Synthesis of fully protected N-arylglycosylamines and factors affecting the configuration of C1-substituents of N-arylglycosylamines

Article abstract of DOI:10.1081/SCC-200026656

An efficient method was reported for preparation of N-arylglycosyl-amines in aqueous THF under reflux in good yields. The factors affecting the configuration of C₁-substituents of N-aryglycosylamines was investigated, that is, the influence of

Full text of DOI:10.1081/SCC-200026656

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Synthesis of Fully Protected
N‐Arylglycosylamines
and Factors Affecting
the Configuration of
C1‐Substituents of
N‐Arylglycosylamines
Wenting Du a & Yongzhou Hu a
a Department of Medicinal Chemistry, School of
Pharmaceutical Science , Zhejiang University ,
Hangzhou, 310031, P.R. China
Published online: 06 Jan 2011.
To cite this article: Wenting Du & Yongzhou Hu (2004) Synthesis of Fully Protected
N‐Arylglycosylamines and Factors Affecting the Configuration of C1‐Substituents of
N‐Arylglycosylamines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:16, 2987-2992, DOI: 10.1081/
SCC-200026656
To link to this article: http://dx.doi.org/10.1081/SCC-200026656
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 16, pp. 2987–2992, 2004
Synthesis of Fully Protected
N-Arylglycosylamines and Factors Affecting
the Configuration of C1-Substituents of
N-Arylglycosylamines
*
Wenting Du and Yongzhou Hu
Department of Medicinal Chemistry, School of Pharmaceutical Science,
Zhejiang University, Hangzhou, P.R. China
ABSTRACT
An efficient method was reported for preparation of N-arylglycosyl-
amines in aqueous THF under reflux in good yields. The factors affecting
the configuration of C1-substituents of N-aryglycosylamines was
investigated, that is, the influence of solvents, substituents of aromatic
amines, and protecting groups of monosaccharides on the ratio of
a- and b-N-arylglycosylamines.
Key Words: Synthesis; N-Arylglycosylamines; Configuration.
*
Correspondence: Yongzhou Hu, Department of Medicinal Chemistry, School of
Pharmaceutical Science, Zhejiang University, Hangzhou 310031, P.R. China;
E-mail: yhu@zju.edu.cn.
2987
DOI: 10.1081/SCC-200026656
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2988
Du and Hu
INTRODUCTION
The finding of wide range of biological activities associated with
various N-alkyl and N-aryl glycosylamines prompted many researchers to
study N-glycosylamines.[1] Glycosylamines are important because these
occur as junctures in glycoproteins.[2] Qian et al.[3] reported the synthesis
and activities of N-arylglycosylamines as trehalase inhibitors. In addition,
Das et al.[4] also reported the synthesis and characterization of different
N-glycosylamines of simple and partially protected saccharides. But as
far as we know, nobody has reported the synthesis of fully protected N-
arylglycosylamines yet.
In this article, we wish to describe an efficient method for preparation of
fully protected N-arylglycosylamines in aqueous THF under reflux in
good yields. Fourteen N-arylglycosylamines of N-arylglucosylamines,
N-arylgalatosylamines, and N-arylrhamnosylamines were synthesized by
D-glucose, D-galactose, D-rhamnose, and four substituted anilines as starting
materials. All the products are the mixtures of a- and b-configuration. Also,
we have investigated the factors affecting the configuration of C1-substituents
of N-arylglycosylamines, that is, the influence of solvents, the substituents of
aromatic amines, and protecting groups of monosaccharides on the ratio of
a- and b-products (Sch. 1).
RESULTS AND DISCUSSION
As reported in the literatures,[5–8] solvent effect can influence the
stereoselectivity of the glycosylation. Therefore, the compound 7a was syn-
thesized, respectively, in THF, acetonitrile, and the mixture of dioxane and
toluene. From Table 1 (entries 1–3), it can be seen that different solvents
indeed influenced theb : a ratios of N-arylglycosylamines. For comparison,
the b : a ratios in acetonitrile and in the mixture of dioxane and toluene
were higher than in THF.
The substituents of aromatic amines also influence the b : a ratios of pro-
ducts. From Table 1, it is shown that the products using substituted anilines as
material had higher ratios of the b/a-configuration than the products using
aniline. Furthermore, the products from 2-methoxy aniline had higher ratios
of the b/a-configuration than the products from 4-methoxy and 4-chloro
aniline too (entries 5, 6, 9, 10, 13, 14).
The protecting groups of glucose also influence the stereoselectivity of
the glycosylation of anilines. Anilines reacted with protected benzoyl
glycose obtained much b-configuration product and protected acetylglycose
obtained less relatively (Table 1, entries 1, 11, 15, 16).

Synthesis of N-Arylglycosylamines
2989

2990
Du and Hu
Table 1. The influence of solvent effect, substituents of aromatic amines, and protect-
ing groups of monosaccharides on the stereoselectivity of the glycosylation.
T
(hr)
Yield
(%)b
Entry
Donor
Acceptor
Product
Solventa
a : bc
1
2
1a
1a
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1a
2
2
2
2
2
2
3
3
3
3
4
4
4
4
5
6
7a
7a
7a
7b
7c
A
B
C
A
A
A
A
A
A
A
A
A
A
A
A
A
94
99
94
81
87
88
80
90
84
81
75
85
88
62
76
84
80
70
35 : 65
29 : 71
28 : 72
25 : 75
31 : 69
19 : 81
27 : 73
27 : 73
24 : 76
14 : 86
38 : 62
27 : 73
23 : 77
16 : 84
15 : 85
33 : 67
3
96
92
4
5
93
6
7d
8a
8b
8c
127
96
7
8
150
89
9
10
11
12
13
14
15
16
8d
9a
9b
9c
75
72
163
115
139
117
124
9d
10a
11a
aA, THF : H2O ¼ 2 : 3 or THF : H2O ¼ 3.4 : 3; B, dioxane : toluene : H2O ¼ 2 : 2 : 3;
C, acetonitrile : H2O ¼ 2 : 3.
bAll yields are isolated yields.
cThe a : b ratio were determined by HPLC analysis [UV detection at l ¼ 302 nm,
gradient elution acetonitrile/water (v/v) ¼ 55 : 45]. The configuration of products
1
was determined by using H NMR spectra.
Water was necessary in each reaction. Reactions did not proceed if water
was not added. On the other hand, 1-deprotected O-acetyl or O-benzoyl
glycoses reacted with alkylamine instead of aromatic amines gave no
product either.
We tried to carry out the synthesis of fully protected N-arylglycosyl-
amines in EtOH under reflux following the literature[4] but failed, whereas
simple saccarides which had been used as material in the literature[4] could
reacted with aniline in the mixture of THF and H2O. This result suggests
that the condition we applied is more appropriate and extensive for the
reaction between saccarides and anilines than the condition applied in the
literature.[4]
On the other hand, the protected N-arylglycosylamines is easy to depro-
tect as shown in Sch. 2.

Synthesis of N-Arylglycosylamines
2991
Scheme 2.
In conclusion, the present procedure provides a facile and an efficient
method for synthesis of N-arylglycosylamines from fully protected monosac-
charides and substituted anilines in aqueous THF under reflux. Fourteen
N-arylglycosylamines were obtained in good yield. Solvent effect, substitu-
ents of aromatic amines, and protecting groups of monosaccharides all can
affect the stereoselectivity of the glycosylation.
EXPERIMENTAL
Melting points are uncorrected. 1H NMR spectra were recorded on
Bruker ADVANCE DMX 500 MHz spectrometers with TMS as an internal
standard. Mass spectra were made with a HP5989B analyzer. The con-
figuration of products was determined using 1H NMR spectra and the
a/b ratio using Agilent 1100 series HPLC on a ZOPRAX Eclipse
XDB-CB column.
General Procedure
The suspension of fully protected sugar 2, 3, 4, 5, or 6 (1.0 mmol) and sub-
stituted aniline (2.0 mmol) in 2 mL THF (if the substituted aniline is 4-Cl
aniline, THF needs 3.4 mL) and 3 mL H2O was stirred under reflux for
about 4 days. The process was monitored by TLC. After completion of the
reaction, THF was removed by evaporating in vacuo and the aqueous solution
was extracted with ethyl acetate (3 ꢀ 12 mL). The combined organic layer
was further washed with brine (12 mL) and dried over anhydrate sodium
sulfate. The solvent was removed by evaporation under reduced pressure.
The crude products were purified by column chromatography over silica gel
(using different ratio of ethyl acetate and petroleum ether as eluent according

2992
Du and Hu
to different products). The products were characterized by 1H NMR, 13C NMR,
and MS.a
REFERENCES
1. Adel, A.H.; Abdel, R.; El, S.H.; El, A.; Richard, R.S. Carbohydr. Res.
1999, 315, 106.
2. Hughes, R.C. Prog. Biophys. Mol. Biol. 1973, 26, 189.
3. Qian, X.H.; Li, Z.B.; Liu, Z.; Song, G.H.; Li, Z. Carbohydr. Res. 2001, 336, 79.
4. Das, T.M.; Rao, C.P.; Kolehmainen, E. Iopharm. Carbohydr. Res. 2001,
334, 261.
5. Chowdhury, A.K. J. Carbohydr. Chem. 1999, 18, 361.
¨
6. Lonn, H. J. Carbohydr. Chem. 1987, 6, 30.
7. Braccini, I. Carbohydr. Res. 1993, 246, 23.
8. William, R.R.; Lin, X.F. J. Am. Chem. Soc. 1995, 117, 2236.
Received in Japan January 19, 2004
1
aFor compound 7a (white solid). H NMR (CDCl3, ppm) b-configuration. d: 7.26–7.19
(m, 2H, Ar-H), 6.89 (d, 0.92H, Ar-H), 6.85 (t, 0.60H, Ar-H), 6.66 (d, 1.48H, Ar-H), 5.37
(t, 0.62H, H-2), 5.08 (dd, 0.62H, J2–1 ¼ 9.8 Hz, H-1), 4.77 (d, 0.62H, Gly–NH), 4.30
(m, 1.24H, H-6), 4.14 (m, 0.62H, H-3), 4.09 (dd, 0.62H, H-4), 3.83 (m, 0.62H, H-5),
2.06–2.03 (4s, 12H, CH3CO); a-configuration. d: 7.26–7.19 (m, 2H, Ar-H), 6.89
(d, 0.92H, Ar-H), 6.85 (t, 0.60H, Ar-H), 6.66 (d, 1.48H, Ar-H), 5.47 (t, 0.38H, H-2),
5.21 (dd, 0.38H, J2–1 ¼ 5.2 Hz, H-1), 4.44 (br, 0.38H, Gly–NH), 4.30 (m, 0.76H, H-6),
4.16 (m, 0.38H, H-3), 4.03 (dd, 0.38H, H-4), 3.83 (m, 0.38H, H-5), 2.06–2.03 (4s, 12H,
CH3CO); 13C NMR (100 MHz, DMSO-d6): 170.34 (C, CO), 170.04 (C, CO), 169.79
(C, CO), 169.68 (C, CO), 146.28 (C, Ar-C), 129.24 (2C, Ar-C), 118.72 (C, Ar-C),
114.36 (2C, Ar-C), 82.32 (C, Gly–C), 73.88 (C, Gly–C), 71.50 (C, Gly–C), 68.93
(C, Gly–C), 65.91 (C, Gly–C), 62.36 (C, Gly–C), 20.96 (C, CH3), 20.90 (C, CH3),
20.83 (C, CH3), 20.78 (C, CH3); MS: m/z, 423 (Mþ). For compound 9a (oil). 1H NMR
(CDCl3, ppm) b-configuration. d: 7.26–7.19 (m, 2H, Ar-H), 6.85 (t, 1.6H, Ar-H),
6.7(d, 1.4H, Ar-H), 5.13–5.05 (m, 0.68H, H-4), 5.50 (t, 0.68H, H-2), 4.98 (d, 0.68H,
Gly–NH), 4.49 (d, 0.68H, J2–1 ¼ 9.7 Hz, H-1), 3.65 (m, 0.68H, H-5), 2.27–2.00 (3s,
9H, CH3CO), 1.27 (d, 2.04H, H-6); a-configuration. d: 7.26–7.19 (m, 2H, Ar-H), 6.85
(t, 1.6H, Ar-H), 6.7 (d, 1.4H, Ar-H), 5.13–5.05 (m, 0.64H, Gly–NH and H-4), 5.36
(t, 0.32H, H-2), 5.24 (dd, 0.32H, H-3), 4.38 (d, 0.32H, J2–1 ¼ 4.5 Hz, H-1), 4.01
(m, 0.32H, H-5), 2.27–2.00 (3s, 9H, CH3CO), 1.23 (d, 0.96H, H-6); 13C
NMR(100 MHz, CDCl3): 170.80 (C, CO), 170.08 (C, CO), 169.92 (C, CO), 144.50
(C, Ar-C), 120.11 (2C, Ar-C), 119.69 (C, Ar-C), 114.48 (2C, Ar-C), 81.09 (C, Gly-C),
71.92 (C, Gly-C), 71.15 (C, Gly-C), 70.72 (C, Gly-C), 69.55 (C, Gly-C), 17.56 (C, Gly-
C), 20.85 (C, CH3), 20.83 (C, CH3), 20.55 (C, CH3); MS: m/z, 365 (Mþ).