Versatile gold catalyzed transglycosidation at ambient temperature

Article abstract of DOI:10.1039/c2cc32649c

Glycosidation with stable alkyl glycosyl donors using a catalytic amount of gold salts is promising. Herein, 1-ethynylcyclohexanyl glycosides are identified as novel donors at room temperature and mechanistic investigation showed that the leaving group simply extrudes out.

Full text of DOI:10.1039/c2cc32649c

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COMMUNICATION
Versatile gold catalyzed transglycosidation at ambient temperaturew
Abhijeet K. Kayastha and Srinivas Hotha*
Received 14th April 2012, Accepted 18th May 2012
DOI: 10.1039/c2cc32649c
Glycosidation with stable alkyl glycosyl donors using a catalytic
amount of gold salts is promising. Herein, 1-ethynylcyclohexanyl
glycosides are identified as novel donors at room temperature and
mechanistic investigation showed that the leaving group simply
extrudes out.
Glycoconjugates and oligosaccharides belong to a class of
biomolecules that play pivotal roles in various cellular events.1
Information transfer across cells, antigen-antibody interactions,
transport of toxins through the cell membrane and a host of
other molecular recognition events are found to occur through
glycoconjugates.2 Glycoconjugates contain an oligosaccharide
unit or glycan attached to a lipid, peptide and/or steroid in a
stereodefined fashion and thus access to oligosaccharides is
required.3 Hence, development of a robust and reliable glycan-
specific platform for the synthesis of oligosaccharides is highly
welcomed by the entire glycobiology community.3b
Fig. 1 Screening of leaving groups for gold-catalyzed transglycosidation
Construction of glycans relies upon two important building
at room temperature. Reaction Scheme (A), Leaving groups studied
blocks which are called glycosyl donors and glycosyl acceptors
(B) and the % yield versus leaving group with AuBr3, AuCl3, HAuCl4(C).
(or aglycons).3a A glycosyl donor is defined as any substance
temperature (60 1C) was found to be limiting in some cases.4j Thus,
systematic investigation of various alkyne bearing appendages at
that can donate its glycon to the acceptor through an inter-
glycosidic bond. Activators promote the formation of an
the anomeric position was carried out to find a leaving group that
intermediate called the oxocarbenium ion which is attacked
would facilitate transglycosidation at ambient temperatures. To
by a nucleophile present in the form of an aglycon to form
begin with, synthesis of mannopyranosyl disaccharide (3) was
glycosides (Scheme 1). Over the last century, several glycosyl
considered as a model reaction (Fig. 1A) in view of earlier
donors have been developed, explored and exploited by various
observations.4a–b,4j Alkyl substituted mannopyranosyl donors
(1A–1L) were prepared in parallel by three simple steps; first,
per-O-acetyl mannopyranose was reacted with alcohols A–L
using BF3ÁEt2O and then deacetylated under Zemplen conditions
and per-O-benzylated using NaH, BnBr in DMF (Fig. 1B).6
Aglycon 2a was allowed to react with potential mannosyl donors
(1A–1L) in the presence of three gold catalysts AuBr3, AuCl3 and
HAuCl4 at room temperature for 12 h in CH3CN.
groups.3 From our laboratory, stable propargyl/methyl glycosides
were discovered as glycosyl donors when activated in the presence
of catalytic amounts of gold(III) halides.4a,b Subsequently, Yu,
Mamidyala and Kunz have independently studied utility of
gold salts in glycosidation reaction (Scheme 1).5
A gold-catalyzed transglycosidation strategy was found
to be superior for glycopolymers4c–i though a high reaction
Glycosyl donors 1A and 1B which do not possess alkyne
groups did not proceed satisfactorily and simple propargyl
substitution (1C) was found to give about 18% yield after 12 h
at room temperature in the presence of AuCl3 (Fig. 1). Single
aromatic substitution on the propargyl moiety (1D and 1E) also
failed to give good yields where methyl substitutions (1F, 1H)
showed good conversion with AuCl3 but not with AuBr3 and
HAuCl4. Between gem-disubstituted donors 1G and 1I, the
dimethyl donor 1I was found to be superior. However, placing
the cyclic substitution (1J–1L) in place of gem-dimethyl was found
to be highly beneficial. Nevertheless, best results in the screening
process were observed with donors 1I, 1K and 1L (Fig. 1C).6,7
Scheme 1 General glycosidation reaction.
Department of Chemistry, Indian Institute of Science Education &
Research, Pune, India. E-mail: s.hotha@iiserpune.ac.in;
Fax: +91 20 2589 9790; Tel: +91 20 2590 8015
w Electronic supplementary information (ESI) available: General
experimental procedures and spectra charts of all compounds. See
DOI: 10.1039/c2cc32649c
c
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Chem. Commun., 2012, 48, 7161–7163 7161

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Increased reactivity of gem-disubstituted donors can be attributed
to the earlier reported Thorpe–Ingold like effect.8 Mannosyl
donors 1I and 1J were not considered further either due to the
observed instability or ease in preparation. Donor 1K was found
be better than 1L purely because of the easy availability and low
cost of 1K though both 1K and 1L fared equally (Fig. 1).
To understand the mechanism, tetrahydropyran (THP) protected
1-ethynylcyclohexanol 4 (Ech–OH) was chosen as the model
glycosyl donor for gas chromatography (GC) studies since
glycosyl donor 1K and THP-Ech ether (4) are both acetals and
hence, the later should be sufficient to act as a glycosyl donor for
the transglycosidation with 4-methylbenzyl alcohol (5).6 Initially,
the individual components THP-Ech ether (4), aglycon (5), the
desired transglycosylated product (6), leaving group (7) and
4-methylbenzyl bromide (8) were injected into the gas chromato-
graph and obtained well separated retention times (Rt) (Fig. 2).
The donor 4 at Rt 36.5 min disappeared completely in 4 h
and a newly formed transglycosylated product 6 (Rt 38.0 min)
coincided with that of the standard and to our surprise, we
observed simple 1-ethynylcyclohexanol 7 at retention time of
25.3 min and 4-methylbenzyl bromide 8 at Rt 33.2 min.
Independently, 4-methylbenzyl alcohol was found to give
bromide 8 in the presence of AuBr3. Formation of inter-
mediate 7 is surprising since it contradicts earlier studies which
postulated that the propargyloxy group is converted to cyclo-
propanone through a series of unidentified intermediates.4a
Therefore the gold-catalyzed transglycosidation mechanism
can be envisaged as alkynophilic AuX3 co-ordinates with exocyclic
oxygen and the alkyne (9) which can collapse to give a cyclo-
propenyl gold halide intermediate 10 (Fig. 3). Subsequently,
exocyclic oxygen can get protonated to give intermediate 11 that
could further get converted to the oxocarbenium ion 12 which is
available for the attack of ROH to result in the transglyco-
sylated product. Prototropic demetallation would result in the
regeneration of AuX3 for further catalytic action and 1-ethynyl-
cyclohexanol (Ech-OH) 7 (Fig. 3). Important to mention that the
leaving group can be removed easily under high vacuum from the
reaction mixture thereby making the leaving group traceless after
the reaction. Addition of a drop of Et3N to the reaction mixture
quenched the reaction suggesting the formation of HX.
Fig. 3 Plausible mechanism for the transglycosidation.
Furthermore, the reaction of 1K and 2a failed to proceed in
the presence of Et2OÁHCl or AgSbF6/tert-BuCl ruling out any
hidden simple Brønsted acid catalysis.8e In addition, reaction
with Au2O3 which has Au(III) but not a Lewis acid showed no
reaction suggesting a role for both Lewis and Brønsted acidity
in the transglycosidation. Identification of a good leaving
group and a plausible mechanism for the gold-catalyzed
transglycosidation reaction prompted us to optimize the reac-
tion for the right catalytic conditions (Table 1).
Heating the donor 1K and aglycon 2a to 45 1C in the presence
of AuCl3 or AuBr3 increased the yield of the reaction sub-
stantially (Table 1, entry 1,2); further increase to 70 1C showed
further improvement of yield (>80%) (Table 1, entry 3,4).
Inspired by several recent literature reports on the enhancement of
performance in gold catalyzed reactions by the addition of Ag-salts,
addition of Ag-based co-catalysts was then studied.9 Accordingly,
optimization of glycosidation with 5 mol% each of AuCl3 and
AgOTf showed that the reaction can be carried out at room
temperature without compromising yields (entry 5). Nevertheless,
transglycosidation between 1K and 2a in the presence of AuX3-
AgSbF6 was found to be highly efficient (91% in 4 h) at desired
room temperature (entry 6,7). The best result (96% in 4 h) of
disaccharide 3 was obtained when the transglycosidation reaction
between 1K and 2a was conducted in acetonitrile–dichloromethane
(1 : 1) at room temperature for 4 h in the presence of 1 : 1 quantity of
5 mol% of AuCl3 and AgSbF6 (entry 8) and thus all further studies
were conducted with these optimized reaction conditions only.
The generality of the newly identified gold-catalyzed trans-
glycosidation at room temperature was evaluated with a panel
of aglycons (2b–2j) and glycosyl donors 1K, 13 and 14.
Table 1 Identification of the right catalytic conditions for the room
temperature activation
Entry Catalyst
Solvent
Time/h T/1C Yield (%)
1
2
3
4
5
6
7
8
AuCl3
AuBr3
AuCl3
AuBr3
CH3CN
CH3CN
CH3CN
CH3CN
8
8
8
8
3
4
12
4
45
45
70
70
25
25
25
25
71
74
86
82
83
91
90
96
AuCl3+AgOTf CH3CN
AuCl3+AgSbF6 CH3CN
AuBr3+AgSbF6 CH3CN
AuCl3+AgSbF6 CH3CN+CH2Cl2
Fig. 2 Gas Chromatography studies.
c
7162 Chem. Commun., 2012, 48, 7161–7163
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Table 2 Transglycosidation at room temperature
Donor
Aglycone
Product
Yield (%)
Donor
Aglycone
Product
a : b
Yield (%)
2b
2c
2d
2e
2f
15
16
17
18
19
93
95
90
68
74
2d
2f
2g
2i
24
25
26
27
28
1 : 8.9
1 : 1.3
1 : 3.1
1 : 3.2
1 : 2.8
92
73
95
73
95
2j
2g
2h
2i
20
21
22
23
91
78
71
96
2d
2f
2g
2j
29
30
31
32
1 : 2.7
1 : 8.1
1 : 8.2
1 : 7.9
94
71
94
95
2j
Transglycosidation reaction using mannopyranosyl donor 1K
and aglycons 2b,2c and 2d resulted in the formation of the
corresponding glycosides 15–17 in excellent yields. Interestingly,
newly identified gold-catalyzed transglycosidation conditions on
monosaccharide-based primary alcohols (2g, 2j) resulted in
quantitative yield to give disaccharides 20,23 where as secondary
alcohols (2h, 2i) gave greater than 70% yield of disaccharides 21,
22. Gratifyingly, secondary alcohols 2e and 2f also underwent
transmannopyranosylation resulting in the formation of corres-
ponding mannopyranosides 18 and 19 (Table 2).
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6 See Supporting Informationw.
7 General transglycosidation procedure for room temperature activation
of1-ethynylcyclohexanol glycosides: To a 3 mL 1 : 1 CH3CN–CH2Cl2
solution of mannopyranosyl donor 1K (100 mg, 0.155 mmol) and
aglycon 2a (86 mg, 0.170 mmol) was added a solution of AuCl3 (2.3 mg,
7.7 mmol) and AgSbF6 (2.7 mg, 7.7 mmol) in 3 mL of 1 : 1
CH3CN–CH2Cl2 and stirred at 25 1C. After 4 h, dark brown
reaction mixture was concentrated in vacuo and purified through
silica gel column chromatography using 1 : 5 ethyl acetate–petroleum
ether to obtain disaccharide 3 (153 mg, 96%) as a pale yellow
solid.
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48, 8361; (e) T. T. Dang, F. Boeck and L. Hintermann, J. Org.
Chem., 2011, 76, 9353.
Furthermore, room-temperature transglycosidation using
Ech-glycosides was successfully extended to glucosyl and
galactosyl donors 13 and 14. For example, aglycons which
are alicyclic or carbohydrate derived primary alcohols resulted
in transglycosylated products in quantitative yields where the
secondary alcohols gave very high yields of tranglycosylated
products (Table 2). Transglycosylated products resulting from
glucosyl donor 13 and galactosyl donor 14 are found to be an
a,b mixture of anomers (24–32) with the b-anomer being the
major anomer due to the participating nature of CH3CN
which is in complete agreement with earlier observations.5
In summary, we identified a new gold-catalyzed transglyco-
sidation that can be conducted at room temperature. We have
studied the reaction with a panel of diverse leaving groups and
found that 1-ethynylcyclohexanyl (Ech) glycosyl donors give
excellent transglycosidations. Furthermore, Ech- glycosyl donors
were found to be superior to simple propargyl glycosyl donors.
Primary alcohols, alicyclic, steroidal alcohols were observed to
give quantitative yields of transglycosylated products whereas
carbohydrate-derived secondary alcohols and others result in
high yields. In addition, we have also performed gas chromato-
graphy studies that gave mechanistic insights and showed that
the leaving group is just coming out as 1-ethynylcyclohexanol.
S.H. thanks the DST, New Delhi for the SwarnaJayanti
Fellowship and AKK thanks UGC for the financial support.
Notes and references
1 (a) P. M. Rudd, T. Elliott, P. Cresswell, I. A. Wilson and R. A. Dwek,
Science, 2001, 291, 2370; (b) J. C. McAuliffe and O. Hindsgaul,
9 (a) A. S. K. Hasmi, Angew. Chem., Int. Ed., 2010, 49, 5232;
(b) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7161–7163 7163