Koenigs–Knorr Glycosylation Reaction Catalyzed by Trimethylsilyl Trifluoromethanesulfonate

Article abstract of DOI:10.1002/chem.201805527

The discovery that traditional silver(I)-oxide-promoted glycosidations of glycosyl bromides (Koenigs–Knorr reaction) can be greatly accelerated in the presence of catalytic trimethylsilyl trifluoromethanesulfonate (TMSOTf) is reported. The reaction conditions are very mild that allowed for maintaining a practically neutral pH and, at the same time, providing high rates and excellent glycosylation yields. In addition, unusual reactivity trends among a series of differentially protected glycosyl bromides were documented. In particular, benzoylated α-bromides were much more reactive than their benzylated counterparts under these conditions.

Full text of DOI:10.1002/chem.201805527

A Journal of
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Title: TMSOTf-Catalyzed Koenigs-Knorr Glycosylation Reaction
Authors: Yahsapal Singh and Alexei V. Demchenko
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10.1002/chem.201805527
Chemistry - A European Journal
TMSOTf-Catalyzed Koenigs-Knorr Glycosylation Reaction
Yashapal Singh and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University Boulevard, St. Louis,
Missouri 63121, USA
ABSTRACT: Presented herein is our discovery that traditional silver(I) oxide-promoted glycosidations of glycosyl bromides
(Koenigs-Knorr reaction) can be greatly accelerated in the presence of catalytic TMSOTf. These reaction conditions are very mild
and allow for maintaining a practically neutral pH while providing high rates and excellent glycosylation yields. In addition, unusual
reactivity trends among a series of differentially protected glycosyl bromides have been documented. Also revealed is an unusual
reactivity trend according to which benzoylated α-bromides are much more reactive than their benzylated counterparts under these
conditions.
In spite of many methods developed for the synthesis of gly-
cans, glycosyl halide donors discovered by Michael[1] continue
to find wide application. Under classical Koenigs-Knorr reac-
tion conditions,[2-4] a glycosyl bromide (or chloride) donor is
coupled with a glycosyl acceptor (alcohol, ROH) in the presence
of silver oxide (or carbonate). This reaction is slow, and even
glycosidations of reactive, per-benzylated donors require
many hours (or even days) to produce the respective glycoside
products. This reaction is particularly sluggish with less reac-
tive per-benzoylated bromides. To advance the classical
Koenigs-Knorr glycosylation, many activators including salts of
mercury,[5-8] cadmium,[9-11] tin,[12-13] zinc,[14-15] indium,[16-17] sil-
ver[18-26] have emerged.[27] Nevertheless, these modifications
failed to adequately enhance the reaction that continued to suf-
fer from fair yields, poor reactivity of donors, substrate scope,
and the requirement to use excess of toxic or expensive rea-
gents. This prompted the investigation of other, non-metallic
activators and promoters including halide ions,[28] iodine or IBr
with DDQ/DABCO,[29-30] bromine,[31] and 3,3-difluoroxindole
(HOFox),[32-33] diarylborinic acid,[34] iodonium ions,[35] halogen
bonding,[36] super critical CO2,[37] and organocatalysis.[38-39]
Many of these conditions still fail to glycosidate per-ben-
zoylated bromides.
nearly quantitatively (99% yield, entry 2). After preliminary
screening of the additives (entries 3-5) we chose 20 mol %
amount of TMSOTf for subsequent experimentation. Practically
no reaction took place in the absence of Ag2O (entry 6) and the
gradual increase of Ag2O (entries 7-11) showed that stoichio-
metric amount is required to obtain practical yields and at least
2.0 equiv of Ag2O are needed to achieve rapid conversion (10
min, entry 11). Herein and below all reactions were performed
in DCM that was found to be the best reaction solvent for these
conditions based of our preliminary screening.
Table 1. TMSOTf-catalyzed glycosidation of bromide 2a
Entry Ag2O (equiv) TMSOTf (equiv) Time, yield of 4a
1
2
3
4
5
6
7
8
9
3.00
3.00
3.00
3.00
3.00
--
1.00
1.25
1.50
1.75
2.00
--
30 h, 5%
5 min, 99%
10 min, 95%
1 h, 61%
Presented herein is our discovery that the addition of catalytic
amounts of a Lewis acid to the Ag2O-promoted glycosylation,
dramatically speeds up the reaction and enhances the yields.
For example, when per-benzoylated mannosyl bromide 2a,
freshly prepared from thioglycoside 1a, was glycosidated with
acceptor 3 under classical Koenigs-Knorr reaction conditions
in the presence of Ag2O (3.0 equiv) in DCM only trace amount
(5%) of disaccharide 4a was isolated, even after 30 h (entry 1,
Table 1). In contrast, when essentially the same reaction was
performed in the presence of 20 mol % of TMSOTf disaccharide
4a was obtained practically instantaneously (<5 min) and
0.20
0.15
0.10
0.05
0.20
0.20
0.20
0.20
0.20
0.20
22 h, 7%
18 h, <2%
18 h, 17%
18 h, 40%
18 h, 72%
18 h, 81%
10 min, 99%
10
11
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10.1002/chem.201805527
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We then began studying the formation of other types of glyco-
sidic linkages with donor 2a. Glycosylation of partially ben-
zylated secondary 2-OH acceptor 5 afforded disaccharide 6 in
98% yield in 10 min (entry 1, Table 2). In case of 3-OH acceptor
7 and 4-OH acceptor 9, a higher amount of promoters (3.0
equiv of Ag2O and 0.25 equiv of TMSOTf) was found beneficial
to afford swift and nearly quantitative formation of disaccha-
rides 8 and 10, respectively (99% yield each, entries 2 and 3).
Higher amounts of the promoters were helpful for all glycosyl-
ations of poorly nucleophilic acceptors to achieve the desired
rates and yields. This trend can be traced in case of benzoylated
acceptors 11 and 13. While the primary 6-OH acceptor 11 af-
forded disaccharide 12 in 99% yield in 10 min (2.0 equiv of
Ag2O and 0.20 equiv of TMSOTf, entry 4), sterically hindered
and deactivated 4-OH acceptor 13 needed additional amounts
(3 equiv of Ag2O and 0.5 equiv of TMSOTf) to afford a swift re-
action (20 min) and a good yield of disaccharide 14 (87%, entry
5). Increasing only one activator, either Ag2O (from 2.0 to 3.0
equiv) or TMSOTf (from 0.20 to 0.25 equiv) resulted in no im-
provement. However, in some cases a significant increase in the
amount of TMSOTf (from 0.2 to 0.5 equiv) allowed to reduce
the amount of Ag2O to 1.5 equiv.
2.5/0.25
10 min
7
8
17
19
18, 99%
20, 65%
2.0/0.20
24 h
2.0/0.20
10 min
9
21
23
22, 96%
24, 91%
2.0/0.20
10 min
10a
Table 2. Glycosidation of bromide 2a with various acceptors
a – 0.9 equiv of acceptor 23 was used
Ag2O (equiv)/
TMSOTf (equiv)
time
Acceptor
(0.8 equiv)
Product,
Yield
Acid-sensitive cyclic ketal/acetal protection in acceptors 15
and 17 are unaffected under these conditions and excellent
yields of disaccharides 16 and 18 were achieved (91-99%, en-
tries 6 and 7). Thioglycoside acceptor 19 also produced disac-
charide 20 in a good yield of 65% (entry 8) ultimately demon-
strating the applicability of these reaction conditions to itera-
tive, selective activations for the synthesis of longer oligosac-
charide sequences. Hindered aliphatic acceptors cholesterol 21
and 1-adamantanol 23 were also glycosylated affording the re-
spective glycosides 22 and 24 in 10 min and in excellent yields
(91-96%, entries 9 and 10).
Entry
2.0/0.20
10 min
1
5
6, 98%
3.0/0.25
10 min
2
3
We then explored differently protected glycosyl donors of
other sugar series. Donors 2b-g were obtained directly prior to
glycosylation from the corresponding ethylthio glycosides 1b-
g by the reaction with bromine.[31, 40-42] In the benchmark ex-
periment, glycosidation of mannosyl donor 2a with acceptor 3
in the presence of 2 equiv. of Ag2O and 20 mol % of TMSOTf
afforded disaccharide 4a in 99% yield in 10 min (entry 1, Table
3). Glycosyl bromides 2b and 2c produced only 48-49% of the
respective disaccharides 4b and 4c under these reaction con-
ditions (entries 2-3). When higher amounts of promoters were
applied (3.0 equiv of Ag2O and 0.25 equiv of TMSOTf), swift re-
action times (10 min) and the excellent yields (99%) for the
formation of disaccharides 4b and 4c have been recorded (en-
tries 4 and 5).
7
8, 99%
OBn
O
HO
BnO
3.0/0.25
10 min
BnO
OMe
9
10, 99%
2.0/0.20
10 min
4
11
12, 99%
14, 87%
16, 91%
We then performed glycosidations of 2-O-benzylated glycosyl
donors 2d-g. The stereoselectivity of these reactions was re-
duced due to the lack of the participating group at C-2. Very un-
expectedly, we also noticed a significant drop in reactivity in all
cases except per-benzylated galactosyl donor 2f that was as re-
active as its per-benzoylated counterpart 2c. Slow glyco-
sidation of donor 2d (16 h, entry 6) could be attributed to the
superdisarming nature of its protecting group pattern.[43]
Nonetheless, disaccharide 4d was produced in an excellent
yield (92 %). In this context, we have also investigated glycosyl
bromides equipped with the superarming 2-O-benzoyl-3,4,6-
tri-O-benzyl protecting group pattern.[44] However, the reactiv-
ity of these compounds could not be differentiated from that of
the per-benzoylated derivatives under these powerful activa-
tion conditions.
3.0/0.50
20 min
5
6
13
15
2.5/0.25
10 min
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10.1002/chem.201805527
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A comparatively slow reaction of the supposedly armed per-
benzylated glucosyl donor 2e (16 h, entry 7) versus glyco-
sidation of the disarmed per-benzoylated counterpart 2b was
striking (10 min, entry 4). In addition, glycosyl donor 2e pro-
duced disaccharide 4e in a moderate yield (46%) even after 18
h. A similar reactivity trend was observed with mannosyl do-
nors. Thus, glycosidation of per-benzylated donor 2g was slow
(4.5 h) and required excess activators to produce disaccharide
4g in a respectable yield of 87% (entry 7). In contrast, the gly-
cosidation of the supposedly disarmed, per-benzoylated donor
2a was consistently swift. Glycosidation of per-benzylated ga-
lactosyl donor 2f was swift and produced the desired disaccha-
ride 4f in 90% yield even with as little as 10 mol % of TMSOTf
(entry 8).
reactive than its β-counterpart. In case of the 1,2-trans-ori-
ented glycosyl bromides α-2a or β-2b, the substituent at C-2 is
able to provide the anchimeric assistance that aids in the leav-
ing group departure. This is the rate-determining step (RDS) of
most glycosylations, and therefore the effect on the reaction
rate can be dramatic. There is no anchimeric assistance in case
of glucosyl donor α-2b or in case of any 2-O-benzylated donors.
As a result, the reactions with these substrates are much
slower. In case of galactosyl bromide 2c though, the anchimeric
effect on the rate of the reaction is negligible because of high
reactivity of galactosyl donors in general. Perhaps the reaction
conditions developed herein are too powerful to differentiate
the reactivity difference between α/β-2c and α-2c. Both glyco-
sidations of α/β-2c and α-2c provided quantitative yields in 10
min (entries 5 and 12). Glycosidation of per-benzylated galac-
tosyl donor 2f proceeded β-stereoselectively. This result is in-
dicative of an SN2-like displacement, but it also implies that the
anchimeric assistance is not the prevalent pathway in the D-ga-
lactosyl series.
Table 3. Glycosylation of acceptor 3 with bromides 2a-g
Figure 1. Relative reactivity of glycosyl bromides
Donor
(α/β)
Ag2O (equiv)/TMSOTf
(equiv), temp, time
2.0/0.20, 0 oC, 10 min
2.0/0.20, 0 oC, 1 h
Product
Entry
yield, ratio α/β
4a, 99%, α only
4b, 48%, β only
4c, 49%, β only
4b, 99%, β only
4c, 99%, β only
4d, 92%, 2.7/1
4e, 46%, 1/1.1
4f, 90%, ˃1/20
4g, 87%, 1.9/1
4a, 98%, α only
4b, 96%, β only
4c, 96%, β only
1
2
3
4
5
6
7
8
9
2a (α only)
2b (1/8.5)
2c (1/3.7)
2b (1/8.5)
2c (1/3.7)
2d (5.9/1)
2e (α only)
2f (α only)
2g (α only)
2a (α only)
2b (α only)
2c (α only)
2.0/0.20, 0 oC, 1 h
3.0/0.25, 0 oC, 10 min
3.0/0.25, 0 oC, 10 min
3.0/0.20, 0 oCrt, 16 h
3.0/0.20, 0 oCrt, 18 h
3.0/0.10, 0 oC, 15 min
3.0/0.20, 0 oCrt, 4.5 h
2.0/0.20, 0 oC, 10 min
3.0/0.25, 0 oC, 2 h
The relative reactivity of glycosyl bromides towards Ag2O (3.0
equiv)/TMSOTf (0.25 equiv) activation are summarized in Fig-
ure 1. In the D-gluco series, donor β-2b is much more reactive
than its α-linked counterpart α-2b. We specifically note a large
gap in reactivity between structurally similar donors α-2b and
2e that differ only by the electronics of their protecting groups.
Also in the D-manno series, a large reactivity difference was ob-
served between highly reactive benzoylated donor 2a and its
per-benzylated counterpart 2g. Practically no donor reactivity
difference was observed in the highly reactive D-galacto series.
To acquire the ultimate evidence of the superior reactivity pro-
file of the “disarmed” benzoylated mannosyl donor, we con-
ducted a direct competition experiment, wherein two manno-
syl donors 2a and 2g were set to compete for acceptor 3 in a
single pot (Scheme 1). As a result of this experiment, disaccha-
ride 4a derived from benzoylated donor 2a was isolated in
75% yield, whereas disaccharide 4g was present only in trace
amounts.
10a
11a
12a
3.0/0.25, 0 oC, 10 min
a – glycosyl bromide donors were presynthesized from the re-
spective penta-benzoates by reaction with HBr in acetic acid
The discrepancies in the reactivities of bromides of the armed
and disarmed series prompted us to investigate structures of
the glycosyl bromide intermediates. The NMR measurements
showed that mannosyl bromide 2a and all per-benzylated bro-
mides 2e-g were pure α-anomers, whereas benzoylated gluco-
syl bromide 2b (α/β = 1/8.5) and galactosyl bromide 2c (α/β =
1/3.7) showed the prevalence of the β-linked isomers. Being
aware that both the anomeric configuration and the relative
orientation of the C-1 and C-2 substituents have effect on the
reactivity, we also obtained pure α-configured donors 2a-c.
This was accomplished by presynthesizing glycosyl bromides
from the respective penta-benzoates by the reaction with HBr
in acetic acid. The presynthesized α-bromides 2a-c were then
glycosidated with acceptor 3 (entries 9-11). Not surprisingly,
the outcome of glycosidation of α-2a was essentially the same
although glycosidation of presynthesized glucosyl bromide α-
2b was much more sluggish (2 h, entry 11, Table 3) compared
to that of α/β-2b (α/β = 1/8.5) generated in situ (10 min, entry
4, Table 3).
We also executed preliminary steps to evaluate the mechanism
by which the Lewis acid additive enhances Koenigs-Knorr gly-
cosylations. First, we investigated whether this enhancement is
due to the direct interaction of the anomeric leaving group with
the Lewis or Bronsted acid. A series of 1H NMR experiments
with donor 2a in the absence/presence of TMSOTf in CDCl3
showed no shift of the anomeric hydrogen indicating that no
direct interaction between the leaving group and the additive
takes place (see the SI for complete details).
The difference in reactivity lies within the orientation of the 2-
O-participating group and the anomeric substituent and ulti-
mately confirms common knowledge that α-bromide 2b is less
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10.1002/chem.201805527
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Second, we investigated whether the initial interaction of
TMSOTf with Ag2O leads to the formation of AgOTf, a known
effective activator for bromides. When equimolecular amounts
of TMSOTf and Ag2O were premixed, a hygroscopic material
was obtained and its overall composition was confirmed by
SEM/EDS (scanning electron microscopy/energy dispersive X-
ray spectroscopy) semi-quantitative elemental analysis
(C4H9F3O4SSiAg2). Glycosidation of donor 2a with acceptor 3 in
presence of this presynthesized promoter was very effective in
producing disaccharide 4a in 99% in 10 min. The preformed
promoter was also very effective in glycosidating per-ben-
zoylated S-thiazolinyl (STaz)[45] and S-benzoxazolyl (SBox)[46-
47] donors that are known to be readily activated by AgOTf. This
result implies that the presynthesized promoter contains
AgOTf.
Therefore, we believe that this reaction proceeds via a cooper-
ative catalysis with Ag2O and a Lewis acid that originates from
the classical pathway of bromide activation via the complexa-
tion of Ag2O with the leaving group (A) as depicted in Scheme
2. While silver is thiophilic, Ag2O is too weak a promoter to ef-
fectively pull the leaving group and pass the energy barrier re-
quired for the dissociation RDS to take place. Koenigs and
Knorr[2] used mildly basic Ag2O or Ag2CO3 as acid scavengers. It
was not until the early 1930’s when it was realized that the sil-
ver salts may play a more active role by assist in the leaving
group departure.[4] The intermediate A will ultimately dissoci-
ate, but this reaction is slow, particularly with unreactive bro-
mides (vide supra). When catalytic TMSOTf (0.2 equiv) is
added, strongly ionized species B are formed as the result of
silylation of the silver oxide oxygen. The intermediate B will
readily break apart leading to the loss of the leaving group that
is irreversible due to the rapid precipitation of AgBr. Also
formed at this stage is AgOTMS and glycosyl cation C that can
be stabilized via acyloxonium or oxacarbenium intermediate
depending on the nature of the substituent at C-2.[48] As an al-
ternative, some donors might be capable of a concerted leaving
group displacement as observed in case of highly reactive ga-
lactosyl bromide 2f. The reactive intermediate C is then at-
tacked by acceptor (ROH) and after the proton exchange step
affords the desired glycoside product and TfOH. The latter re-
acts with AgOTMS to produce TMSOTf that becomes available
for the next catalytic cycle for the activation of complex A. Also
generated is unstable AgOH that undergoes the loss of water,
scavenged by the molecular sieves (MS), and contributes to the
regeneration of Ag2O and helps to maintain the overall neutral
pH of the reaction medium. In our experience, AgOTf-promoted
glycosidations of bromides are highly acidic and often provide
only moderate yields due to occurrence of side reactions
caused by the acidic medium.
Scheme 1. Competition experiments show superior reactivity
of per-benzoylated bromide 2a
Scheme 2. Plausible mechanistic pathway
Third, we investigated whether AgOTf that might be forming in
the reaction medium gets regenerated to perform subsequent
catalytic cycles. Glycosidation of thioimidate donors in the
presence of Ag2O (2.0 equiv) and cat. TMSOTf (0.2 equiv) was
practically ineffective and only small amounts of disaccharide
4b (<10%) have been obtained with the SBox donor that is
known to be slowly activated with TMSOTf.[46-47] Although we
cannot entirely exclude a possibility of forming small amounts
of AgOTf in situ, this results implies that it neither contributes
in the acceleration of the reaction with bromide donors nor
gets regenerated as shown in failed activations of thioimidates.
Fourth, previous studies dedicated to the activation of glycosyl
bromide with AgOTf were effective in the presence of 1,1,3,3-
tetramethylurea (TMU) as the proton scavenger. When our
standard experiment was performed in the presence of TMU
(1.0 equiv), only a small amount (<10%) of the disaccharide
was produced. This observation suggests that TMU scavenges
the protons needed to regenerate TMSOTf to run the catalytic
cycle. This observation also reduces the likelihood of the in-
volvement of AgOTf in the activation process.
In conclusion, the effective reaction conditions for rapid
Koenigs-Knorr glycosylation catalyzed with TMSOTf are re-
ported. The glycosylation products form in minutes and the
neutral activation conditions are compatible with many pro-
tecting and leaving groups. Also revealed is an unusual reactiv-
ity trend according to which benzoylated α-bromides are much
more reactive than their benzylated counterparts. The reactiv-
ity difference was demonstrated by the competition experi-
ment. Also studied is the reaction mechanism by which the
Koenigs-Knorr’s promoter silver oxide acts in cooperation with
the Lewis acid catalyst. Further studies dedicated to the
Fifth, we investigated whether other Lewis acids that cannot
form AgOTf would activate bromides. Similar experiments per-
formed with Ag2O and BF3-Et2O have ultimately confirmed that
AgOTf is not involved in the acceleration of Koenigs-Knorr re-
actions. Nevertheless, the premixed Ag2O and BF3-Et2O gave a
swift and nearly quantitative glycosidations of donor 2a with
acceptor 3 (see the SI for details).
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10.1002/chem.201805527
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AUTHOR INFORMATION
Corresponding Author
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* Department of Chemistry and Biochemistry, University of
Missouri – St. Louis, One University Boulevard, St. Louis, Mis-
souri 63121, USA; demchenkoa@umsl.edu
ACKNOWLEDGMENT
This work was supported by the National Institute of General
Medical Sciences (GM120673) and the National Science Foun-
dation (CHE-1800350).
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