Electrochemical generation of 2,3-oxazolidinone glycosyl triflates as an intermediate for stereoselective glycosylation

Article abstract of DOI:10.3762/bjoc.8.52

Glycosyl triflates with a 2,3-oxazolidinone protecting group were generated from thioglycosides by low-temperature electrochemical oxidation. The glycosyl triflates reacted with alcohols to give the corresponding glycosides β-selectively at low temperatur

Full text of DOI:10.3762/bjoc.8.52

Electrochemical generation of 2,3-oxazolidinone
glycosyl triflates as an intermediate for
stereoselective glycosylation
Toshiki Nokami1, Akito Shibuya1, Yoshihiro Saigusa1, Shino Manabe*2,
Yukishige Ito2,3 and Jun-ichi Yoshida*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 456–460.
1Department of Synthetic Chemistry and Biological Chemistry, Kyoto
University, Nishikyo-ku Kyoto 615-8510 Japan, 2Advanced Science
Institute, RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan and
3ERATO JST, Hirosawa, Wako, Saitama 351-0198, Japan
doi:10.3762/bjoc.8.52
Received: 11 January 2012
Accepted: 06 March 2012
Published: 28 March 2012
Email:
Shino Manabe* - smanabe@riken.jp; Jun-ichi Yoshida* -
yoshida@sbchem.kyoto-u.ac.jp
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
* Corresponding author
Guest Editor: T. K. Lindhorst
Keywords:
© 2012 Nokami et al; licensee Beilstein-Institut.
License and terms: see end of document.
amino sugar; anomerization; electrochemical oxidation; glycosylation;
thioglycoside
Abstract
Glycosyl triflates with a 2,3-oxazolidinone protecting group were generated from thioglycosides by low-temperature electrochem-
ical oxidation. The glycosyl triflates reacted with alcohols to give the corresponding glycosides β-selectively at low temperatures.
However, α-selectivity was observed in the absence of base at elevated reaction temperatures. In situ generated triflic acid promotes
the isomerization of β-products to α-products.
Introduction
Stereoselective formation of glycosidic linkages is the key issue the selectivity highly depends on the nature of the glycosyl
in oligosaccharide synthesis, because both 1,2-trans and 1,2-cis acceptors and reaction conditions. In the last decade, 2,3-oxazo-
aminoglycosides are ubiquitous in biologically active oligo- lidinone protected 2-amino-2-deoxy-glycosides have been
saccharides [1-5]. The 1,2-trans aminoglycosides, which are developed as glycosyl donors for the stereoselective synthesis
found in Nod factor [1] and lipid A [2], can be easily prepared of amino sugars [9-24]. These glycosyl donors afford the
by protecting the 2-amino group with phthaloyl or carbamate corresponding glycosides in a 1,2-trans or 1,2-cis selective
groups [6]. On the other hand, 1,2-cis glycosidic linkages are manner by action with various types of glycosyl acceptors.
still difficult to make with perfect stereoselectivity. Although However, it is still uncertain whether glycosyl triflate inter-
2-azido-substituted glycosyl donors are commonly used for the mediates [25], which were detected by NMR, play an important
preparation of 1,2-cis glycosidic linkages of amino sugars [7,8], role in the stereoselective formation of both α- and β-isomers.
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Beilstein J. Org. Chem. 2012, 8, 456–460.
We have developed an electrochemical method to generate and (6.89 ppm) than those of glycosyl triflates 2b (5.97 ppm) and 2c
accumulate highly reactive glycosyl triflates by low-tempera- (5.95 ppm), the chemical shift of the anomeric carbon is around
ture electrochemical oxidation of thioglycosides [26-30]. 100 ppm in all cases and the corresponding cross peaks of the
Although Kerns and Ye have already reported a chemically anomeric protons and carbons were observed in HMQC spectra.
generated glycosyl triflate equipped with an acetylated 2,3-
oxazolidinone protecting group [11,19], we envisioned that the
electrochemically generated glycosyl triflate with a 2,3-oxazo-
lidinone protecting group could be a useful intermediate to
reveal stereoselectivity in glycosylations via glycosyl triflate
intermediates. In this paper, we report the generation, accumu-
lation, and characterization by low-temperature NMR analyses,
of the corresponding glycosyl triflates. Electrochemical
glycosylation of the thioglycoside donor with 2,3-oxazolidi-
none protecting group gave both 1,2-trans linkages in the pres-
ence of a base at low temperatures and 1,2-cis glycosidic link-
ages in the absence of a base at elevated temperatures.
Results and Discussion
We began by conducting the electrochemical oxidation of 2,3-
Figure 1: 1H NMR spectrum of glycosyl triflate 2a.
oxazolidinone thioglycosides 1a–1c in the absence of a glycosyl
acceptor at low temperatures in order to generate and accumu-
Table 1: 1H- and 13C NMR chemical shifts of the anomeric proton and
late the corresponding glycosyl triflates (Scheme 1). Low-
temperature NMR measurements of the anodic solution were
carried out to confirm the structure of the glycosyl triflates. For
example, the anodic solution obtained by the electrochemical
oxidation of thioglycoside 1a (4 mA, 1 h) exhibited a single set
of peaks for glycosyl triflate 2a in the 1H NMR spectrum at
−80 °C (Figure 1). In contrast to the previous reports by Kerns
and Ye, the corresponding β-triflate was not observed under
these conditions [11,19]. The small coupling constant of the
anomeric proton (J = 2.1 Hz) indicates α-configuration of the
carbon of glycosyl triflates 2a–c.
entry glycosyl triflate
1H NMR
13C NMR
[δ (ppm)a]
[δ (ppm)a, J (Hz)b]
1
2
3
2a
2b
2c
6.89, 2.1c
99.9
99.9
100.7
5.97, singlet
5.95, singlet
achemical shift; bcoupling constant; cdoublet.
anomeric triflate. The 1H and 13C NMR chemical shifts of the Using electrochemically generated glycosyl triflate 2a, the
anomeric protons and carbons of glycosyl triflates 2a–c are stereoselectivity of the glycosylation was investigated by the
listed in Table 1. In all cases, the starting thioglycosides 1a–c addition of five equiv of various alcohols (Table 2). In accor-
were quantitatively converted to the corresponding glycosyl dance with our previous results [26,29], high β-selectvity was
triflates 2a–c, which have α-configuration of the anomeric observed with highly reactive alcohols (Table 2, entries 1 and
triflate. Although the chemical shift of the anomeric proton H-1 2). On the other hand, less nucleophilic alcohols, such as benzyl
of glycosyl triflate 2a appears at a lower chemical shift alcohol and CF3CH2OH, gave the corresponding glycosides in
lower β-selectivity than methanol or ethanol (Table 2, entries 3
and 4) [31].
Next, we examined the electrochemical activation of thioglyco-
side 1a to generate glycosyl triflate 2a in the presence of
glycosyl acceptor 7. In order to improve the yield and the
stereoselectivity of glycosylation, we examined the effects of
the reaction temperature and base (Table 3). Although poor
β-selectivity and yield were observed at low temperatures in the
absence of a base (Table 3, entry 1), the addition of an organic
base such as 2,6-di-tert-butyl-4-methylpyridine (DTBMP),
Scheme 1: Electrochemical conversion of thioglycosides to glycosyl
triflates.
significantly improved the β-selectivity and yield (Table 3,
entry 2). In both cases small amounts of the α-isomers of the
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Beilstein J. Org. Chem. 2012, 8, 456–460.
often observed for pyranosides with a 2,3-trans carbamate
group, under acidic conditions. The yield of disaccharide 8 was
improved by raising the temperature to 0 °C after the comple-
tion of electrolysis at −78 °C (Table 3, entry 5). The fact that
disaccharide 8 was obtained in higher yields (59% to 78%) and
that only a trace amount of α-isomer 9 (4%) was obtained
strongly suggests that the isomerization of thioglycoside donor
1a occurs during the electrolysis at 0 °C. It is noteworthy that
the α- and β-glycosides could be selectively prepared from the
same glycosyl donor with a 2,3-trans carbamate group, simply
by changing the reaction conditions.
Table 2: Glycosylation of electrochemically generated glycosyl triflate
2a.
entry
ROH
product: yielda, ratio (α to β)b
1
2
3
4
MeOH
3: 76% (<1 to >99)
4: 71% (<1 to >99)
5: 89% (9 to 91)
EtOH
BnOH
In order to confirm that the anomerization of 8β to 8α could
take place under the reaction conditions, we examined the acid-
mediated isomerization of the β-isomer of disaccharide 8β to
the α-isomer 8α (Scheme 2). Triflic acid (TfOH) must be gener-
ated in situ by the reaction of glycosyl triflate 2a with alcohols.
CF3CH2OH
6: 82% (15 to 85)
aisolated yields; bdetermined by 1H NMR.
starting thioglycoside 9 and glucal 10 were obtained as byprod- Thus, TfOH (1.0 equiv) and tetrabutylammonium triflate
ucts (Table 3, entries 1 and 2). The yield was further increased (Bu4NOTf) (5.0 equiv), which was used as a supporting elec-
and the formation of byproducts was suppressed by raising the trolyte for electrolysis, were added to a CH2Cl2 solution of the
reaction temperature to 0 °C (Table 3, entry 3). On the other β-isomer of disaccharide 8β at 0 °C. After stirring at 0 °C for
hand, the corresponding α-isomer of disaccharide 8α was 1 h, the reaction was quenched by the addition of Et3N. The
obtained as a major product together with the anomerized donor α-isomer of the disaccharide 8α was obtained in 83% yield as a
9 when the reaction was performed at 0 °C in the absence of single isomer. This experiment shows that the α-product 8α is
DTBMP (Table 3, entry 4). These anomerizations may be the isomerization product of the β-isomer 8β as a result of endo-
caused by the endocyclic cleavage reaction [22-24], which is cyclic cleavage, as shown in Scheme 2.
Table 3: Electrochemical glycosylation in the presence of glycosyl acceptor.
entry
T
base
product: yield, ratio (8α to 8β)a
1
2
3
4
5
−78 °C
–
8b: 36% (46 to 54)
8: 60% (4 to 96)
8: 79% (3 to 97)
8: 59% (α only)
8: 78% (α only)f
9: <3%c
9: <3%c
9: trace
9: 29%c
9: 4%c
10: 34%c
10: 24%c
10: trace
10: 2%c
10: 8%c
−78 °C
DTBMPd
0 °C
DTBMPd
0 °C
–
–
−78 °C then 0 °Ce
adetermined by 1H NMR; b1a (ca 15%) was recovered; cyields are based on 1a; d5.0 equiv; ethe reaction temperature was raised after electrolysis;
f1a (ca 6%) was recovered.
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Beilstein J. Org. Chem. 2012, 8, 456–460.
Scheme 2: Triflic acid mediated isomerization of β-glycoside.
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