Methyl glycosides are identified as glycosyl donors for the synthesis of glycosides, disaccharides and oligosaccharides

Article abstract of DOI:10.1039/b822526e

Stable methyl glycosides are identified as glycosyl donors in the presence of AuBr₃ in acetonitrile; a panel of aglycones comprising aliphatic, alicyclic, steroidal and sugar alcohols are examined successfully for the glycosylation reaction and

Full text of DOI:10.1039/b822526e

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Methyl glycosides are identified as glycosyl donors for the synthesis
of glycosides, disaccharides and oligosaccharidesw
Srinivasa Rao Vidadala and Srinivas Hotha*
Received (in Cambridge, UK) 17th December 2008, Accepted 9th March 2009
First published as an Advance Article on the web 31st March 2009
DOI: 10.1039/b822526e
Stable methyl glycosides are identified as glycosyl donors in the
presence of AuBr3 in acetonitrile; a panel of aglycones
comprising aliphatic, alicyclic, steroidal and sugar alcohols are
examined successfully for the glycosylation reaction and methyl
glycosides of di- and tri- saccharides are converted to corres-
ponding tri- and tetra-saccharides exploiting salient features of
Scheme 1 Synthesis of disaccharide.
our novel activation protocol.
In our glycoconjugate syntheses program, we contemplated
upon utilizing propargyl mannopyranoside (1) as the glycosyl
donor and aglycone 2a to synthesize the disaccharide 3a in the
presence of 3 mol% AuCl3 in acetonitrile at 70 1C.7a
Gratifyingly, we observed the formation of disaccharide 3a
along with 20% of the 1,6-anhydro sugar derivative 4a.6
Interestingly, the 1,6-anhydro derivative 4a was not observed
when the Au-mediated reactions were conducted at 25 1C
indicating a strong temperature dependence.7 The formation
of 4a could be prevented by adjusting the reactivity of the
monosaccharide from the armed 2a to a disarmed aglycone 2b
to afford disaccharide 3b (Scheme 1).8 The formation of 4a can
be envisioned due to the activation of the methyl glucoside of
2a leading to the oxocarbenium ion, which could have been
trapped by the primary hydroxyl group in an intramolecular
fashion. Nevertheless, we questioned whether methyl glyco-
sides could be activated to become glycosyl donors if we mask
the intramolecular hydroxyl group and introduce an aglycone
to enable transglycosylation. It is pertinent to mention that
methyl glycosides are one of the earliest synthesized glyco-
sides, which can be easily synthesized from aldoses to lock the
anomeric configuration under Fischer’s acidic conditions with
a wishful thinking that they rarely act as glycosyl donors and
they are known to be inert to diverse chemical manipulations.9
Therefore, we probed the utility of methyl glycosides for the
synthesis of oligosaccharides as a part of our program on
novel methods for glycoconjugate syntheses.
Advances in glycobiology have demonstrated various roles
played by oligosaccharides and glycoconjugates in a plethora
of biological events.1 Oligosaccharides are isolated from
nature as micro-heterogeneous forms and thus the chemical
synthesis is the most preferred method to obtain sufficient
quantities.2 The chemical synthesis of oligosaccharides often
involves a glycosylation reaction between a glycosyl donor and
an aglycone.3 The glycosyl donor (A), a fully protected
saccharide unit possesses an appendage, which can be
activated to become a leaving group (L) at the anomeric
position whereas the aglycone (ROH) frequently bears only
one hydroxyl group (Fig. 1). Activators promote the easy
formation of an oxocarbenium ion intermediate (B), which
will then be attacked by the aglycone to afford glycosides (C)
(Fig. 1). In this connection, various glycosyl donors are
developed, which are effectively used in the oligosaccharide
syntheses.4 Glycosyl donors developed till date can be
classified into stable (e.g. n-pentenyl,5a thio-,5b–d vinyl-,5e
2-carboxybenzyl-,5f etc.) and unstable (e.g. imidate-,4a,5g
halo-3b etc.) donors depending on the shelf life of the actual
glycosyl donor. It is important to mention that the leaving
group of a stable glycosyl donor serves initially as a robust
protecting group and later participates in the glycosylation
reaction upon activation with an appropriate promoter.4a
Thus, methyl per-O-benzyl-a-D-mannopyranoside (5a) was
allowed to react with aglycone 2b in the presence of AuCl3 in
acetonitrile at 70 1C for 24 h to afford disaccharide 3b in 47%
yield (entry 1, Scheme 2).5e,10w Changing the catalyst to AuBr3
increased the yield to 65%, AuCl resulted in 32% of
disaccharide 3b whereas Au2O3 and AuPPh3Cl did not show
any disaccharide 3b even after 36 h (entries 2–5).w HAuCl4
promoted the glycosylation affording 3b in 55% yield along
with 15% of the unwanted hemiacetal (entry 6). The addition
of organic bases such as triethylamine was detrimental to the
progress of the reaction (entry 7).w The efficacy of the reaction
was also checked with other Lewis acids [BF3ÁEt2O and
Sc(OTf)3] and found to give low yields (entries 8 and 9). The
effect of AuBr3 in acetonitrile on a selected panel of alkyl
Fig.
1 A general glycosylation reaction (L = leaving group;
P = protecting group).
Division of Organic Chemistry, Combi Chem–Bio Resource Center,
National Chemical Laboratory (CSIR), Pune 411 008, India.
E-mail: s.hotha@ncl.res.in; Fax: +91 20 2590 2624;
Tel: +91 20 2590 2401
w Electronic supplementary information (ESI) available: General
experimental procedures and 1H, 13C, DEPT NMR spectral charts.
See DOI: 10.1039/b822526e
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Table 1 Synthesis of glycoconjugates from methyl glycosidesa
Scheme 2 Investigation of methyl glycosides as glycosyl donors.
glycosides (5b–5f) was then investigated. Interestingly, ethyl-
(5b) and isopropyl- (5c) mannosides gave disaccharide 3b in
average yields, whereas benzyl- (5d), cholesteryl- (5e) and allyl-
(5f) glycosides resulted in poor yields of 3b (entries 10–14).w
Switching the solvent from acetonitrile to dichloromethane
and/or addition of 4 A molecular sieves powder was harmful
to the progress of the reaction. Conducting the reaction at
110 1C in propionitirle did not improve the net yield. Never-
theless, the above studies clearly signified that methyl manno-
pyranoside (5a) emerged as the best glycosyl donor and AuBr3
in acetonitrile as the promoter, might be due to the inherent
Lewis and Brønsted acidity of AuBr3.11
Furthermore, the scope of the reaction was gauged by a
panel of aglycones comprising 4-penten-1-ol (2c), menthol
(2d), cholesterol (2e) and sugar aglycones (2f, 2g) and found
that the methyl mannoside (5a) behaved as a glycosyl donor
giving good yields of corresponding glycosides (6a, 6b and 5e)
and disaccharides (6c, 6d) except with 2e, which could be
attributed to the poor solubility of cholesterol 2e in aceto-
nitrile.w The overall yield of 5e could be improved to 64%
when the reaction was conducted in acetonitrile containing few
drops of dichloromethane. 1,2-Trans diastereoselectivity of the
transglycosyled products can be endorsed to the steric
crowding due to the axially disposed benzyl ether at C-2 of
the donor as well as the anomeric effect.
Furthermore, the current strategy has been successfully
extended to the methyl per-O-benzylated glucoside (5g) and
galactoside (5i) to obtain disaccharides (7a–b, 8a–b) as
a,b-mixtures (Table 1). The effect of anomeric configuration
of the glycosyl donor and acceptor was then investigated.
b-Methyl glucosyl donor (5h) reacted with the aglycone 2b
to give disaccharide 7a in a diastereomeric ratio and yield
comparable to the corresponding reaction with a-methyl
glucosyl donor (5g + 2b to give 7a).w The acceptor containing
the b-methyl residue (2h) gave disaccharide (7c) upon reaction
a
All reactions were performed with 10 mol% of AuBr3, 1.0 equiv. of
glycosyl donor, 1.2 equiv. of aglycone in acetonitrile at 70 1C.
b Isolated and un-optimized yield by considering recovered acceptor.
c The a : b ratio was deduced from H and 13C NMR analysis.
1
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Scheme 3 Synthesis of tri- and tetra- saccharides using methyl glyco-
sides as glycosyl donors.
with glucosyl donor 5h. Similar results were also noticed with
galactosyl residues (entries 12–13).w
In addition, we envisioned that the novel gold catalyzed
activation of methyl glycosides could be ideal for the addi-
tion of a sugar residue to methyl glycosides of di- and
_
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disaccharide (9a) was synthesized exploiting gold mediated
propargyl 1,2-orthoester methodology.7b,c The AuBr3-promoted
reaction between 9a and aglycone 2b under above identified
conditions gave a complex mixture of products might be due
to the presence of more sensitive interglycosidic bond. However,
swiping the protecting groups from benzyls to benzoates as in
disaccharide 9b gave the required trisaccharide (10b) in 61%
yield. Similarly, methyl glycoside of the trisaccharide 11
afforded corresponding tetrasaccharide 12 (Scheme 3).w
In conclusion, methyl glycosides are identified as novel and
stable glycosyl donors. A diverse range of aglycones are shown
to react with methyl glycosides, resulting in the formation of
corresponding glycosides and disaccharides in good yields.
The anomeric configuration of either the glycosyl donor or the
glycosyl acceptor did not influence progress of the reaction nor
the anomeric diastereoselectivity of the resulting disaccharide.
It is interesting to note that tri- and tetra-saccharides are
synthesized from respective di- and tri-saccharides exploiting
salient features of this novel glycosylation protocol. Exploita-
tion of the current methodology to the synthesis of immuno-
genic epitopes of infectious bacteria is currently undergoing in
our laboratory and results will be communicated in due course
of time.
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10 General Procedure for AuBr3-mediated transglycosylation: To a
solution of the glycosyl donor (0.1 mmol) and aglycone
(0.12 mmol) in anhydrous acetonitrile (4 mL) was added 10 mol%
of AuBr3 under an argon atmosphere at room temperature. The
resulting mixture was heated to 70 1C and stirred till the comple-
tion of the reaction as judged by TLC analysis (Table 1). The
reaction mixture was concentrated in vacuo to obtain a crude
residue, which was purified by silica gel column chromatography
using ethyl acetate-petroleum ether as mobile phase.
S. H. thanks financial support from CSIR (NWP0036-B)
and Director NCL for LC-MS facility. The authors thank the
individual groups of Dr C. V. Ramana and Dr H. V.
Thulasiram for checking the model reaction. S. R. V. acknowl-
edges a CSIR fellowship.
Notes and references
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Chem. Commun., 2009, 2505–2507 | 2507