8B
12A
12B
16A
16B
5 : 1
(83%)
1.2 : 1
(85%)
4.8 : 1
(96%)
1.2 : 1
(82%)
>20 : 1
(86%)
>20 : 1
(93%)
>20 : 1
(84%)
>20 : 1
(99%)
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10.1002/anie.201802899
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Figure 2. Structures of nitrobenzoyl acceptors 21-24, and gluco-, galacto-, manno-configured acceptors 25-38.
reactivity of the C-4-OH acceptors as judged form the identical
stereoselectivities of -anomers 1-4 and -anomers 17-20 (Table
2). Also the relatively remote protecting group at the C-2 position
has no apparent effect on the glycosylation stereoselectivities
(compare 1A-4A, Table 1, to 5A-8A, Table 2).
glycosylations tabularized in Tables 1 and 3, the order of reactivity
of the different hydroxyl groups on the glucose ring in combination
with the benzylidene glucose donors studied, appears to be: C-3-
OH > C-4-OH > C2-OH.[14]
However, the nature of the protecting group at the C-3 position
has a dramatic effect on the stereoselectivity. A significant shift in
the /-selectivity is observed in favor of the cis-glycosides upon
changing the C-3-O-benzyl group for a benzoyl functionality.
Where acceptors 1-4 showed poor -selectivity with donor A and
-selectivity when paired with donor B (Table 1, products 1A/B-
4A/B), the introduction of a strategically positioned benzoate
turns these acceptors in highly (or even completely) -selective
acceptors (Table 2, products 9A/B-12A/B). These results show
that the mere change of two C-H bonds for a C=O bond can have
a tremendous impact on the stereoselectivity of a glycosylation
reaction. The only glycosylation in the latter series that was not
completely -selective, i.e. the condensation of glucosazide B
and acceptor 9 (product 9B, / = 6.7: 1), could be rendered fully
-selective, by changing the C-6-O-benzyl for a benzoyl, thereby
further disarming this acceptor building block (product 11B).
To further examine whether reactivity tuning can be achieved
using more electron-withdrawing protecting groups, we probed a
series of nitrobenzoyl ester protected acceptors (Table 3, 21-24).
Placing a single nitrogroup on the C-6-benzoate (at the ortho,
meta- or para-position) of the acceptor does not have a significant
effect on the stereoselectivity of the condensation reactions (cf.
products 21A-23A, Table 3, vs product 3A, Table 1). However,
the introduction of two ortho-nitrogroups on the benzoate, as in
acceptor 24, does lead to a slight change in stereoselectivity
towards the -product.[13]
We next examined the reactivity of C-3-OH and C-2-OH glucosyl
acceptors and also here probed the influence of benzoyl vs benzyl
protecting groups. Table 3 lists the results obtained with acceptors
25-28. From these results it becomes apparent that, in line with
the results described above, the reactivity of the C-2- and C-3-OH
acceptors can be tuned, and thus the stereoselectivity of the
glycosylations controlled, by changing the nature of the protecting
groups. Clearly, the steric effects that play a role in the transition
state of the reactions of the C-2, C-3, and C-4-hydroxyls will differ
and comparing the reactivity of these alcohols has to be done,
bearing this in mind. But based on the stereoselectivity of the
Table 3. Glycosylation results of C-6-nitrobenzoate glucosyl acceptors 21-
24, C-3-OH glucosyl acceptors 25 and 26, and C-2-OH glucosyl acceptors
27 and 28.
Donor A
Donor A
Donor B
Acceptor
 : 
Acceptor
 : 
 : 
(yield)
(yield)
(yield)
21
21A
25
25A
25B
3 : 1
(92%)
1 : 2.7
(78%)
<1 : 20
(70%)
22
23
24
22A
3.3 : 1
(49%)
26
27
28
26A
>20 : 1
(100%)
26B
11 : 1
(83%)
23A
3.5 : 1
(83%)
27A
9 : 1
(76%)
27B
1.6 : 1
(66%)
24A
28A
28B
5.6 : 1
(83%)
>20 : 1
(85%)
13 : 1
(92%)
Finally, we extended our study to manno- and galacto-configured
acceptors (29-36, Table 4). From the stereoselectivities with
which products 29A/B – 31A/B are formed, the reactivity order for
the galactose alcohols appears to be C-3-OH > C-2-OH > C4-OH,
with the axial C-4-OH clearly the least reactive of the series. As
noted above, the steric requirements for each of these alcohols
will be different and this may be an important factor in the
relatively low reactivity of the latter alcohol. Also here the
introduction of benzoate esters instead of benzyl groups, turns
poorly/moderately -selective acceptors into highly -selective
nucleophiles (cf. products 32A/B vs product 30A/B, Table 4). For
the mannose configured acceptors (33-35) the following reactivity
trend can be distilled from Table 4: C-4-OH > C-3-OH > C-2-OH.
In line with the galactose-series, the axial OH is least reactive and
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10.1002/anie.201802899
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COMMUNICATION
provides the highest -stereoselectivity. Reactivity tuning through
protecting group alteration is equally effective in this series (cf.
products 36A/B vs product 34A/B, Table 4). In this series we
finally probed mannuronic acid acceptors 37 and 38. The C-5-
carboxylate in these acceptors has a similar disarming effect on
the reactivity of the C-4-OH as observed in the corresponding
glucose acceptors 1 and 17 and glucuronic acid acceptors 4 and
20.
Keywords: Glycosylation, stereoselectivity, acceptor reactivity,
reactivity tuning, mechanism.
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29
29A
12 : 1
(72%)
29B
3 : 1
(86%)
33
33A
1 : 2
(76%)
33B
<1 : 20
(72%)
30
31
32
37
30A
6 : 1
(85%)
30B
1 : 1.3
(88%)
34
35
36
38
34A
8 : 1
(82%)
34B
1.1 : 1
(70%)
31A
10 : 1
(87%)
31B
1 : 1.3
(73%)
35A
>20 : 1
(95%)
35B
7 : 1
(65%)
[5]
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>20 : 1
(83%)
32B
11 : 1
(90%)
36A
>20 : 1
(100%)
36B
>20 : 1
(92%)
37A
2.5 : 1
(100%)
37B
1 : 5
(61%)
38A
2.2 : 1
(64%)
38B
1 : 4.8
(60%)
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Overall, the acceptor reactivity-glycosylation stereoselectivity
relationship that was established with a set of fluorinated model
nucleophiles can be directly translated to carbohydrate acceptors.
Just like the reactivity of glycosyl donors, the reactivity of
carbohydrate acceptors can be tuned by manipulation of their
protecting groups, and their reactivity can be exploited to skew
the stereoselectivity of glycosylations in the desired direction.[8a]
This adds a powerful tool for the stereoselective construction of
glycosidic linkages. Commonly used protecting- and functional
groups can be used to moderate the reactivity of the glycosyl
acceptors, and the protecting groups can be further fine-tuned by
changing their electron-withdrawing properties. It is shown that
the strategic replacement of a single benzyl group for a benzoyl
ester (in effect only changing two hydrogen atoms for an oxygen
atom) can turn a non-selective condensation into a highly
selective cis-glycosylation. The concept of acceptor reactivity
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nucleophilic sites in the acceptor. By using the two model donors
A and B, the reactivity of any other relevant acceptor can be
gauged in simple test reactions, through comparison to the
reactivity/selectivity of the current set of acceptors. The reactivity
can then be appropriately adjusted by installation of the proper
functional/protecting group pattern.
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Deslongchamps, Org. Lett. 2000, 2, 2275–2277; b) A.-R. de Jong, B.
Hagen, V. van der Ark, H. S. Overkleeft, J. D. C. Codée, G. A. Van der
Marel, J. Org. Chem. 2012, 77, 108–125; c) Q. Zhang, E. R. van Rijssel,
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M. T. C. Walvoort, H. S. Overkleeft, G. A. van der Marel, J. D. C. Codée,
Angew. Chem. Int. Ed. 2015, 54, 7670–7673.
[13] The addition of a third nitro group on the benzoate did not lead to a further
increase in -selectivity. In fact, slightly more -product was obtained
with the C-6-trinitrobenzoate acceptor 39 (39A, / = 2.1: 1) (See ESI).
[14] a) M. S. Taylor, in Sel. Glycosylations Synth. Methods Catal. (Ed.: C.S.
Bennett), Wiley-VCH Verlag GmbH & Co. KGaA, 2017, pp. 231–253; b)
J. Lawandi, S. Rocheleau, N. Moitessier, Tetrahedron 2016, 72, 6283–
6319.
[12] The C-6-OBn has the possibility to hydrogen-bond with the 4-OH,
rendering the acceptor more nucleophilic. This effect is seen for 6-OBn
protected acceptor 1 versus acceptor 2, which based on the absence of
the electronegative oxygen atom at C6 should be a more reactive
acceptor than 1. The hydrogen-bond may also be the contribution that
prevents donor B in providing full -selective condensations (Table 2; 9B,
13B).
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An operationally simple system to
gauge glycosyl acceptor reactivity is
presented, which employs two
Stefan van der Vorm, Jacob M. A. van
Hengst, Marloes Bakker, Herman S.
Overkleeft, Gijsbert A. van der Marel,
and Jeroen D. C. Codée*
conformationally locked donors whose
stereoselectivity critically depends on
the reactivity of the acceptor. The
structure-reactivity-stereoselectivity
relationship was established of a wide
array of acceptors. By systematically
varying protecting groups it is shown
how the reactivity of glycosyl
Page No. – Page No.
Mapping Glycosyl Acceptor
Reactivity - Glycosylation
Stereoselectivity Relationships
acceptors can be adjusted to attain
stereoselective cis-glucosylations.
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