Pre-activation protocol leading to highly stereoselectivity-controllable glycosylations of oxazolidinone protected glucosamines

Article abstract of DOI:10.1039/b712591g

Under pre-activation glycosylation conditions, the 4,6-di-O-acetyl-N- acetyloxazolidinone protected donor afforded either excellent β- or α-stereoselectivity simply by means of the addition of hindered base TTBP or the absence of base, leading to the cont

Full text of DOI:10.1039/b712591g

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Pre-activation protocol leading to highly stereoselectivity-controllable
glycosylations of oxazolidinone protected glucosamines{
Yiqun Geng, Li-He Zhang and Xin-Shan Ye*
Received (in Cambridge, UK) 15th August 2007, Accepted 6th November 2007
First published as an Advance Article on the web 23rd November 2007
DOI: 10.1039/b712591g
above-mentioned shortages and verify the influence on glycosyla-
tions by the activation manner, we focused on our studies on
stereoselective glycosylations using a oxazolidinone-containing
glucosamine donor by a pre-activation protocol.
Under pre-activation glycosylation conditions, the 4,6-di-O-
acetyl-N-acetyloxazolidinone protected donor afforded either
excellent b- or a-stereoselectivity simply by means of the
addition of hindered base TTBP or the absence of base, leading
to the controllable stereochemistry of coupling reactions.
2-Amino-2-deoxy sugars are essential residues incorporated in a
spread of oligosaccharides and glycoconjugates with biologically
important roles.1 However, the stereoselective formation of the
glycosidic bond is still a challenge to synthetic chemists. The
b-linked glycosides are usually constructed by means of a
participating neighboring group at the 2-amino position,2 while
the formation of a-linked glycosides remains a difficult task.3 The
present methods for a-stereoselective glycosylation of amino
sugars mainly involve in strategies of various protective groups
for the amino group such as the introduction of an azido moiety at
the 2-position as a non-participating group,4 but the anomeric
stereoselectivities during coupling reactions vary greatly,5 good
stereoselectivity often requires considering reactivity or conforma-
tional constraints of the acceptors.6
To examine the distinction between the pre-activation protocol
and the reported procedure,9c the known 2,3-oxazolidinone
protected thioglycoside 19c was chosen as the glycosyl donor.
Combination of benzenesulfinyl morpholine (BSM) and triflic
anhydride (Tf2O)12 was used as the promoter system in the pre-
sence of hindered base 2,4,6-tri-tert-butylpyrimidine (TTBP)13,14 in
the pre-activation operations. Donor 1 was pre-activated at 273 uC
in anhydrous dichloromethane using BSM–TTBP–Tf2O, and after
disappearance of donor 1 by TLC detection after several minutes,
the acceptor was added to the reaction mixture to furnish the
glycosidic bond formation. The coupling reaction of 1 and 2a
was carried out. Very fortunately, donor 1 exhibited complete
b-selectivity with high yield as shown in Table 1 (entry 1). Next,
our investigation was expanded to other glycosyl acceptors 2b–2k,
and the results are listed in Table 1. The yields are high and all
the glycosylations proceeded with excellent b-selectivity (only
b-anomer) except for the acceptor 2j (entry 10, Table 1). The
The development of new protocols for stereoselective glycosyla-
tions is a major focus in synthetic carbohydrate chemistry due to
its essentiality for oligosaccharide assembly. In recent years, ‘‘pre-
activation’’ as a new glycosylation approach has received
increasing interest.7 Especially, this protocol was developed as an
effective strategy for iterative one-pot synthesis of oligosaccharides
in this laboratory.8 The ‘‘pre-activation’’ protocol means that a
glycosyl donor is completely activated and consumed (by TLC
detection) prior to the addition of a glycosyl acceptor. We
reasoned that a pre-activation protocol might influence the
stereochemistry outcomes of glycosylations. Since the 1,2-cis
stereoselective glycosylation for 2-amino-2-deoxy sugars is a
principal challenge, we want to tackle this problem by applying
the pre-activation strategy. Although great advances in this field
have been achieved recently by the use of 2,3-trans-oxazolidinone
as a non-participating group for glucosamine donors including
2,3-oxazolidinone protected 2-amino-2-deoxy-D-glucose thioglyco-
sides,9a,b its N-acetyl9c,10 and N-benzyl11 analogues, some draw-
backs such as the undesired glycosylation and sulfenylation of
the nitrogen atom,9a,b reduction of a-selectivity,9c low yields,11
and limited scope of acceptors10,11 still exist. To overcome the
1
b-anomers were identified by their H NMR coupling constants
for the anomeric protons (J1,2 = 6.5–7.5 Hz). Compared with the
reported work using the same donor,9c it was found that the pre-
activation protocol dramatically increased the b-selectivity and
almost complete b-selective glycosylations for the glucosamine
donor was obtained. According to the literature work,9c a 2-N-acyl
group appended to the 2,3-oxazolidinone ring did not provide
anchimeric assistance during glycosidation, so the b-selectivity is
not caused by neighboring group participation. Neglecting this
factor, we reasoned that the glycosylation could be a SN2-like
process via the a-glycosyl triflate9c,15 intermediate based on the pre-
activation protocol.
Since the use of hindered base is not necessary in our previous
pre-activation protocol,8,12 our attention turned to BSM–Tf2O
promoted pre-activation in the absence of TTBP. The glycosyla-
tion reaction between 1 and 2a was performed again at 273 uC
in CH2Cl2 pre-activated by the BSM–Tf2O system without base.
Surprisingly, the stereochemistry outcome was completely reversed
to give a-linked coupling product 4a in 90% isolated yield (entry 1,
Table 2). Encouraged by this result, a series of glycosylations with
the same donor 1 and acceptors 2b–2k using the same protocol
The State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd #38, Beijing,
100083, China. E-mail: xinshan@bjmu.edu.cn; Fax: +86 10-82802724;
Tel: +86 10-62014949
{ Electronic supplementary information (ESI) available: NMR spectra
and characterization data for all new compounds, details on the
glycosylation couplings. See DOI: 10.1039/b712591g
This journal is ß The Royal Society of Chemistry 2008
Chem. Commun., 2008, 597–599 | 597

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Table 2 The glycosylation of donor 1 with various acceptors by pre-
activation in the absence of TTBP
Table 1 The glycosylation of donor 1 with various acceptors by pre-
activation in the presence of TTBP
Isolated Anomeric
yield
(%)
Isolated Anomeric
yield
(%)
Ratio
(a : b)
ratio
(a : b)
Entry Acceptor (ROH) Product
1
Entry Acceptor (ROH) Product
1
90
a only
83
83
b only
b only
2
81
a only
2
3
4
83
84
b only
b only
3
4
85
82
a only
a only
5
6
85
89
b only
b only
5
6
82
86
a only
a only
7
8
82
87
b only
7
8
80
83
a only
a only
b only
9
87
84
1.5 : 1
9
98
87
b only
10
1 : 5
10
a only
11
87
b only
11
81
3 : 1
598 | Chem. Commun., 2008, 597–599
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were also undertaken and the results are displayed in Table 2.
Excitingly, the yields are high and all the glycosylations proceeded
with excellent a-selectivity (only a-anomer) except for the acceptors
2i and 2k (entries 9 and 11, Table 2). The a-anomers were
identified by their 1H NMR coupling constants for anomeric
protons (J1,2 = 2.5–3.0 Hz). That is, the absence of TTBP during
the pre-activation glycosylations led to a totally reversed stereo-
chemistry outcome (cf. Table 1 and Table 2). The reversal of the
stereoselectivity in the absence of TTBP perhaps resulted from
in situ anomerisation of the b-glycoside under acidic condi-
tions.10,16 Another possible reason would be that the glycosylation
is a SN2-like process via the b-glycosyl triflate intermediate.15a In
terms of these results, it appears that the glycosylation stereo-
chemistry of donor 1 can be controllable and predictable based on
the pre-activation strategy, either a- or b-linked coupling products
towards multifarious glycosyl acceptors can be obtained simply by
the addition of hindered base or without base.
Notes and references
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14 Although we did not use TTBP in our routine pre-activation protocol,
we carried out the glycosylations in the presence of hindered base TTBP
for comparison with Kerns’ procedure.
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In summary, a new efficient strategy for both a- and
b-stereoselective glycosylations of glucosamine donors based on
pre-activation protocol was developed. By comparison with the
routine glycosylation operations, the pre-activation manner can
greatly influence the stereochemistry outcomes of glycosylations.
The 4,6-di-O-acetyl-N-acetyloxazolidinone protected donor 1 dis-
plays excellent a-selectivity for the couplings of a series of glycosyl
acceptors conducted by the BSM–Tf2O pre-activation protocol,
more importantly, the presence of hindered base TTBP leads to
totally reversed stereochemistry outcomes with excellent b-selec-
tivity towards glycosylations. Thus, by virtue of the BSM–Tf2O
pre-activation strategy, either a- or b-linked glucosamine-contain-
ing glycosides can be efficiently prepared by the use of 2,3-
oxazolidinone protected thioglycoside 1, by the addition of
hindered base or the absence of base. It seems that the controllable
and stereoselective glycosylations are realized by this protocol. It is
expected that the disclosed pre-activation methodology may be
widely applied to the assembly of either a- or b-linked 2-amino-2-
deoxy-D-glycopyranose-containing complex oligosaccharides with
important biological functions. Further extension of this protocol
to other sugars and the mechanistic understandings of stereo-
selectivity are currently under investigation.
This work was financially supported by the National Natural
Science Foundation of China, ‘‘973’’ and ‘‘863’’ grants from the
Ministry of Science and Technology of China.
This journal is ß The Royal Society of Chemistry 2008
Chem. Commun., 2008, 597–599 | 599