Propargyl 1,2-orthoesters as glycosyl donors: stereoselective synthesis of 1,2-trans glycosides and disaccharides

Article abstract of DOI:10.1016/j.tetlet.2007.07.015

Propargyl 1,2-orthoesters are identified as glycosyl donors. Various glycosides and disaccharides were synthesized in a stereoselective manner using AuBr₃ as the promoter. AuBr₃ may activate the alkyne resulting in the formation of a

Full text of DOI:10.1016/j.tetlet.2007.07.015

Tetrahedron Letters 48 (2007) 6564–6568
Propargyl 1,2-orthoesters as glycosyl donors:
stereoselective synthesis of 1,2-trans glycosides and disaccharides
Gopalsamy Sureshkumar and Srinivas Hotha*
Division of Organic Chemistry: Synthesis, National Chemical Laboratory, Pune 411 008, India
Received 16 May 2007; revised 28 June 2007; accepted 5 July 2007
Abstract—Propargyl 1,2-orthoesters are identified as glycosyl donors. Various glycosides and disaccharides were synthesized in a
stereoselective manner using AuBr3 as the promoter. AuBr3 may activate the alkyne resulting in the formation of a 1,2-dioxolenium
ion and also behaves as a Lewis acid to facilitate the attack of the glycosyl acceptor. The versatility of the protocol was demon-
strated using a panel of aglycones comprising aliphatic, alicyclic, steroidal and sugar alcohols.
ꢀ 2007 Elsevier Ltd. All rights reserved.
OR
OR
Oligosaccharides and glycoconjugates are well known to
play key roles in various biologically important pro-
cesses.1 Nature synthesizes glycans stereoselectively
and the chemical synthesis of oligosaccharides2 in such
a manner is still a formidable task in spite of several ele-
gant established approaches signifying scope for novel
glycosyl donor development.3 The 1,2-trans glycosidic
bond has been achieved stereoselectively by employ-
ing the neighbouring group participation of a chiral
auxiliary4a,b or often through a 2-O-acyl group 1
(Fig. 1).2,4c Alternatively, 1,2-trans glycosidation can
also be accomplished with the intermediacy of a 1,2-
dioxolenium ion 2, which can be envisaged as being
available from 1,2-orthoesters.5 Orthoesters (or masked
esters) are stable to bases but in the presence of mild
acids, undergo stereoelectronic rearrangement.5a,6
RO
RO
O
O
RO
RO
RO
RO
O
O
O
RO
+
O
L
O
AcO
R1
OR2
R1
3 R2
=
1
2
HO
HO
HO
HO
OH
O
O
HO
HO
OR
OH
OR
manno-
gluco-
4 (1,2-trans glycosides)
HO
HO
HO
HO
HO
HO
OH
O
O
OR
HO
gluco-
OR
manno-
5 (1,2-cis glycosides)
However, in the absence of an aglycone, 1,2-orthoesters
undergo acid-catalyzed rearrangement to give the corre-
sponding glycosides due to the transfer of an alkoxy
group to the anomeric centre.7 One of the orthoester-
based glycosyl donors 3 exploits activation of pent-4-
enyl group using halonium ions and a Lewis acid.5a–c
Figure 1. Structures of intermediates, and 1,2-trans and 1,2-cis
glycosides.
to carry out the transglycosylation reaction in a stereo-
selective manner to obtain 1,2-trans glycosides utilizing
a 2-O-acyl group proved futile. In continuation of this
work, the search for a stereoselective 1,2-trans glycosyl-
ation by activation of propargyl groups8a,9 prompted us
to investigate propargyl orthoesters as possible glycosyl
donors due to the alkynophilicity of gold reagents and
their characteristic Lewis acidity.9m Accordingly, as part
of our research programme8 directed towards the devel-
opment of protocols for novel glycoconjugate syntheses,
Recent observations from our laboratory led to a novel
AuCl3 mediated transglycosylation protocol from per-
O-benzylated propargyl glycosides to access a mixture of
1,2-trans 4 and 1,2-cis 5 glycosides (Fig. 1).8a Our efforts
*
Corresponding author. Tel.: +91 20 2590 2401; fax: +91 20 2590
2624; e-mail: s.hotha@ncl.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.015

G. Sureshkumar, S. Hotha / Tetrahedron Letters 48 (2007) 6564–6568
6565
HO
BnO
BnO
we explored the utility of propargyl orthoesters for the
1,2-trans stereoselective synthesis of glycosides and
disaccharides.
O
OR
BnO
OMe
O
RO
RO
7
RO
RO
O
O
To commence our investigation, propargyl orthoester
6a was conveniently prepared10 from tetra-O-benzoyl
glucosyl bromide11 using propargyl alcohol and 2,6-
lutidine. Next, propargyl orthoester 6a and aglycone 7
were subjected to AuCl3 catalyzed glycosylation in
CH3CN at 60 ꢁC (Scheme 1). The glycosyl donor 6a
was resistant to these reaction conditions, but switching
the solvent to CH2Cl2 led to the formation of disaccha-
ride 8a (30%) and per-O-benzoylated propargyl b-gluco-
side 9a (entries 1 and 2).12 Efforts to promote the
transformation with AuCl and Au2O3 were unsuccessful
whereas HAuCl4 catalyzed the glycosylation to give 45%
of 8a and 28% of 9a (entries 3–5). Gratifyingly,
O
+
Conditions
O
BzO
BnO
BnO
+
RO
RO
RO
RO
O
4 Å MS Powder
BzO
BnO
OMe
8
9
O
O
a R = Bz
b R = Bn
Ph
O
6
Time (h)
Entry
Conditions
%8a
%9a
AuCl3 (5 mol%)/CH3CN/60 o
AuCl3 (10 mol%)/CH2Cl2/25 o
AuCl (10 mol%)/CH2Cl2/25 o
Au2O3 (10 mol%)/CH2Cl2/60 o
HAuCl4 (10 mol%)/CH2Cl2/25 o
AuBr3 (10 mol%)/CH2Cl2/25 o
C
1
2
3
36
24
36
0
30
0
0
50
0
C
C
C
4
5
6
72
1
0
0
C
45
63
28
20
˚
10 mol % of AuBr3 in CH2Cl2 in the presence of 4 A
C
5
powdered molecular sieves under argon at room temper-
ature for 5 h delivered the 1,2-trans disaccharide in
Scheme 1. Propargyl 1,2-orthoesters as glycosyl donors.
Table 1. Propargyl 1,2-orthoesters as glycosyl donors for glycoside synthesis
Entry
Glycosyl donor
Aglycone
Product
Time (h)
8
Yield (%)
81
OBz
O
HO
BzO
BzO
O
O
1
6a
10a
OBz
11a
BzO
BzO
O
HO
2
3
6a
6a
2
1
74
60
BzO
OBz
10b
11b
H3C
H3C
CH3
CH3
H3C
OBz
O
H3C
H
H
O
BzO
BzO
H
OBz
HO
11c
10c
OBz
Ph
O
OBz
BzO
O
O
H3C
O
O
BzO
BzO
4
5
BzO
10c
24
60
75
BzO
O
12
13a
OBz
BzO
O
BzO
BzO
OH
12
0.5
O
10d
13b
OBz
H3C
BzO
OBz
O
BzO
BzO
O
O
BzO
6
7
10c
10d
1
63
72
O
O
OBz
Ph
14
O
15a
OBz
O
BzO
BzO
14
0.5
O
BzO
15b

6566
G. Sureshkumar, S. Hotha / Tetrahedron Letters 48 (2007) 6564–6568
Table 2. Propargyl 1,2-orthoesters as glycosyl donors for disaccharide syntheses
Entry
1
Glycosyl donor
Aglycone
Product
Time (h)
10
Yield (%)
42
O
O
O
Ph
O
O
O
Ph
O
BnO
BzO
BzO
BnO
6a
OMe
O
O
OH
OMe
BzO
16a
BzO
17a
BzO
OH
O
O
O
BzO
O
BzO
O
2
3
6a
0.5
80
50
OBz
O
O
O
O
O
16b
O
17b
O
O
BzO
NH
NH
O
BzO
BzO
O
HO
O
N
O
O
N
O
O
6a
O
2
OBz
O
O
16c
17c
OBz
OBn
O
OBn
O
O
HO
BzO
O
BnO
4
5
6a
8
45
70
BnO
BzO
OBn
OMe
BzO
OBn
OMe
16d
17d
BzO
OBz
O
Ph
BzO
O
BzO
BzO
BzO
O
O
O
7
24
O
BzO
O
BnO
BnO
12
18a
OBn
OMe
OBz
O
BzO
BzO
BzO
O
O
6
7
12
16b
6
2
68
77
18b
O
O
O
O
OMe
OMe
BzO
BzO
O
OBz
O
O
O
O
12
BzO
O
O
O
HO
18c
16e
OBz
OBz
O
OBz
BzO
O
O
O
BzO
BzO
8
16b
O
1
70
45
52
O
OBz
O
O
Ph
O
O
O
14
19a
O
O
Ph
O
BnO
BzO
OBz
O
OMe
9
14
14
16a
16d
10
24
O
BzO
19b
BzO
OBz
OBz
BzO
OBn
O
O
O
BnO
10
BzO
BnO
OMe
19c

G. Sureshkumar, S. Hotha / Tetrahedron Letters 48 (2007) 6564–6568
6567
satisfactory yield (entry 6).12,13 It is significant that
Acknowledgements
the glycosylation of 6a and 7 did not proceed in the
presence of organic bases and the addition of freshly
activated 4 A powdered molecular sieves was essential
for minimizing the formation of the per-O-benzoylated
lactol.
S.H. thanks the DST, New Delhi (SR/S1/OC-06/2004)
and DAE-BRNS-Young Scientist Research Award for
financial support. S.H. is grateful for the encouragement
of Dr. M. K. Gurjar and Dr. K. N. Ganesh. G.S.K.
acknowledges a fellowship from CSIR-New Delhi.
˚
The glycosylation reaction performed between donor 6b
and aglycone 7 resulted in the isolation of per-O-benzyl-
ated disaccharide 8b in 58% yield.12 The scope of this
novel glycosylation method was explored in the perspec-
tive of glycoside and disaccharide syntheses.
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2007.07.015.
Initially, we explored the utility of propargyl orthoesters
for glycoside synthesis. As is evident from Table 1, the
AuBr3 promoted glycosylation reaction between glucos-
yl donor 6a and various aglycones comprising aliphatic
10a, alicyclic 10b and steroidal 10c gave the respective
glucosides 11a–c in a 1,2-trans stereoselective manner.12
We extended the scope of this method to mannosyl 12
and galactosyl 14 1,2-orthoesters11 resulting in the
formation of glycosides 13a and 15a in good yields.12
Interestingly, glycosyl donors 12 and 14 reacted with
4-penten-1-ol to give the corresponding 4-pent-1-enyl
glycosides 13b and 15b, which in turn can behave as
glycosyl donors.5
References and notes
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The utility of 1,2-orthoester 6a was gauged in the per-
spective of disaccharide formation using various sugar-
based aglycones comprising primary alcohols (7, 16b),
secondary alcohols (16a, 16d) and a nucleoside-based
primary alcohol (16c). Gratifyingly, 1,2-orthoesters
behaved as glycosyl donors in all the reactions giving
the corresponding disaccharides in good yields.12 It is
pertinent to mention that the current glycosylation
strategy was extended to mannosyl 12 and galactosyl
14 1,2-orthoesters to obtain disaccharides 18a–c and
19a–c, respectively. The glycosylation reaction between
a 1,2-orthoester-based glycosyl donor and carbohydrate
derived secondary alcohols resulted in lower yields
(Table 2, entries 1, 4 and 10) presumably due to the
steric environment of the aglycone. It is important to
mention that acid sensitive isopropylidene and benzyl-
idene groups remained intact during the AuBr3
mediated glycosylation reaction. In addition, we
successfully carried out the glycosylation between donor
6a and nucleoside 16c to give disaccharide 17c.12
Though a thorough mechanistic investigation is pend-
ing, it was envisioned that AuBr3 might activate the
propargyl moiety8a leading to the formation of a 1,2-
dioxolenium ion 2 and also acted as a Lewis acid9m to
promote the aglycone attack affording 1,2-trans glyco-
sides in a stereoselective fashion.
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In summary, we have developed a new O-glycosylation
method that enables the synthesis of 1,2-trans glycosides
from propargyl 1,2-orthoesters stereoselectively. We
have demonstrated the scope and utility of propargyl
1,2-orthoesters as glycosyl donors in the syntheses of
glycosides and disaccharides. Propargyl orthoesters gave
access to 4-pentenyl glycosides, which can in turn
behave as glycosyl donors.
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13. Synthesis of glycosyl donor 6a: To a solution of 2,3,4,6-
tetra-O-benzoyl-a-D-glucopyranosyl bromide (20.0 g,
0.0303 mol) in anhydrous CH2Cl2 (150 ml) was added
2,6-lutidine (15 ml), propargyl alcohol (9 ml, 0.1517 mol)
and tetra-n-butylammonium iodide (50 mg) under argon
at room temperature. Then, the reaction mixture was
refluxed at 65 ꢁC for 48 h, diluted with water and extracted
with DCM (2 · 100 ml). The combined organic layers
were washed with water and brine, dried over anhydrous
sodium sulfate and concentrated in vacuo to yield a
brownish-black residue which was purified by silica gel
column chromatography using ethyl acetate–petroleum
ether as the mobile phase to afford the glycosyl donor 6a
(16.34 g, 85%) as a white solid. General experimental
procedure for AuBr3 mediated 1,2-trans stereoselective
glycosylation: To a solution of glycosyl donor (0.1 mmol),
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˚
glycosyl acceptor (0.12 mmol) and 4 A powdered mole-
cular sieves in anhydrous CH2Cl2 (10 ml) was added
AuBr3 (10 mol %) under argon at room temperature. The
reaction mixture was stirred at room temperature for the
specified time and then filtered and the filtrate concen-
trated in vacuo. The resulting residue was purified by silica
gel column chromatography using ethyl acetate–petro-
leum ether as the mobile phase.