Development of a highly α-selective galactopyranosyl donor based on a rational design

Article abstract of DOI:10.1016/j.tetlet.2011.08.091

A galactosyl donor was rationally designed based on protecting group-stereoselectivity study. This donor was prepared and tested in a series of glycosylation reaction. Excellent α-selectivity was observed in the test reactions.

Full text of DOI:10.1016/j.tetlet.2011.08.091

Tetrahedron Letters 52 (2011) 5629–5632
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of a highly
a-selective galactopyranosyl donor based
on a rational design
⇑
Zhitao Li , Lisheng Zhu, Jane Kalikanda
Department of Chemistry, Binghamton University, Binghamton, NY 13902, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A galactosyl donor was rationally designed based on protecting group-stereoselectivity study. This donor
Received 27 July 2011
Revised 11 August 2011
Accepted 15 August 2011
Available online 24 August 2011
was prepared and tested in a series of glycosylation reaction. Excellent
test reactions.
a-selectivity was observed in the
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Galactosyl donor
Stereoselectivity
Rational design
Carbohydrates are important biopolymers playing pivotal roles
in many cellular processes.1 Glycomics, the comprehensive study
of all glycan structures, has become an increasingly interesting
research field for both life science and bio-medical research.2,3 At
the same time, chemical synthesis provides one of the major means
to access large quantity of carbohydrate compounds in homogenous
and structurally defined form.4,5 However, synthesis of oligosaccha-
rides is much more challenging than synthesis of other types of bio-
polymers (like peptides and nucleotides), largely due to the
difficulties in controlling the stereoselectivity and regioselectivity.
The control of the stereochemistry (which is not present in cases
of peptide linkages and nucleotide linkages) is especially difficult
because of the complexityof the contributingfactors to the stereose-
lectivity, including the configuration of the glycosyl donor,6–11 the
structure of the leaving group,12 the reaction conditions, the reactiv-
ity of the glycosyl acceptor,13,14 and the protecting groups on the
donor. Protecting groups, in particular, have a profound influence
on the stereoselectivity of donors.15–21 Neighboring group participa-
tion, for example, has been one of the most powerful strategies for
the stereoselective synthesis of 1,2-trans glycosidic linkages. On
the other hand, development of an efficient method to synthesize
1,2-cis glycosidic linkages is difficult due to the lack of neighboring
a highly
ing groups.
Our group recently reported a correlation between
a
-selective Gal donor based on a rational design of protect-
a
-selectivity
and acyl protecting group at 3- and 4-positions of 2-azido-2-deoxy-
galactose (GalN3) donors.26 The observation was that acyl groups at
3- and 4-positions of GalN3 donors promote the a-selectivity. At the
same time, acetyl group at 6-position seems to have little or even
adverse effect. Based on this discovery, we rationally designed a
highly a-selective GalN3 donor and successfully applied in the syn-
thesis of Tn antigen and O-glycan core 7 derivatives.27 The mecha-
nism we proposed to explain this remote protecting group effect is
shown in Scheme 1. If the glycosylation reaction takes a SN1-like
pathway, oxocarbenium ion (like A and B in Scheme 1) should be
the key intermediate in the reaction. There are two likely conforma-
tions for the galactose oxocarbenium ions, 4H3 (A) and 3H4 (B).
When nucleophile reacts with the oxocarbenium ion, it tends to
attack the anomeric carbon through pseudoaxial direction. This
attack can happen from either top-face or bottom-face to afford
products of different stereochemistry. For 4H3 oxocarbenium ion
(A), bottom attack to give
a-product is more favorable than the
top attack (b-product), because the bottom attack goes through a
chair-like transition state instead of a twist-boat transition state
when attack from the top face. For 3H4 oxocarbenium ion (B), the
situation is opposite: attack from the top face to afford the
b-product is more favorable. This is why both anomers are often
observed in glycosylations. When the acetyl groups are present at
3- and 4-position, the carbonyl oxygen can approach the anomeric
carbon to form the participation intermediate. In case of 4H3
oxocarbenium ion, 4-acetyl can participate to form an intermediate
like C; in case of 3H4 oxocarbenium ion, 3-acetyl can participate to
form the intermediate D. In both participating intermediates, the
group participating.
a-Galactosidic linkage, for example, has been
an interesting researchtarget due to its wide presencein biologically
interesting oligosaccharides.22–25 Our group is particularly inter-
ested in the influence of remote protecting groups on the stereose-
lectivity of glycosyl donors. Here we report our recent discovery of
⇑
Corresponding author.
E-mail address: zli@binghamton.edu (Z. Li).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.091

5630
Z. Li et al. / Tetrahedron Letters 52 (2011) 5629–5632
OAc
OAc
RO
OR
OR
O
O
O
O
OAc
OR
O
O
O
X
AcO
O
AcO
OAc
X
N3
A
X
C
B
D
X = nonparticipating group
R = protecting group
Scheme 1. Mechanism of the remote protecting group directing effect.
OH
HO
OBn
O
OBn
AcO
AcO
a, b, c
d, e
O
S
O
O
S
HO
S
O
OH
OBn
OBn
3
1
2
(a) 2,2-dimethoxypropane, CSA; (b) MeOH/H2O (10 : 1), heat; (c)BnBr, NaH, DMF, 88% three steps; (d) 80% HOAc, 90 °C;
(e) Ac2O, Et3N, DCM, DMAP, 70% two steps
Scheme 2. Preparation of donor 1.
OBn
RO
O
OBn
O
RO
RO
RO
HO
BnO
BnO
ROH, TMSOTf, NIS
O
BnO
S
O
O
BnO
CH2Cl2, Molecular sief, 0°C, 20 mins
BnO
OBn
BnO
OMe
BnO
OMe
1 R = Ac
4 R = Bn
6
5
Scheme 3. Glycosylation reaction with acceptor 5.
top-face of the anomeric carbon is covered and the nucleophile can
only approach from the bottom-face to afford product.
Since galactose (Gal) has very similar configurations to GalN3
monosaccharides, it is reasonable to believe that the -directing
effect of acetyl groups observed in GalN3 donors is also valid for
Gal donors. Based on this hypothesis, we designed a Gal donor (com-
pound 1) that has the following pattern of the protecting group:
acetyl groups at 3- and 4-positions and benzyl groups at 2- and
6-positions. The rationale is that the benzyl group at 2-position
would avoid the neighboring group participation; the acetyl groups
hand, showed no stereoselectivity and afforded a 1:1 mixture of
anomers. These results demonstrated the superior stereoselectivity
of donor 1 compared to donor 4.
a
a
This donor was then further tested with a number of other gly-
cosyl acceptors. These acceptors were carefully chosen to represent
some of the commonly used acceptors (Table 1). Representative
acceptors include primary alcohol (5 and 9), secondary equatorial
alcohol (7 and 8), secondary axial alcohol (10), primary alcohol
with electron-withdrawing protecting groups (9), and secondary
alcohol with electron withdrawing protecting groups (8). All the
reactions were carried out under the same conditions. Donor 1
at 3- and 4-positions would favor the
a-selectivity through the
mechanism proposed in Scheme 1; the benzyl group at the
6-position would avoid possible adverse effect of acetyl group. This
donor can be readily prepared from known thioglycoside 2 in five
steps (Scheme 2). Compound 2 was first protected with isopropyli-
dene in two steps by following literature procedure.28 The crude
product was benzylated to afford compound 3, which was then trea-
ted under acidic conditions to remove the isopropylidene protecting
group.29 An acetylation reaction would therefore afford the desired
compound 1. Surprisingly, this donor has never been prepared
before. The only similar donor identified through literature search
is an ethyl thiogalactoside with same protecting pattern, but no
detailed study of the stereoselectivity was reported.30
show excellent stereoselectivity in the test reactions, only
ucts were isolated in all the reactions (Table 1). These results
further demonstrated that donor 1 is a donor with high -selectiv-
ity. Further application of using this donor in preparation of biolog-
a-prod-
a
ically interesting
underway.
a-galactosyl epitope containing molecules is
In conclusion, a rationally designed galactose donor was pre-
pared and tested in glycosylation reactions with a series of glycosyl
acceptors. Excellent a-selectivity was observed in all test reactions.
Superior stereoselectivity was also observed comparing with
tetrabenzyl protected galactose donor. This research not only
provides a new highly stereoselectivity donor for future synthesis
of complex oligosaccharides, but also demonstrates that the
rational design of glycosyl donor is a powerful approach to achieve
highly efficient and selectivity glycosylation reactions.
Typical procedure for the glycosylationreactions: Donor (0.11 mmol,
1.1 equiv) and acceptor (0.1 mmol, 1 equiv) were dissolved in anhy-
drous dichloromethane (2 mL). Flame-dried molecular sieve was
added. The mixture was stirred at room temperature for 30 min and
then cooledto 0 °C inice bath. NIS (0.11 mmol, 1.1 equiv) and TMSOTf
This new donor was then compared with a commonly tetraben-
zyl protected donor 4 in glycosylation reactions with a common
acceptor 5 (Scheme 3). The reactions are carried out using NIS/
TMSOTf as promoter, DCM as solvent at 0 °C. In the test reactions,
donor 1 showed excellent stereoselectivity with only
a-product
isolated. The 1H NMR spectra of compound 6 showed a doublet
at d 5.02 for anomeric proton with J1,2 = 4.0 Hz which confirm the
a-stereochemistry in the dissacharide 6. Donor 4, on the other

Z. Li et al. / Tetrahedron Letters 52 (2011) 5629–5632
5631
Table 1
Glycosylation results of donor 1
OBn
O
OBn
O
AcO
AcO
AcO
AcO
ROH, TMSOTf, NIS
S
OBn
CH2Cl2, Molecular sief, 0°C, 20 mins
BnO
OR
Entry
R-OH
HO
Products
Yielda (%)
a
:bb
OBn
RO
O
BnO
BnO
O
RO
BnO
OMe
BnO
O
BnO
BnO
1
95
a
Only
5
O
BnO
OMe
HO
BnO
BnO
OBn
O
RO
RO
O
BnO
OMe
BnO
2
60
1:1
5
O
O
BnO
BnO
BnO
OMe
BnO
HO
BnO
OBn
O
AcO
AcO
O
BnO
OMe
3
4
95
95
a
a
Only
BnO
BnO
BnO
7
O
O
BnO
OMe
BnO
HO
AcO
OBn
O
AcO
AcO
O
AcO
OMe
Only
BnO
AcO
BnO
8
O
O
AcO
OMe
HO
BzO
BzO
OBn
O
RO
RO
O
BzO
OMe
BnO
5
68
a Only
9
O
BzO
BzO
O
BzO
OMe
OH
O
OBn
O
RO
RO
BnO
BnO
BnO
OMe
BnO
6
97
a
Only
O
10
BnO
BnO
BnO
O
OMe
a
Isolated yield.
Determined by NMR.
b
(5
lL) was added. After 30–60 min, the reaction was quenched with
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