Syntheses of N-aryl-protected glucosamines and their stereoselectivity in chemical glycosylations

Article abstract of DOI:10.1016/j.tetlet.2017.06.037

N-Aryl-protecting groups were introduced in glucosamines to achieve β-selective glycosylation. Various N-aryl aminosugars were synthesized via Buchwald–Hartwig reaction. Glycosylation using glycosyl trichloroacetimidates of N-aryl aminosugars smoothly proceeded in the presence of trimethylsilyl trifluoromethanesulfonate. Use of a glycosyl donor comprising an electron-donating 2,4-dimethoxyphenyl (DMP) group led to the glycosylation proceeding with high β selectivity. This stereoselectivity seemed to be derived from the formation of an aziridine intermediate. The DMP-protecting group can be removed immediately by using ammonium hexanitratocerate (IV).

Full text of DOI:10.1016/j.tetlet.2017.06.037

Accepted Manuscript
Syntheses of N-aryl-protected glucosamines and their stereoselectivity in chem-
ical glycosylations
Yuji Otsuka, Toshihiro Yamamoto, Koichi Fukase
PII:
S0040-4039(17)30759-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.037
TETL 49029
Reference:
Tetrahedron Letters
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Revised Date:
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11 June 2017
13 June 2017
Please cite this article as: Otsuka, Y., Yamamoto, T., Fukase, K., Syntheses of N-aryl-protected glucosamines and
their stereoselectivity in chemical glycosylations, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.06.037
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Graphical Abstract
Syntheses of N-aryl-protected glucosamines
and their stereoselectivity in chemical
glycosylations
Leave this area blank for abstract
info.Leave this area blank for abstract info.
Yuji Otsuka, Tosihiro Yamamoto, Koichi Fukase*
Syntheses of N-aryl-protected glucosamines

1
Tetrahedron Letters
journal homepage: www.els evier.com
Syntheses of N-aryl-protected glucosamines and their stereoselectivity in chemical
glycosylations
Yuji Otsukaa,b , Toshihiro Yamamotoa,b , and Koichi Fukase b, *
a Peptide Institute, Inc., Saito Research Center, Ibaraki, Osaka 567-0085, Japan
b Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
N-Aryl-protecting groups were introduced in glucosamines to achieve β-selective glycosylation.
Various N-aryl aminosugars were synthesized via Buchwald–Hartwig reaction. Glycosylation
using glycosyl trichloroacetimidates of N-aryl aminosugars smoothly proceeded in the presence
of trimethylsilyl trifluoromethanesulfonate. Use of a glycosyl donor comprising an electron-
donating 2,4-dimethoxyphenyl (DMP) group led to the glycosylation proceeding with high β
selectivity. This stereoselectivity seemed to be derived from the formation of an aziridine
intermediate. The DMP-protecting group can be removed immediately by using ammonium
hexanitratocerate (IV).
Received in revised form
Accepted
Available online
Keywords:
Glycosylation
N-Aryl glucosamine
2009 Elsevier Ltd. All rights reserved
.
2,4-Dimethoxyphenyl group
Buchwald–Hartwig reaction
1. Introduction
In the field of synthetic carbohydrate chemistry, stereocontrol at the anomeric center is one of the most important subjects of
chemical glycosylation.1 Stereoselectivity to produce 1,2-trans glycosides has been achieved through the participation of neighboring
acyl- or carbamate-protecting groups located at the 2-position of the glycosyl donor. On the other hand, 1,2-cis glycosides have been
obtained by solvent effect of ether or DMF2, the intramolecular aglycone delivery (IAD) method3, and other approaches. Recently,
various participating groups introduced at the 2-OH of the glycosyl donor have been applied to chemical glycosylation. For example,
the dialkylphosphate group,4 picolinyl group,5 2-nitrobenzyl group,6 and 2-cyanobenzyl group7 have been developed to assist the
synthesis of 1,2-trans glycosides. Conversely, the phenylthiophenylbenzyl8 and thiophen-2-ylmethyl groups9 have been developed to
assist the synthesis of 1,2-cis glycosides. In the case of 2-aminosugars, the phthaloyl group and carbamate groups, such as Troc, are
frequently used for β-glycosylation with high selectivity. In some cases, however, the use of these groups is not compatible, particularly
when approaching a complex carbohydrate because of the difficulty of the removal step. Therefore, the development of new N-
protecting groups is still an important task in oligosaccharide synthesis.
With the exception of the 2,4-dinitrophenyl group, which can be removed under strong basic conditions, N-aryl groups have been
rarely used as protecting groups. The 2,4-dinitrophenyl group was used for the 2-N protection of a glucosaminyl donor.10 No
neighboring group participation was observed, hence, glycosylation in this case leads to the formation of an anomeric mixture (2:1–
3.5:1 α/β ratio). We thought that the electron density of the lone pair on nitrogen would be readily controlled by the introduction of
appropriate functional groups on the aromatic ring; electron-donating substituents should increase the nucleophilicity of the nitrogen to
enable the neighboring group to participate in the glycosylation, whereas electron-withdrawing substituents on the aromatic ring should
afford non-participating protecting groups. In the present study, we synthesized various N-aryl derivatives11 utilizing the Buchwald–
Hartwig reaction12 and investigated the effects of substituted N-aryl groups on the stereoselectivity of glycosylation.
2. Results and discussion
Initially, we investigated the Buchwald–Hartwig reaction of the aminosugars 1–5 and 2-methoxyphenyl triflate 6 in the presence of
tBuXPhos Pd G3 and tBuXPhos as a catalyst12 and tBuONa as a base under reflux condition in toluene (Table 1). The reaction of
1,3,4,6-tetra-O-benzyl-β-D-glucosamine 1, which was reported as a model compound for a copper-catalyzed N-arylation,13 gave only a
1
-glucosamine 2, which has a C4
trace amount of the desired product 10 (Entry 1). Next, we used 1,6-anhydro 3,4-di-O-benzyl-D
conformation, and obtained the desired product 11 in 44% yield (Entry 2). We then examined 4,6-benzylidene-
D
-glucosamine
derivatives 3–5 that contain a free hydroxy group at the C-3 position, which has no influence on the cross-coupling reaction. Although
the reaction with β-trimethylsilylethyl (TMSEt) glycoside 3 provided the desired product 12 in low yield probably due to the steric
hindrance of the TMSEt group (Entry 3), the use of β-methylthio glycoside 4 or α-benzyl glycoside 5 improved the yield to 73% and

2
79%, respectively (Entries 4 and 5). The reaction conditions with benzyl glycoside 5 were then optimized to afford 14 in 90% yield
(Entry 6). On the other hand, use of aryl iodide, bromide, and chloride (7–9) decreased the yields of the desired products (Entries 7–9).
Table 1. Screening of conditions for N-aryl aminosugar synthesis
Entry
1a
Aryl-X
6
Aminosugar
Products
Isolated Yield
trace
2a
6
6
44%
22%
3a
Ph
O
O
4a
6
6
73%
79%
O
SMe
HO
H2N
4
5a
6b
7b
8b
9b
6
7
8
9
90%
48%
43%
50%
5
5
5
5
14
14
14
14
a tBuXPhos Pd G3 0.3 eq, tBuXPhos 0.3 eq, tBuONa 3.0 eq was used
b tBuXPhos Pd G3 0.1 eq, tBuXPhos 0.1 eq, tBuONa 4.0 eq was used
With optimized conditions (Table 1, Entry 6), we prepared phenyl, 4-methoxyphenyl, and 2,4-dimethoxyphenyl (DMP) derivatives
of 5 via the coupling reaction (Scheme 1). The phenyl derivative 18 and the 4-methoxyphenyl derivative 19 were synthesized from the
corresponding phenyl triflate 15 and 4-methoxyphenyl triflate 16, respectively. On the other hand, the DMP derivative 20 was obtained
from the commercially available DMP bromide 17. Removal of benzylidene groups from 14, 18, 19, and 20 with 80% acetic acid
(AcOH) in water, followed by acetylation with acetic anhydride and pyridine, gave 21, 22, 23, and 24 in good yields (2 steps),
respectively. Subsequently, the removal of benzyl group of 21 with Pd black as a catalyst afforded the desired product only in low yield.
Use of Pd/Al2O3 as a catalyst and HCO2NH4 as a hydrogen source,14 a combination of reactants known as a catalytic transfer
hydrogenation (CTH) condition, led the yield of the reaction to the increase to 79%. Similarly, analogous reaction conditions with 22,
23, and 24 produced 26 (74% yield), 27 (79% yield), and 28 (86% yield), respectively. Next, introduction of a trichloroacetimidate
group in the anomeric position provided the desired products 29–32 in 71%–76% yield.

3
Scheme 1. Coupling reactions and syntheses of glycosyl trichloroacetimidates.
In order to investigate the substituent effects of N-aryl groups in the glycosylation, 2,4-dinitrophenyl derivative 35 and 2-nitrophenyl
derivative 4015 were also synthesized by SNAr reaction using the corresponding aryl fluorides (Scheme 2). Compound 3316 was readily
converted to compound 34 by treatment with hydrazine acetate, followed by trichloroacetimidation. On the other hand, N-2-nitrophenyl
glucosamine 37 was synthesized from the partially protected glucosamine 3617 because 2-nitrophenylation required strongly basic
conditions. The product was then treated with 80% AcOH in water, and the hydroxyl group was acetylated. The allyl group of 38 was
forced to isomerize with an Ir complex18, and the resulting compound was oxidatively cleaved by I2 and water to give 39, which was
converted to trichloroacetimidate 40.
Scheme 2. Syntheses of glycosyl trichloroacetimidates containing
nitrophenyl group.
The stereoselectivity of the glycosylation was then investigated using benzyl alcohol as a glycosyl acceptor at −20 °C in the presence
of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf) acting as a Lewis acid (Table 2) in either CH2Cl2 or diethyl
ether. The glycosidation of N-2-methoxyphenyl glucosamine 29 performed in the mentioned conditions in CH2Cl2 for 2 h led to the
formation of glycoside 41 in 81% yield with a 1:19 α/β selectivity ratio (Entry 1). In diethyl ether, glycoside 41 was obtained in 93%
yield with low selectivity (1:1.4 α/β ratio) owing to the α-orienting solvent effect of ether (Entry 2). The glycosidation of N-phenyl
derivative 30, N-4-methoxyphenyl derivative 31, and N-DMP derivative 32 also proceeded to give the corresponding glycosides 42, 43,
and 44 with β-selectivity in CH2Cl2 (Entries 3, 5, and 7). In addition, the extent of β-selectivity increased with the number of methoxy
groups on the aryl ring; notably, glycosidation of the N-DMP derivative 32 proceeded with the highest selectivity (1:49 α/β ratio) (Entry
7). By contrast, glycosidation of 2,4-dinitrophenyl derivative 35 and 2-nitrophenyl derivative 40 proceeded with α-selectively (5.7:1 and
14:1 α/β ratio, respectively) in diethyl ether (Entries 10 and 12). These results suggested that the glycosylations proceed via the
aziridine intermediate derived from the intermolecular nucleophilic attack of the aromatic amine from the α-face. β-Selectivity of the
glycosylation is brought about by the neighboring participation, as suggested by the evidence that β-selectivity increases with the
number of electron-donating groups on the aryl ring, which in turn enhance the nucleophilicity of the amine. We also confirmed that N-
nitrophenyl groups are non-participating protective groups and therefore can be used for α-selective glycosylations.
Table 2. Glycosidation of N-aryl glycosyl donors
Entry
Donor
29
Solvent
CH2Cl2
Et2O
Product
41
Isolated Yield
80% (β)
93% (α + β)
Selectivity*(α : β)
1 : 19
1
2
1 : 1.2
29
41

4
3
4
CH2Cl2
Et2O
1 : 3.6
1 : 4.0
1 : 15
1 : 12
1 : 49
1 : 5.6
1 : 1.4
5.6 : 1
1 : 1.0
14 : 1
30
30
31
31
32
32
35
35
40
40
42
42
43
43
44
44
45
45
46
46
85% (α + β)
78% (α + β)
62% (β)
5
CH2Cl2
Et2O
6
86% (β)
95% (β)
72% (β)
7
CH2Cl2
Et2O
8
9
CH2Cl2
Et2O
95% (α + β)
95% (α + β)
quant. (α + β)
quant. (α + β)
10
11
12
CH2Cl2
Et2O
* The anomer ratio was determined by HPLC (UV260nm)
The scope and limitations of glycosidation using the N-DMP glycosyl donor 32 were then investigated by using derivatives of
galactose 47, serine 48, glucosamine 49, and fucose 50 as glycosyl acceptors (Table 3). Glycosylation of 47 and 48, which have a
primary hydroxyl group, afforded the desired products in high yields and high β-selectivities (Entries 1 and 2). Glycosylation of
acceptors 49 and 50 that have secondary hydroxyl groups also smoothly proceeded to give the corresponding disaccharides with high β-
selectivity in good or moderate yields (Entries 3 and 4).
Table 3. Glycosylation using various acceptors
Entry
1
Acceptor
Products
Isolated Yield
92%
Selectivity*(α : β)
1 : 27
HO
FmocHN
48
OAllyl
2
3
1 : 50 <
93%
90%
O
1 : 50 <
4
1 : 27
67%
* The anomer ratio was determined by HPLC (UV260nm)
Finally, the DMP-protecting group was removed from the product of the glycosylation reaction using ammonium hexanitratocerate
(IV) (CAN)19; the following step consisted in an acetylation of the resulting compound with acetic anhydride and pyridine (Scheme 3).
In the cases of 24 and 51–54, removal proceeded smoothly to give the desired products in good yields. Conditions for this removal step

5
are orthogonal to those necessary for the removal of important hydroxyl and amino protecting groups, such as Ac, benzyl, allyl,
isopropylidene, benzylidene, Fmoc, and Troc. This feature makes the described approach highly suitable to the synthesis of complex
carbohydrates. The DMP group is stable in acidic, basic, and reducing conditions, as well as in the presence of various nucleophiles,
and it can be removed with an oxidizing agent, such as CAN.
Scheme 3. Removal of the DMP-protecting group using CAN and N-acetylation.
4. Conclusion
In summary, we succeeded in synthesizing glucosamine derivatives that comprise various N-aryl structures through the Buchwald–
Hartwig reaction. We used these compounds as glycosyl donors in chemical glycosylations and found that the N-DMP glucosaminyl
donor showed high β-selectivity. It has been reported that glycosylation with an N,N-dibenzyl glucosaminyl donor affords β-glycosides
via the aziridinium intermediate.20 Because increasing the electron-donating property of the aromatic ring of the N-aryl groups enhances
β-selectivity, glycosylation probably proceeds via the aziridine intermediate. The DMP-protecting group can be readily removed by
using CAN, but it is otherwise stable under various conditions. Therefore, use of this protecting group is expected to be applicable to
various carbohydrate syntheses.
Acknowledgments
We are grateful to Dr. Kazuya Kabayama, Dr. Atsushi Shimoyama and Dr. Yoshiyuki Manabe of Osaka University, for their helpful
discussions. This work was partially supported by JSPS KAKENHI Grant Number 15H05836 in Middle Molecular Strategy and JSPS
KAKENHI Grant Number 16H01885 (KF).
References and notes
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A. Supplementary data
B. Supplementary data associated with this article can be found, in the online version, at xxxxxxxxxxxxxxxx.

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・N-Aryl groups can be introduced to glucosamine through Pd-catalyzed C-N coupling.
・N-2,4-Dimethoxyphenyl (DMP) glucosaminyl donor was synthesized in good yield.
・ β-Selective glycosylation was achieved by using N-DMP protected donor.
・Glycosylation with donors having nitroaryl group preferentially afforded α-glycoside.
・DMP group can be readily deprotected by using CAN.