Chemoselective per-O-trimethylsilylation and homogeneous N-functionalisation of amino sugars

Article abstract of DOI:10.1039/c4cc06645f

A highly efficient CH₃CN-promoted hexamethyldisilazane per-O-trimethylsilylation of amino sugars was developed. Its applications in homogenous N-functionalisation and a concise synthesis of glucosamine 6-phosphate are described.

Full text of DOI:10.1039/c4cc06645f

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Chemoselective per-O-trimethylsilylation and
homogeneous N-functionalisation of amino
sugars†
A. Abragam Joseph,ab Vijay M. Dhurandhare,acd Chun-Wei Chang,ac
Ved Prakash Verma,a Girija Prasad Mishra,ae Chiao-Chu Ku,a Chun-Cheng Lin*b
and Cheng-Chung Wang*ac
Cite this: Chem. Commun., 2015,
51, 104
Received 23rd August 2014,
Accepted 4th November 2014
DOI: 10.1039/c4cc06645f
www.rsc.org/chemcomm
A highly efficient CH3CN-promoted hexamethyldisilazane per-O-
trimethylsilylation of amino sugars was developed. Its applications
in homogenous N-functionalisation and a concise synthesis of
glucosamine 6-phosphate are described.
Scheme 1 Per-O-functionalised glucosamine derivatives.
Amino sugars are widely dispersed in nature and have been
found in numerous biologically potent polysaccharides such as moderate. Therefore, upscaling these reactions is often difficult even
mucopolysaccharides or mucoproteins, bacterial capsular poly- though it is often the first step in the synthesis process.3 To enable
saccharides, lipopolysaccharides, glycolipids, N-glycans, glycos- homogeneous N-functionalisation of glucosamine, per-O-acetylated
aminoglycans, and numerous antibiotics.1,2 More than 60 amino glucosamine hydrochloride 1,4 which requires three steps to prepare,
sugars are known, and amongst them, D-glucosamine and its is usually used as an alternative.5 Hence, to produce these function-
N-acetylated and -sulfonated derivatives are commonly found in alised amino sugars on a large scale, an efficient, simple, economic,
bioactive molecules.2 Therefore, amino group functionalisation is and reliable method is still required (Scheme 1).
one of the most fundamental modifications when dealing with
Because solubility is the key concern in the synthesis of amino
amino sugars, but the current methods are laborious. Efforts have sugar derivatives, we propose chemoselective masking of all hydro-
been made to functionalise the amino groups in the presence of xyl groups over the amine group to enable subsequent amine
multiple hydroxyl groups of sugar molecules. Amine groups can modification as an efficient solution to the aforementioned pro-
be chemoselectively functionalised in the presence of multiple blems. Therefore, we expected that per-O-trimethylsilylated glucos-
hydroxyl groups by using the reactivity differences in nucleo- amine 2 would satisfy the requirements. Although 26 and its
philicity under the Schotten–Baumann conditions (acid chloride triethylsilyl derivatives have been prepared and Boysen et al. used
and aqueous NaHCO3); however, this method requires an excessive them to prepare Glucobox derivatives,7 the existing method to
number of reagents. Moreover, isolating products from aqueous prepare them needs a large excess of silylating reagents, including
media and salts is often difficult and time consuming. In many TMSCl (10 eq.), hexamethyldisilazane (HMDS) (10 eq.) and bis-
cases, reverse-phase chromatography or per-O-acetylation of the (trimethylsilyl)acetamide (BSA) (1 eq.), and a longer reaction time.
product after the reactions are occasionally required because of the Difficult workup and additional purifications are required to remove
high polarity of desired molecules, but the yields are usually only the extra reagents, the N-trimethylsilylated derivative and salts,
giving lower yield.6 The applications of 2 have neither been studied
a Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
E-mail: wangcc@chem.sinica.edu.tw; Fax: +886-2-2783-1237;
Tel: +886-2-2789-8618
b Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
E-mail: cclin66@mx.nthu.edu.tw; Fax: +886-2-2783-1237; Tel: +886-2-2789-8618
c Chemical Biology and Molecular Biophysics Program, Taiwan International
Graduate Program, Academia Sinica, Taipei 115, Taiwan
d Institute of Bioinformatics and Structural Biology, National Tsing Hua University,
Hsinchu 300, Taiwan
e Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterisation data for new compounds, and copies of NMR spectra.
See DOI: 10.1039/c4cc06645f
extensively nor extended, probably because it is difficult to prepare.
Per-O-trimethylsilyl derivatives of carbohydrates have been applied
widely in the preparation of building blocks for oligosaccharide
synthesis.8 We recently developed a highly efficient TMSOTf-
catalysed HMDS silylation of carbohydrates.9 Although nitromethane-
promoted HMDS silylation of alcohols was reported,10 no effective
solvent-promoted HMDS trimethylsilylation of amino sugars has been
described. Here, we report that glucosamine hydrochloride (3) can be
treated with 2.5 equivalents of HMDS in acetonitrile for 3 h at room
temperature under catalyst-free conditions to yield 2 as a single
a-isomer in a nearly quantitative yield after simply filtering and
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Table 2 Chemoselective silylation followed by diazotransfer reaction of
amino sugars
Scheme 2 CH3CN-promoted chemoselective silylation of glucosamine
hydrochloride (3).
Entry
1
Amino sugar
Product
evaporating acetonitrile (Scheme 2), and the reaction can be
easily scaled up to a 25 g scale (see ESI†). Therefore, the hydroxyl
groups of an amino sugar can be masked efficiently and easily
with the amine groups unaffected by taking advantage of the
stronger bond dissociation energy of O–Si compared with that of
the N–Si bond.
In addition, our method involves using a minimal amount of
reagents and enables amine protection or functionalisation reac-
tions after simple filtration and evaporation. Because the amino
group remains intact, we screened various N-functionalisation for 2
by using various amine protecting groups in CH2Cl2/Pyr (7/3) at 0 1C
to produce compounds 4–15 with 75% to 95% yields as summarised
in Table 1.
Azide is amongst the few neighbouring nonparticipating amine
protecting groups and is essential for 1,2-cis glycosylation reactions of
2-amino glycosides.3b,11 The diazotransfer reactions of amino glyco-
sides traditionally begin with direct amine functionalisation of amino
sugars under heterogeneous H2O/CH2Cl2 biphase conditions, and,
thus, vigorous stirring and a long reaction time are required. Further-
more, the arduous workup and purification processes require large
quantities of solvents and eluents. Although further acetylation11a,c or
silylation11d of the crude products can facilitate purification, these
treatments are also inefficient and require an excessive number of
reagents. By contrast, we per-O-trimethylsilylated the amino sugars
first, thus, the diazotransfer reactions could be conducted under
homogeneous conditions with TfN3 and DMAP in CH2Cl2 (Table 2).12
Considering D-glucosamine (3) as an example (entry 1), the reaction
was completed within 12 h, and, without workup and extraction,
2
3
product 16 was obtained easily by evaporation and simple filtration
through a short pad of silica gel to give 96% yield of 16 as a single
a-anomer. Similarly, by using the same reaction conditions and starting
from D-galacto- (17) and D-mannosamine (19) (entries 2 and 3), the
corresponding azide products 18 and 20 were obtained in 91% and
90% yields, respectively, as single a-anomers. With the amino group
functionalised, the O-trimethylsilyl groups can be easily removed or
further utilized for other functional group modifications.8,9
Based on these results, we extended our method to sialic acid.
Specifically, we applied our method to the sialic acid derivative 2113
to prepare sialic acid donors with various N-functional groups,
which play crucial roles in the stereoselectivity of sialylation reac-
tions.14 The chemoselective HMDS silylation of 21 yielded 22
quantitatively, and then amine functionalisation was performed in
the same pot. Sialic acid derivatives with C5 NHTroc (23), NHTCA
(24), and N3 (25) were easily obtained in 84%, 92%, and 91% yields,
respectively (Scheme 3).
To test the applicability of our method to molecules contain-
ing multiple amine groups, we applied our method to neomycin
sulphate (26). Because of the poor solubility of 26, the chemo-
selective per-O-silylation required a longer reaction time (36 h)
and more HMDS (7.0 eq.) as compared to the previous examples.
However, the pure product 27 was obtained after simple filtra-
tion and solvent evaporation in an 82% yield. Compound 27 was
subjected to amine functionalisation reactions, which yielded
per-N-trichloroacetylated 28 and per-N-azidated 29 in 85% and
91% yield, respectively (Scheme 4).
Table 1 N-Functionalisation of compound 2 with various protecting
groups
Yield
(%)
Entry Reagent
R (product)
1
2
3
4
5
6
7
8
9
10
TCACl
Ac2O
TFAA
TrocCl
CbzCl
MsCl
TsCl
DNSCl
TCA (4)
Ac (5)
TFA (6)
Troc (7)
Cbz (8)
Ms (9)
Ts (10)
DNS (11)
Benzenesulfonyl (12)
p-Nitrobenzenesulfonyl
(13)
87
77
88
91
81
85
75
89
78
77
Benzenesulfonyl chloride
p-Nitro-benzenesulfonyl
chloride
2,4-Dinitrobenzenesulfonyl 2,4-Dinitrobenzenesulfonyl 78
chloride
Scheme 3 Chemoselective amine functionalisation of the sialic acid
a
derivative. Reagents and conditions: HMDS (3.0 eq.), CH3CN, rt, 3 h.
b
c
TrocCl (1.1 eq.), CH2Cl2/Pyr (7/3), 0 1C to rt, 2 h. TCACl (1.1 eq.), Pyr/
11
12
CH2Cl2 (7/3), 0 1C to rt, 2 h. d TfN3 (1.1 eq.), DMAP (3.0 eq.), CH2Cl2, 0 1C to
(14)
Lauoryl (15)
rt, 12 h.
Lauoryl chloride
86
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Scheme 4 Chemoselective per-O-trimethylsilylation and amine function-
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This work was supported by the Ministry of Science and
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106 | Chem. Commun., 2015, 51, 104--106
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