Stereoselective Construction of β-Mannopyranosides by Anomeric O-Alkylation: Synthesis of the Trisaccharide Core of N-linked Glycans

Article abstract of DOI:10.1002/anie.201600488

A new and efficient approach for direct and stereoselective synthesis of β-mannopyranosides by anomeric O-alkylation has been developed. This anomeric O-alkylation of mannopyranose-derived lactols is proposed to occur under synergistic control of a kinetic anomeric effect and metal chelation. The presence of a conformationally flexible C6 oxygen atom in the sugar-derived lactol donors is required for this anomeric O-alkylation to be efficient, probably because of its chelation with cesium ion. In contrast, the presence of a C2 oxygen atom plays a minor role. This glycosylation method has been successfully utilized for the synthesis of the trisaccharide core of complex N-linked glycans. Lactol in control: The title reaction is believed to occur under synergistic control of a kinetic anomeric effect and metal chelation. The presence of a conformationally flexible C6 oxygen atom in the lactol is required for the reaction to be efficient, probably due to its chelation with cesium ion. This glycosylation method was successfully utilized for the synthesis of the trisaccharide core of complex N-linked glycans.

Full text of DOI:10.1002/anie.201600488

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201600488
German Edition: DOI: 10.1002/ange.201600488
Glycosylation
Stereoselective Construction of b-Mannopyranosides by Anomeric
O-Alkylation: Synthesis of the Trisaccharide Core of N-linked Glycans
Hai Nguyen, Danyang Zhu, Xiaohua Li,* and Jianglong Zhu*
Abstract: A new and efficient approach for direct and
stereoselective synthesis of b-mannopyranosides by anomeric
O-alkylation has been developed. This anomeric O-alkylation
of mannopyranose-derived lactols is proposed to occur under
synergistic control of a kinetic anomeric effect and metal
structurally complex N-linked glycans, is a long-standing
challenge in glycosylation chemistry.[12] Over the past several
decades, numerous efforts have been dedicated to addressing
this difficulty to facilitate the chemical synthesis of N-linked
glycans for studies of their biological function. Those efforts
include: 1) use of a nonparticipating group[13] for protection of
O2 and insoluble silver salts for activation of mannopyrano-
sidic halide;[13a–d] 2) inversion of the C2 stereochemistry of b-
glucopyranosides[14] or stereoselective reduction[15] of b-2-
ulosyl glycosides; 3) de novo synthesis of b-mannopyrano-
sides by a-selective quenching of C1-alkoxy radicals by
suitable hydrogen-atom donors;[16] 4) synthesis of b-manno-
pyranosides involving intramolecular aglycone delivery;[17–20]
5) use of 4,6-O-benzylidene-[21] or 4,6-O-silylene-protected[22]
a-mannopyranosyl triflates; 6) use of hydrogen-bond-medi-
ated aglycone delivery mediated by a remote 3-O-picoloyl
group.[23] Despite the remarkable success, oftentimes certain
amounts of minor a-mannopyranosides were also formed in
the reaction and purification of b-mannopyranosides from
their corresponding a-anomers could be time-consuming and
challenging. Therefore, it would be desirable to develop an
approach which ideally only produces b-mannopyranosides.
Herein we disclose an approach for stereoselective construc-
tion of the b-mannopyranosidic linkage by anomeric O-
alkylation.
Our group has recently developed a method for stereo-
selective synthesis of 2-deoxy-b-glycosides[24] by anomeric O-
alkylation[25,26] controlled by a kinetic anomeric effect.[25] In
addition, we have reported stereoselective synthesis of 2-
deoxy-a-glycosides by chelation-controlled anomeric O-alky-
lation.[27,28] Based on aforementioned success, we wondered if
a kinetic anomeric effect in conjunction with chelation control
could be applied to the stereoselective synthesis of b-
mannopyranosides. As shown in Scheme 1, after deprotona-
tion of the d-mannose 1 with a suitable base, a mixture of the
dianions 2 and 4 may be produced and interconvert via the
open intermediate 3. As a result of the chelation effect, the
chelation. The presence of
a conformationally flexible
C6 oxygen atom in the sugar-derived lactol donors is required
for this anomeric O-alkylation to be efficient, probably
because of its chelation with cesium ion. In contrast, the
presence of a C2 oxygen atom plays a minor role. This
glycosylation method has been successfully utilized for the
synthesis of the trisaccharide core of complex N-linked glycans.
P
rotein glycosylation is known as one of the major types of
post-translational modifications. In general, there are two
types of glycans attached to proteins: 1) N-linked glycans
attached to asparagine and 2) O-linked glycans attached to
serine or threonine.[1] Recent biological studies have demon-
strated that the glycans of glycoconjugates play essential roles
in numerous biological[2] and cellular processes.[3] Cell-surface
glycans serve as receptor ligands for proteins, for example,
enzymes,[4] antibodies,[5] and lectins.[6] In addition, it was also
found that the degree of cell-surface carbohydrate antigen
expression is closely associated with tumor progression, and
diagnostic results may guide the use of corresponding
approach for cancer treatment.[7,8] Furthermore, carbohy-
drate moieties are known to stabilize protein folding[9] and
modify physical, chemical, and biological properties of their
carrier molecules.
Because of the heterogeneous glycoforms of glycopro-
teins, it is difficult to understand the exact function of these
complex glycans. To address the challenge, researchers seek
to obtain single glycoforms of biologics by either total
chemical synthesis[10] or chemoenzymatic synthesis.[11]
Although great progress has been achieved,[10,11] the synthesis
of complex N-linked glycans remains a daunting task. In
particular, stereoselective construction of the b-mannopyra-
noside, one of the key glycosidic linkages existing in
[*] H. Nguyen, D. Zhu, Prof. Dr. J. Zhu
Department of Chemistry and Biochemistry and
School of Green Chemistry and Engineering
The University of Toledo
Toledo, OH 43606 (USA)
E-mail: Jianglong.Zhu@Utoledo.edu
Prof. Dr. X. Li
Department of Natural Sciences
University of Michigan-Dearborn, Dearborn, MI 48128 (USA)
E-mail: shannli@umich.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600488.
Scheme 1. Proposed stereoselective synthesis of b-mannopyranosides
by anomeric O alkylation.
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equatorial anomeric alkoxide 4 would be preferentially
formed over the axial counterpart 2. In addition, 4 should
be more nucleophilic than 2 because of the double electron–
electron repulsion, also known as kinetic anomeric effect.[25,29]
Subsequent SN2 reaction of 4 with suitable electrophiles may
afford the desired b-mannopyranosides 5.
solvents as well as co-solvents,[32] we found that 1,2-dichloro-
ethane was the optimal solvent for this reaction, which
provided 7 in 48% yield (b only; entry 2). Increasing the
amount of 6a to 2.0 equivalents and Cs2CO3 to 2.5 equivalents
increased the yield of the isolated 7 to 67% (b only; entry 3).
Changing the base to Cs3PO4 or elevating the reaction
temperature afforded inferior yields (entries 4 and 5). Finally,
use of 6a (2.5 equiv) and Cs2CO3 (3.0 equiv) furnished 7 in
75% yield (b only; entry 6). Attempting to let the reaction
proceed longer (40 hours) gave comparable results.[32] Over
alkylation at O2 was not observed in any of these experi-
ments. Notably, the use of 2-aminoethyl diphenylborinate
(0.1 equiv.), a catalyst well-demonstrated by Taylor and co-
workers[33] for regioselective alkylation of cis diols, in this type
of b-mannosylation was not effective.[32] These results sug-
gested that the anomeric cesium alkoxide was the key active
intermediate for anomeric O-alkylation with sugar-derived
triflates. The reason why cesium bases turned out to be
efficient for this type of b-mannosylation is not entirely clear,
but it is probably a result of well-known cesium effect.[34] In
addition, in contrast to traditional glycosylations which are
usually performed under anhydrous conditions, this anomeric
O-alkylation with cesium carbonate is not very moisture-
sensitive.
With the optimal reaction conditions established, we next
performed studies on the reaction scope using 1a and 4-O-
benzyl-3,6-di-O-(4-methoxybenzyl)-d-mannopyranose (1b)
with various sugar-derived triflates (6b–g). As shown in
Table 2, under optimal reaction conditions, the b-mannopyr-
anosides 8, 9, and 10 were produced, from 1a/b and the
corresponding relatively unreactive triflates 6a–c, in syntheti-
cally useful to good yields and excellent anomeric selectivity,
respectively.[31] In addition, the b-mannopyranosides 11, 12,
and 13 were obtained in good to excellent yields and excellent
anomeric selectivity[31] from the more-reactive triflates 6d–
f,[24] and even less triflate (2.0 equiv) was used. Furthermore, if
most reactive primary triflate, 6g, was employed, only
1.5 equivalents of the triflate was needed for the reaction
and the b-mannopyranosides 14 and 15 were obtained in
excellent yields and anomeric selectivities.[31]
To demonstrate the utilization of this method in complex
oligosaccharide synthesis, we next performed the synthesis of
the trisaccharide core of the N-linked glycan 21 (Scheme 2).
The synthesis commenced with the traditional glycosylation
between the known glycosyl donor 16[35] and acceptor 17[36]
under previously reported reaction conditions,[37] which
afforded the desired b-linked disaccharide 18 in 97% yield.
Deacetylation of 18 afforded the desired alcohol 19, which
was subsequently subjected to triflation to produce the triflate
20. Finally, cesium-carbonate-mediated anomeric O alkyla-
tion of 1a with 20 (2.5 equivalents) gave the desired
trisaccharide core of the N-linked glycan 21 in 72% yield (b
only).
To gain insight into this type of anomeric O-alkylation, we
studied various d-mannopyranose-type donors, such as 3,4-di-
O-benzyl-6-O-tert-butyldiphenylsilyl-d-mannopyranose (22),
3-O-benzyl-4,6-O-benzylidene-d-mannopyranose (24), 3,4-
di-O-benzyl-d-rhamnose (26), 3,4,6-tri-O-benzyl-2-deoxy-d-
glucose (28), and 3,4-di-O-benzyl-d-olivose (30) for this type
Previously, Schmidt and co-workers reported limited
studies on anomeric O-alkylation of partially or fully pro-
tected d-mannopyranoses with simple primary electrophiles
under various reaction conditions.[28c,d] In their experiments
either poor to moderate yields[28c] or moderate selectivity[28d]
was observed when either NaH or KOtBu was used as the
base. When 3,4,6-tri-O-benzyl-d-mannopyranose (see 1a in
Table 1) was employed, over-alkylation was found to be
a problem.[28c] Some success was also achieved by others[30]
when 1a or other partially protected d-mannopyranoses were
converted into their corresponding 1,2-O-dibutylstannylene
complexes followed by O-alkylation with various electro-
philes. However, organostannanes are highly toxic and the use
of stoichiometric amounts of organostannanes is certainly not
desirable.
In consideration of the natural b-(1!4)-linked manno-
pyranosidic linkage in complex N-linked glycans, we chose to
study the anomeric O-alkylation reaction between 1a and the
d-galactose-derived C4 secondary triflate 6a for selective
production of the corresponding b-mannopyranoside
7
(Table 1). Initially, we applied the optimal reaction condi-
tions, which we had discovered previously,[24,27] for the
Table 1: Anomeric O alkylation of 1a with 6a.[a]
Entry
Reaction conditions
Yield [%][b]
1[c]
2
3
Cs2CO3 (1.5 equiv), 6a (1.5 equiv)
Cs2CO3 (1.5 equiv), 6a (1.5 equiv)
Cs2CO3 (2.5 equiv), 6a (2.0 equiv)
Cs3PO4 (2.5 equiv), 6a (2.0 equiv)
Cs2CO3 (2.5 equiv), 6a (2.0 equiv)
Cs2CO3 (3.0 equiv), 6a (2.5 equiv)
25
48
67
59
64
75
4
5[d]
6
[a] Unless otherwise noted, all reactions were performed using 0.1 mmol
of 3,4,6-tri-O-benzyl-d-mannopyranose 1a in 1 mL ClCH2CH2Cl at 408C
for 24 hours. [b] Yield of isolated product (calculated based on 1a). Only
b products are formed. [c] CH3CN was used as solvent. [d] This reaction
was carried out at 508C. Tf =trifluoromethanesulfonyl.
synthesis of 2-deoxy glycosides to this type of b-mannopyr-
anosylation. However, only a trace amount of product was
obtained. Changing the solvent to dichloromethane[28c,d] gave
similar results. Base-mediated 1,2-elimination of 6a was
found to be the major problem. During the search for bases
which could react with 1a to form more nucleophilic
anomeric alkoxides, we were excited to discover that warming
a mixture of 1a (1 equiv), 6a (1.5 equiv), and Cs2CO3
(1.5 equiv) in acetonitrile at 408C afforded the desired b-
mannopyranoside 7 in 25% yield upon isolation (b only)[31]
(entry 1). After screening a range of polar and nonpolar
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Table 2: Cs2CO3-mediated b-mannosylation involving various sugar-
Table 3: Anomeric O alkylation of various d-mannopyranose-type
derived triflates.[a,b]
donors.[a,b]
Entry
1
Donor
Product
Yield [%]
40
2
3
4
5
0
30
64
15
[a] General reaction conditions: lactol donors (1.0 equiv), 6a (2.0 equiv),
and Cs2CO3 (2.5 equiv) in ClCH2CH2Cl at 408C for 24 h. [b] Yield of the
isolated product (calculated based on the lactol donors). Only b
products are formed.
desired b-linked disaccharide 29 in 64% yield (entry 4), and
this result was comparable to the reaction outcome 1a
(entry 3, Table 1). However, use of 30 (2,6-dideoxy-d-glucose/
mannose) only afforded 15% yield of the corresponding 2,6-
dideoxy glycoside 31, albeit with excellent anomeric selectiv-
ity. These results suggested that the presence of a conforma-
tionally flexible C6 oxygen atom in the sugar-derived lactol
donors is required for this anomeric O-alkylation to be
efficient, probably because of its chelation with the cesium
ion. In contrast, the presence of C2 oxygen atom was found to
play a minor role in this type of reaction.
[a] General reaction conditions: either 1a or 1b (1.0 equiv), triflate 6
(2.5 equiv), and Cs2CO3 (3.0 equiv) in ClCH2CH2Cl at 408C for 24 h.
[b] Yield of the isolated product (calculated based on 1). Only b products
are formed. [c] Use the triflate 6 (2.0 equiv) and Cs2CO3 (2.5 equiv).
[d] Used the triflate 6 (1.5 equiv) and Cs2CO3 (1.5 equiv).
In conclusion, an efficient approach for stereoselective
synthesis of challenging b-mannopyranosides has been devel-
oped by anomeric O-alkylation of mannopyranoside-derived
lactols. It was believed that this type of b-mannosylation
occurs under synergistic control of the kinetic anomeric effect
and chelation effect. It was found that the presence of
a conformationally flexible C6 oxygen atom in the sugar-
derived lactol donors is indispensable for this anomeric O-
alkylation to be efficient, while the presence of the C2 oxygen
atom was found to play minor role. This approach has been
successfully utilized for the synthesis of the trisaccharide core
of N-linked glycans. Further mechanistic studies of this
cesium-carbonate-mediated b-mannosylation and application
of this methodology to the synthesis of complex N-linked
glycans are currently underway.
Scheme 2. Synthesis of the trisaccharide core of N-linked glycans by
anomeric O alkylation. Reagents and conditions: a) NIS, TfOH, 4 Š
molecular sieves, CH2Cl2, À208C, 97%; b) NaOMe, MeOH/THF (1:1),
RT, 72% yield; c) Tf2O, pyridine, CH2Cl2, 08C, 90% yield; d) 1a
(1.0 equiv), 20 (2.5 equiv), Cs2CO3 (3.0 equiv), ClCH2CH2Cl, 408C,
24 h, 72% (yield calculated based on the lactol donor 1a). NIS=
N-iodosuccinimide, THF=tetrahydrofuran.
of anomeric O-alkylation with 6a (2.0 equivalents). As shown
in Table 3, while the b-mannopyranoside 23[31] was obtained
in 40% yield from 22, bearing a 6-O-TBDPS ether (entry 1),
surprisingly, we did not observe the production of the b-
mannopyranoside 25 from 24 (entry 2). In addition, use of 26,
lacking a C6 oxygen atom, in the reaction afforded only 30%
of the b-linked disaccharide 27[31] (entry 3). Furthermore, use
of 28 (also can be viewed as 2-deoxy-d-mannose) gave the
Acknowledgments
We are grateful to National Science Foundation (CHE-
1464787), The University of Toledo, and University of
Michigan-Dearborn for support. This research was also
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from University of Toledo, Justin Woodward and Ali Hourani
from University of Michigan-Dearborn for experimental
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Keywords: anomeric O-alkylation · glycosylation ·
N-linked glycans · oligosaccharides · b-mannosylation
How to cite: Angew. Chem. Int. Ed. 2016, 55, 4767–4771
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[29] Previous studies also indicated that as a result of electron–
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J(C,H) values were measured to be in the range of 157 to 160 Hz,
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[32] See the Supporting Information for detailed results on screening
a range of polar and nonpolar solvents as well as cosolvents for
this anomeric O alkylation.
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Received: January 16, 2016
Published online: March 7, 2016
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