AuCl3-AgOTf promoted O-glycosylation using anomeric sulfoxides as glycosyl donors at room temperature

Article abstract of DOI:10.1016/j.carres.2016.11.012

Activation of sulfoxide as glycosyl donors using AuCl₃/AgOTf reagent system has been described. Under optimal reaction conditions, both armed and disarmed glycosyl sulfoxide donors were found to react with a range of primary, secondary, and tertiary alcohol acceptors, and sugar derived glycosyl acceptors to afford the corresponding glycosides in moderate to good yields with predictable selectivity. The reactions are quick (20–60 min), facile at room temperature and the reactions conditions tolerate acid sensitive groups.

Full text of DOI:10.1016/j.carres.2016.11.012

Accepted Manuscript
AuCl -AgOTf promoted O-glycosylation using anomeric sulfoxides as glycosyl donors
3
at room temperature
Ashokkumar Palanivel, Ande Chennaiah, Sateesh Dubbu, Asadulla Mallick, Yashwant
D. Vankar
PII:
S0008-6215(16)30339-1
10.1016/j.carres.2016.11.012
CAR 7295
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 30 August 2016
Revised Date: 21 November 2016
Accepted Date: 21 November 2016
Please cite this article as: A. Palanivel, A. Chennaiah, S. Dubbu, A. Mallick, Y.D. Vankar, AuCl -
3
AgOTf promoted O-glycosylation using anomeric sulfoxides as glycosyl donors at room temperature,
Carbohydrate Research (2016), doi: 10.1016/j.carres.2016.11.012.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
AuCl3-AgOTf promoted O-glycosylation using anomeric sulfoxides
as glycosyl donors at room temperature
Ashokkumar Palanivel, Ande Chennaiah, Sateesh Dubbu, Asadulla Mallick and
Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology Kanpur 208 016, India
Fax: 0091-512-259 0007; E mail: vankar@iitk.ac.in
ABSTRACT
Activation of sulfoxide as glycosyl donors using AuCl3/AgOTf reagent system has been
described. Under optimal reaction conditions, both armed and disarmed glycosyl sulfoxide
donors were found to react with a range of primary, secondary, and tertiary alcohol acceptors,
and sugar derived glycosyl acceptors to afford the corresponding glycosides in moderate to good
yields with predictable selectivity. The reactions are quick (20-60 min), facile at room
temperature and the reactions conditions tolerate acid sensitive groups
KEYWORDS: gold(III) chloride, silver triflate, anomeric sulfoxides, O-glycosylation
.
INTRODUCTION
Oligosaccharides and glycoconjugates (glycolipids and glycoproteins) constitute an
important class of biomolecules that play crucial roles in many biological processes [1–3].
Synthesis of such molecules is an important area of modern research to procure them in pure
forms and in good quantities. One of the most crucial steps that is needed in the synthesis of
oligcosaccharides is glycosylation reaction [4–8] where a glycosidic bond is formed by reacting
a glycosyl donor and a glycsoyl acceptor in the presence of a promoter or a catalyst. Different
types of glycosyl donors and activators have been developed over the years and the search is still
on, as not one set of conditions are good enough from the point of view of yield, α/β anomeric
selectivity, stability of glycosyl donors etc. Nevertheless, a few glycosyl donors such as glycosyl
trichloroacetimidates [8], thioglycosides and modifications thereof [9–10], n-pentenyl glycosides
[11], glycosyl halides [12] including glycosyl fluorides [13], are routinely used by a number of
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chemists. Depending on the type of glycosyl donor, different catalysts (or promoters) such as
BF3.Et2O, TMSOTf, N-iodosuccinimide (NIS)-TfOH, AgClO4 etc. are used to activate the
leaving group at the anomeric carbon. Glycosyl sulfides are commonly used when there is a need
to utilize a relatively stable glycosyl donor in an oligosaccharide synthesis. However, these
thioglycosides need molar equivalent of an activator such as NIS along with a catalytic amount
of TfOH to permit glycosylations effectively. In this regard, recently, an interesting report by
Sureshan et al. [14] appeared but this also needs close to stoichiometric amount of activator
(AuCl3) to effect glycsoylation using thioglycosides. Prior to this report, we recently published
the use of AuCl3-Phenyl acetylene as a new relay catalyst system to activate glycosyl acetates for
O-glycosylations [15]. This catalyst system was also found to activate both armed and disarmed
glycosyl trichloroacetimidates [16], as well as 1-O-acetylfuranoses and pyranose 1,2-orthoesters
[17]. During the period this work was being carried out, we had also explored the possible
activation of a thioglycoside to effect glycosylation and found that the use of AuCl3 alone, or
along with phenylacetylene in catalytic amounts led to glycosylated products in only 5-10%
yield. In continuation of our studies towards introducing new methods of glycosylations, we
wondered if, instead of thioglycosides, anomeric sulfoxides could be activated with AuCl3.
Further, glycosyl sulfoxides can easily be prepared from the corresponding thioglycosides by
oxidation, for example, with m-CPBA and thus thioglycosides can be used and be converted into
sulfoxides when needed. Glycosyl sulfoxides have been used as glycosyl donors ever since the
report by Kahne and co-workers [18] appeared where they activated the anomeric sulfoxides
with triflic anhydride in the presence of stoichiometric 2,6-di-tert-butyl-4-methyl pyridine
(DTBMP) as a triflic acid scavenger [19]. Later, some other reagents such as TMSOTf [20],
triflic acid [21], Cp2ZrCl2/AgClO4 [22], H3PW12O40 (a heteropoly acid) [23], nafion-H [24], and
iodine [25] have also been reported to activate glycosyl sulfoxides to lead to O-glycosylation.
However, some of the drawbacks associated with these glycosylation methods are [18] (i) the use
of stoichiometric amount of promoters, (ii) requirement of very low temperature [18] and (iii)
longer reaction times in some cases [22].
In this communication, we report that a combination of 10 mol% of AuCl3 and 30 mol%
of AgOTf effectively activates both armed and disarmed glycosyl sulfoxides to lead to O-
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glycosylations at room temperature. We believe that with this newly discovered reagent system,
problems associated with the traditional activation of sulfoxides can be overcome.
RESULTS AND DISCUSSION
To demonstrate the utility of our methodology, we chose compounds 1–5 [26] (Scheme
1) as standard glycosyl donors. Initially, we examined the glycosylation using anomeric
sulfoxide 1 with l-menthol in the presence of 10 mol% of AuCl3 in dry dichloromethane as
solvent which led to only 10% conversion in 12 h (Table 1, entry 1). Increasing the catalyst
loading to 30 mol% led to a maximum of 30% conversion even after leaving the reaction to
continue for a longer time (Table 1, entry 2). Further, we checked the reactivity of Au(III)
bromide [17, 27] under the same set of reaction conditions but disappointingly its reactivity was
no
Scheme 1. Armed and disarmed glycosyl sulfoxide donors employed for glycosylation
better than that with AuCl3 (Table 1, entry 3). Further, gold(I) salts like AuCl and AuCl(PPh3)
[28] were found unreactive under the same reaction conditions (Table 1, entries 4 and 5). Later,
after examining various combinations, we found that the use of 10 mol% of AuCl3 along with 30
mol% of AgOTf as a co-catalyst promoted the reaction to completion in 30 min with 75%
isolated yield of the glycoside 6 (Table 1, entry 6) possibly due to silver effect in gold catalysis
[17, 29]. By using increased amount of AuCl3 even upto 30 mol% either alone or along with
AgOTf did not make any significant difference on yield or the selectivity. To check if AgOTf
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alone can catalyse the glycosylation, we reacted glycosyl sulfoxide 1 with l-menthol in the
presence of upto one equivalent of AgOTf, however, the reaction did not take place (Table 1,
entry 8). It became evident that 10 mol% of AuCl3 is essential along with AgOTf for the
glycosylation to proceed.
Table 1. Optimization of reaction conditions for gold catalyzed glycosylation.[a]
Menthol
OBn
O
OBn
O
AuX or AuX3
BnO
BnO
SOPh
BnO
BnO
O
OBn
4 Å mol.sieves
dry CH2Cl2
OBn
1
6
/
ratioc
-
Yieldb
Time
Entry
Catalyst
1
10 mol % AuCl3
30 mol % AuCl3
10 mol % AuBr3
12 h
10% conversion
2
3
12 h
12 h
30% conversion
10%
2:1
2:1
-
10 mol % AuCl(PPh3)
10 mol % AuCl
4
5
no reaction
12 h
12 h
no reaction
-
6
7
10 mol % AuCl3, 30 mol% AgOTf 20 m
2:1
75%
12 h
10 mol % AuBr3, 30 mol% AgOTf
2:1
10%
AgOTfd
-
-
12 h
12 h
8
no reaction
no reaction
no reaction
30 mol % Yb(OTf)3
9
12 h
30 mol % Sc(OTf)3
-
-
10
11
30 mol % InCl3
12 h
12 h
no reaction
no reaction
30 mol % BF3.OEt2
-
12
o
[a] Room temperature was 35-39 C. Reactions were performed in dry dichloromethane as
solvent in the presence of 4 Å molecular sieves at room temperature. [b] Isolated yield. [c] The
a/b ratio was determined from 1H spectral analysis. [d] One equivalent of AgOTf was used
Reactions of glycosyl sulfoxide 1 with l-menthol in the presence of upto 30 mol% of
some other Lewis acid catalysts such as BF3.OEt2, Yb(OTf)3, InCl3, and Sc(OTf)3 were also
screened (Table 1, entries 9-12). However, none of these catalysts was able to effect the
4

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expected glycosylation. Thus, with the above described optimized conditions of a combination
of 10 mol% AuCl3 and 30 mol% of AgOTf we performed the remaining study, results of which
are being reported here.
Table 2. Gold catalyzed glycosylation for the synthesis of glycosides 6-14[a]
OBn
O
10 mol% AuCl3
30 mol% AgOTf
OBn
O
BnO
BnO
BnO
BnO
SOPh
ROH
OR
BnO
BnO
dry CH2Cl2, 20-60 min
1
6-14
OBn
O
OBn
O
OBn
O
BnO
BnO
BnO
BnO
O
BnO
BnO
O
O
BnO
OBn
OBn
6
7
8
20 minb, Yieldc = 75%, 2:1 (α/β)d
25 min, 77%, 2.2:1 (α/β)
60 min, 62%, 1.5:1 (α/β)
OBn
OBn
O
OBn
O
Me
BnO
BnO
OBn
O
O
BnO
BnO
O
O
BnO
BnO
BnO
O
BnO
BnO
OBn
O
BnO
9
BnO
BnO
OMe
11
BnO
10
OMe
25
, 71%, 1:1 (α/β)
30
, 68%, 2.5:1 (α/β)
45 , 55%, 1.2:1 (α/β)
min
min
min
OBn
O
OBn
O
BnO
BnO
OBn
O
BnO
BnO
BnO
O
O
O
O
O
BnO
BnO
OBn
BzO
O
O
OBn
BzO
O
BzO
OMe
O
12
30 min, 85%, 2.5:1 (α/β)
13
14
30 min, 73%, 1:1 (α/β)
25 min, 60%, 1.2:1 (α/β)
[a] Room temperature was 35-39 °C. Reactions were performed in dry dichloromethane as
solvent in the presence of 4 Å molecular sieves at room temperature. [b] Time [c] Isolated yield.
[d] The α/β ratio was determined from 1H spectral analysis.
Accordingly, we next explored the scope of the reaction with variety of glycosyl
acceptors with armed glycosyl sulfoxides (1-3). As shown in Table 2, the sulfoxide 1 underwent
smooth reactions with primary, secondary, and tertiary alcohols as glycosyl acceptors to afford
the desired glycosides, including some disaccharides, 6−14 in moderate good to yields. In these
glycosylation reactions, it was found that acid sensitive groups present in glycosyl acceptors
remained unaffected during the glycosylation reaction. Thus, glycosylation with diacetone
D-
5

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galactose, produced the corresponding glycoside 13 in 73% yield in 25 min. Similarly, with a
benzoyl protected glycosyl acceptor, the disaccharide 12 was obtained in 85% yield in 30 min.
Table 3. Gold catalyzed glycosylation for the synthesis of glycosides 15-24[a]
10 mol% AuCl3
O
30 mol% AgOTf
O
BnO
SOPh
OR
BnO
ROH
15-24
2-3
4 Å mol. sieves
dry CH2Cl2, rt, 20-60
min
OBn
OBn
O
BnO
BnO
BnO
BnO
OBn
BnO
O
O
BnO
15
O
BnO
O
BnO
O
OBn
17
16
25 min, 68%, 1.2:1 (α/β)
20 minb, Yieldc = 68%, 2.5:1 (α/β)d
30 min, 68%, 1.1:1 (α/β)
OBn
BnO
OBn
BnO
OBn
O
BnO
BnO
O
OBn
O
O
BnO
O
O
BnO
O
BnO
O
O
BnO
BnO
OBn
BzO
BnO
BnO
BzO
OMe
BnO
OBz
OMe
BnO
OMe
19
20
18
25 min, 68 %, 1.5:1 (α/β)
60 min, 54%, 1.5:1 (α/β)
35 min, 80%, 2.5:1
(α/β)
OBn
BnO
O
BnO
OBn
BnO
BnO
O
O
O
BnO
O
O
O
BnO
O
O
21
22
30 min, 70%, 2.5:1 (α/β)
25 min, 62%, 3:1 (α/β)
OBn
BnO
BnO
BnO
O
OBn
O
BnO
BnO
BnO
O
O
O
BnO
BnO
23
25 min, 72%, 2.5:1 (α/β)
24
30 min, 70%, 3:1 (α/β)
BnO
OMe
[a] Room temperature was 35-39 °C. Reactions were performed in dry dichloromethane as
solvent in the presence of 4 Å molecular sieves at room temperature. [b] Time [c] Isolated yield.
[d] The α/β ratio was determined from 1H spectral analysis.
In a similar way, glycosyl sulfoxides 2 and 3 derived from
D-galactose and D-mannose
respectively were subjected to glycosylations with a range of nucleophiles to produce the
corresponding glycosides 15-24 as a mixture of α− and β−anomers in good yields as depicted in
Table 3. As expected, the
α glycoside was the major product during glycosylation of mannosyl
sulfoxide 3 as exemplified by the formation of glycosides 23 and 24 in 2.5:1 and 3:1 α/β ratio.
To explore further the synthetic utility of this convenient glycosylation method, the
glycosylation of disarmed glycosyl donors 4 and 5 with a variety of glycosyl acceptors were
6

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examined. These results are summarized in Table 4. All the glycosylations of 4 and 5 were
performed using 10 mol% AuCl3 and 30 mol% AgOTf in the presence of 100 wt% MS 4 Å in
dry dichloromethane at room temperature which proceeded to give the corresponding glycosides
25-34 in good to high yields with high β−selectivity in all the cases due to anchimeric assistance
from –OAc group at C2. Surprisingly, however, in case of galactose derived glycosyl donor 5
reacting with l-menthol we found that a small amount of α-glycoside 32 was found to form. It
may be likely that the chair conformation of menthol may exert a steric hindrance when in β-
position thus allowing the formation of the α-glycoside to some extent.
Table 4. Gold catalyzed glycosylations for the synthesis of glycosides 25-34.[a]
10 mol% AuCl3
O
O
4-5
30 mol% AgOTf
AcO
OR
AcO
SOPh
ROH
25-34
dry CH2Cl2
20-60 min
OAc
OAc
OAc
O
AcO
AcO
O
O
O
O
AcO
AcO
AcO
O
Ph
AcO
AcO
AcO
AcO
25
26
27
30 minb, yieldc = 88%, β onlyd
20 min, 73%, β only
25 min, 61%, β only
OAc
OAc
OMe
OBn
OBn
O
O
O
O
AcO
AcO
O
AcO
AcO
O
AcO
BnO
AcO
OBn
OBn
BnO
OMe
28
35 min, 71%, β only
29
60 min, 53%, β only
OAc
OAc
O
AcO
AcO
AcO
AcO
OAc
AcO
O
O
O
Ph
O
O
AcO
AcO
AcO
AcO
30
31
32
35 min, 69%, β only
25 min, 77%, β only
OAc
25 min, 63%, 1:3 (α/β)
AcO
AcO
OAc
O
AcO
AcO
O
OBn
O
O
O
AcO
BnO
O
BnO
AcO
BnO
BnO
OMe
BnO
OMe
33
34
50 min, 50%, β only
35 min, 72%, β only
[a] Room temperature was 35-39 °C. Reactions were performed in dry dichloromethane as
solvent in the presence of 4 Å molecular sieves at room temperature. [b] Time [c] Isolated yield.
[d] The α/β ratio was determined from 1H spectral analysis.
7

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A tentative mechanism is shown in scheme 2 proving that combination of one equivalent of
AuCl3 and three equivalents of AgOTf is required in a catalytic process. We propose that AuCl3
reacts with AgOTf to form Au(OTf)3, A, which further reacts with glycosyl sulfoxide B to form
intermediate C. Next, the lone pair of the ring oxygen assists in the formation intermediates
oxonium ion D and sulfoxide–gold complex F. The nucleophile then attacks at the anomeric
centre to form the required glycoside E. Meanwhile, the sulfoxide–gold complex F gets
protonated by triflic acid and breaks down in to benzenesulfenic acid and regenerates Au(OTf)3
to enter into the next catalytic cycle. In order to prove the formation of benzenenesulfenic acid
H, a crude reaction mixture was subjected to mass analysis and was confirmed its formation
from ESI-HRMS data (m/z 125.0067). However, we did not observe any addition product of
benzenenesulfenic acid on olefinic substrates/products. It is possible that since the olefinic
substrates are either weekly nulceophilic being mono-substituted terminal olefin (1-pentenyl
alcohol derived) or somewhat sterically hindered (cholesterol derived), the addition is not
observed.
AuCl3 + 3AgOTf
3AgCl
O
O
S
Au(OTf)3
Ph
Ph
Ph
S
OH
H
A
RO
B
H
O
OTf
S
Au
OTf
OTf
G
OTf
Ph
S O Au
OTf
OTf
F
O
Au OTf
O
S
TfOH
Ph
OTf
RO
C
"ROH
OTf
O
OR"
O
RO
E
RO
D
Scheme 2: Proposed mechanism
It is worth mentioning here that our previous attempts to activate the disarmed glycosyl acetates9
with AuCl3 were unsuccessful but pleasantly, our new catalyst system comprising of 10 mol% of
8

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AuCl3 and 30 mol% of AgOTf works well with both D-gluco and D-galacto derived disarmed
glycosyl sulfoxides to produce the corresponding glycosides efficiently and all the glycosylations
were completed in 20-60 min of duration (Table 4).
CONCLUSION
In conclusion, we have described for the first time that a combination of 10 mol% of AuCl3-30
mol% of AgOTf is an effective, mild and selective promoter system for the activation of glycosyl
sulfoxides. This reagent system works well with both armed and disarmed glycosyl sulfoxides
and it overcomes the problems associated with the previous methods like use of stoichiometric
amount of promoter, longer reaction time and temperature. Thus, the present method gives a
platform for the synthesis of a variety of oligosaccharides and glycoconjugates.
EXPERIMENTAL SECTION
General Methods: All the experiments were performed in a oven dried apparatus and under inert
atmosphere. All the solvents were dried using the standard procedures and stored in 4Å
1
molecular sieves. H (500 and 400 MHz) and 13C (125 and 100 MHz) NMR spectra were
recorded using JEOL ECX-500 and 386 JEOL JNM-LA 400 spectrometers in solutions of CDCl3
using tetramethylsilane as the internal standard. High resolution mass spectra were recorded by
Q-TOF using electrospray ionization (ESI) method. Column chromatography was carried out
over silicagel (100–200 mesh), and TLC was carried out using silica gel plates made with grade
G silica gel from S. D. Fine-chem Ltd., Mumbaion microscopic slides. Drying and purification
of solvents as well as required reagents were done by standard procedures as described in the
book of “Purification of Laboratory chemicals, third edition” by D. D. Perrin and W. L. F.
Armarego. The salts AuCl3 and AgOTf were purchased from Sigma-Aldrich.
General Procedure for glycosylation of glycosyl sulfoxides catalyzed by AuCl3 and AgOTf:
To a solution of glycosyl sulfoxide 1-5 (100 mg) and 4 Å molecular sieves (100 mg) in
anhydrous dichloromethane (5 mL), were added a glycosyl acceptor (1.2 equiv), AuCl3 (10 mol
9

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%) and AgOTf (30 mol %) at room temperature. The resulting solution was stirred at room
temperature until the starting material was completely consumed (TLC monitoring). The organic
layer was evaporated to dryness under reduced pressure to get crude glycoside which was further
purified by silica-gel column chromatography using hexane and ethyl acetate as the eluting
system to get pure glycosides, yield 6 (78 mg, 75%), 7 (74 mg, 77%), 8 (65 mg, 62%), 9 (100,
71%), 10 (104 mg, 68%), 11 (83 mg, 55%), 12 (135 mg, 85%), 13 (88 mg, 73%), 14 (54 mg,
60%), 15 (70 mg, 68%), 16 (65, 68%), 17 (95 mg, 68%), 18 (104 mg, 68%), 19 (82 mg, 54%),
20 (127 mg, 80%), 21 (84 mg, 70%), 22 (56 mg, 62%), 23 (74 mg, 72%), 24 (106 mg, 70%), 25
(94 mg, 88%), 26 (71 mg, 73%), 27 (65 mg, 61%), 28 (126 mg, 71%), 29 (92 mg, 53%), 30 (73
mg, 69%), 31 (75 mg, 77%), 32 (67 mg, 63%), 33 (88 mg, 50%), 34 (127 mg, 72%). The
α/β ratio of the glycosides was determined by the integration values of the anomeric protons and
those of the OMe- protons in their 1H NMR spectra.
Supporting Information
1H and 13C for all synthesized compounds.
AUTHOR INFORMATION
Corresponding Author
*E-mail: vankar@iitk.ac.in
Notes
The authors declare no competing financial interest.
Acknowledgement
We thank the Department of Science and Technology, New Delhi, for the J. C. Bose
National Fellowship to Y. D. V. (JCB/SR/S2/JCB-26/2010). AP, AC, DS and AM thank the
Council of Scientific and Industrial Research, New Delhi for senior research fellowships.
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ACCEPTED MANUSCRIPT
Highlights
Our work in this manuscript describes the utility of a catalyst system (AuCl3-AgOTf) for
an important reaction that is O-glycosylation at room temperature. This has been discovered after
screening different combinations of catalysts. Both armed as well as disarmed glycosyl
sulfoxides are readily activated with this catalyst system to lead to the corresponding
O-glycosides at room temperature within 25-60 min. Thus, we are sure that this method will find
usefulness in organic synthesis, in general, and in carbohydrate chemistry in particular.