Synthesis of unnatural N-glycosyl α-amino acids via Petasis reaction

Article abstract of DOI:10.1016/j.cclet.2014.01.035

A convenient and efficient protocol for the synthesis of unnatural N-glycosyl α-amino acids was developed. Condensation of 1,3,4,6-tetra-O-actyl-β-d-glucosamine hydrochloride, alkenyl boronic acid, and glyoxylic acid was achieved in CH₂Cl₂

Full text of DOI:10.1016/j.cclet.2014.01.035

Chinese Chemical Letters 25 (2014) 532–534
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of unnatural N-glycosyl
a-amino acids via Petasis reaction
a
a
a
a,b
Chuan-Zhou Tao a,b, , Zhong-Tang Zhang , Jian-Wei Wu , Rong-Hua Li , Zhi-Ling Cao
*
a School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, China
b Jiangsu Marine Resources Development Research Institute, Lianyungang 222005, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient and efficient protocol for the synthesis of unnatural N-glycosyl
a-amino acids was
Received 17 October 2013
Received in revised form 30 December 2013
Accepted 2 January 2014
developed. Condensation of 1,3,4,6-tetra-O-actyl- -glucosamine hydrochloride, alkenyl boronic acid,
b-D
and glyoxylic acid was achieved in CH2Cl2 to give the derivatives of 2-(N-glycosyl)aminobut-3-enoic acid
which may find applications in glycobiology research and medicinal chemistry.
ß 2014 Chuan-Zhou Tao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Available online 25 January 2014
Keywords:
N-Glycosyl
Petasis reaction
-Glucosamine
a-amino acid
D
Alkenyl boronic acid
1. Introduction
To the best of our knowledge, this is the first time that Petasis
reaction has been employed to synthesize biologically important
Possessing both the structures of amino acid and sugar, glycosyl
amino acids have been extensively studied in recent years [1–3].
They are important building blocks for synthesis of glycoproteins
and have potential utilities in medicinal chemistry [4–8]. Because
of the limited accessibility of well-defined glycoproteins from
natural sources, recent efforts have been focused on the chemical
synthesis of glycosyl amino acids where the amino acid side chains
are connected to the sugar unit via linkers such as O-linker,
C-linker, S-linker and N-linker (Fig. 1) [9–12].
N-glycosyl a-amino acids. Accessibility of the reagents and the
mild reaction conditions make the method highly practical [21–
23]. More importantly, owing to the easy functionalization of C55C
double bonds, this protocol can provide various glycosyl amino
acids for glycoproteins synthesis.
2. Experimental
All chemicals were obtained from commercial sources and used
without further purification. Flash column chromatography was
performed on silica 230–400 mesh. IR spectra were recorded on a
Bruker Tensor 27 spectrometer with KBr pellets. 1H NMR spectra
were recorded on a Bruker Advance 400 spectrometer at ambient
temperature in CDCl3. Chemical shifts were reported in ppm
relative to TMS. HRMS analysis was performed on a Mariner ESI-
TOF system.
Among the glycosyl amino acids, N-glycosyl a-amino acids have
gained great attention (Fig. 1) because they not only have
significant biological activity [13–15] but also can be used as
ligands in coordination chemistry [16]. The current method to
prepare N-glycosyl
acids, where the amino acids are usually natural [13–16]. However,
unnatural N-glycosyl -amino acids, which are from unnatural
a-amino acids is to condense sugar with amino
a
amino acids, have rarely been studied due to their synthetic
difficulties. Recently, we have been interested in carbohydrate
chemistry and developed several general protocols to synthesize
Synthesis of N-glycosyl
flask containing magnetic stirring bar was charged with
-glucosamine hydrochloride 2a or its derivative 2b (1.0 mmol,
a-amino acids: A 50 mL round-bottom
a
D
the derivatives of
efficient, high-yielding synthesis of unnatural N-glycosyl
acids (1) through Petasis reaction (Fig. 2) [19,20].
D
-glucosamine [17,18]. Herein, we report an
1 equiv.), glyoxylic acid hydrate (1.0 mmol, 1 equiv.), and alkenyl
boronic acid (1.0 mmol, 1 equiv.). CH2Cl2 (5.0 mL) and triethyla-
mine (1.0 mmol, 1 equiv.) were injected, and the suspension was
stirred for 24 h at room temperature. The resulting mixture was
filtered through a pad of silica gel with the help of CH2Cl2 (30 mL).
The filtrate was concentrated, and the residue was purified by
column chromatography (silica gel, EtOAc-PE) to afford the
product 1 (see Supporting information).
a-amino
*
Corresponding author at: School of Chemical Engineering, Huaihai Institute of
Technology, Lianyungang 222005, China.
E-mail address: taocz@hhit.edu.cn (C.-Z. Tao).
1001-8417/$ – see front matter ß 2014 Chuan-Zhou Tao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2014.01.035

C.-Z. Tao et al. / Chinese Chemical Letters 25 (2014) 532–534
533
Fig. 1. Glycosyl amino acids.
Table 1
Optimizing the Petasis reaction condition.a
Entry
R
2
Solvent
Temp. (8C)
1 yield (%)b
1
2
H
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
CH3OH
22–25
22–25
22–25
22–25
22–25
22–25
22–25
22–25
22–25
22–25
22–25
0
0
Fig. 2. Unnatural N-glycosyl
a-amino acids.
H
CH3CH2OH
CH2Cl2
3
H
0
4
H
CHCl3
0
5
H
Toluene
CH3OH
0
3. Results and discussion
6
Ac
Ac
Ac
Ac
Ac
Ac
15
20
81
57
53
11
7
CH3CH2OH
CH2Cl2
We commenced our study with styryl boronic acid, glyoxylic
acid, and -glucosamine hydrochloride (2a) as model substrates.
Petasis reaction was carried out at room temperature and
triethylamine was added to release the free amine of -glucos-
amine. Different solvents were examined but we could not obtain
the designed N-glycosyl -amino acids 1 from -glucosamine
8
D
9
CHCl3
10
11
ClCH2CH2Cl
Toluene
D
a
Reaction condition: 2, 1 mmol; styryl boronic acid, 1 mmol; glyoxylic acid
hydrate, 1 mmol; triethylamine (TEA), 1 mmol; solvent, 5 mL; temperature, room
temperature (22–25 8C).
a
D
(Table 1, entries 1–5). We speculated that the hydroxyl groups,
especially the 1-hydroxyl, influenced the reaction. Then, we turned
b
Isolated yield.
to the substrate derived from O-protected-D-glucosamine.
It is well-known that acetyl is a versatile group for protecting
hydroxyl groups in carbohydrate chemistry and can be removed
the surrogate of D-glucosamine hydrochloride, CH2Cl2 as the
solvent at room temperature.
under mild conditions [24]. If 1,3,4,6-tetra-O-acetyl-
amine hydrochloride (2b) was used as surrogate of
b
-
D
-glucos-
-glucos-
Subsequently, we tested whether the same system can be
applied to the coupling of 1,3,4,6-tetra-O-acetyl-b-D-glucos-
D
amine hydrochloride (2a), it would probably easily participate in
the Petasis reaction to produce N-glycosyl -amino acids. This
hypothesis prompted us to investigate 1,3,4,6-tetra-O-acetyl-
-glucosamine hydrochloride as a surrogate of -glucosamine.
amine hydrochloride with various boronic acids and carboxyl
acids. It was found that other substituted alkenyl boronic acids
could also be smoothly converted to the desired products. For
instance, when pentenyl boronic acid was used, the designed
a
b
-
D
D
Gratifyingly, the designed product (1) was obtained with 15% -
20% yields in protic solvents CH3OH and CH3CH2OH (entries 6
and 7). Then, we evaluated the polar solvents, and the yield was
increased to 85% when CH2Cl2 was used as solvent (entries 8–10).
Nevertheless, less polar solvents were not suitable for the
transformation, and only 11% yield was obtained with toluene
as the solvent (entry 11). Therefore, our optimal protocol
N-glycosyl a-amino acid 1b was obtained with high isolated
yield (up to 88%, Scheme 1).
However, other carbonyl acids are minimally conducive to the
reaction. For example, even at 40 8C, only 9% yield was obtained
when keto acid was introduced (Scheme 2).
Then, we investigated the stereoselectivities of N-glycosyl
a
-amino acids through the 1H NMR of the products 1a and 1b
for synthesis of N-glycosyl
a
-amino acids was as follows:
(see figures in Supporting information). Since the amine of 1,3,4,6-
tetra-O-acetyl- -glucosamine hydrochloride (2b) is chiral, we
1,3,4,6-tetra-O-acetyl- -glucosamine hydrochloride (2b) as
b
-
D
b-D
Scheme 1. Synthesis of N-glycosyl
a-amino acid 1b.

534
C.-Z. Tao et al. / Chinese Chemical Letters 25 (2014) 532–534
Scheme 2. Synthesis of N-glycosyl
a-amino acid 1c.
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glycosyl
a-amino acids. Nevertheless, styryl boronic acid gave 1a
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for the synthesis of unnatural N-glycosyl
Tetra-O-actyl- -glucosamine hydrochloride (2b) was used as the
surrogate of -glucosamine hydrochloride, and alkenyl boronic acid
and glyoxylic acid were used to achieve Petasis reaction. The
efficiency of this procedure has been demonstrated by synthesizing
derivatives of 2-(N-glycosyl)aminobut-3-enoic acids. Given the fact
that glycosyl amino acids play an important role in glycobiology
research and medicinal chemistry, we anticipate that the method
described in the present report will find applications in a number of
fields, such as biomedical and pharmaceutical researches.
a-amino acids. 1,3,4,6-
b-D
D
Acknowledgments
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We are grateful to the Natural Science Foundation of Jiangsu
Province (No. BK20130404), the Scientific and Technological
Research Project of Lianyungang (No. CG1303), and the project
funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions.
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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.01.035.
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