One-pot synthesis of d-glucosamine and chitobiosyl building blocks catalyzed by triflic acid on molecular sieves

Article abstract of DOI:10.1039/c3cc48078j

Combining triflic acid-catalyzed acetalation, benzylation, reductive ring opening of benzylidene acetal and glycosylation in one-pot transformations leads to a wide range of d-glucosamine building blocks for assembling oligomers.

Full text of DOI:10.1039/c3cc48078j

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One-pot synthesis of D-glucosamine and
chitobiosyl building blocks catalyzed by triflic acid
on molecular sieves†
Guillaume Despras,a Dominique Urban,a Boris Vauzeillesab and Jean-Marie Beau*ab
Cite this: Chem. Commun., 2014,
50, 1067
Received 21st October 2013,
Accepted 15th November 2013
DOI: 10.1039/c3cc48078j
www.rsc.org/chemcomm
Combining triflic acid-catalyzed acetalation, benzylation, reductive In carbohydrate chemistry, TfOH was notably used in glycosylations10
ring opening of benzylidene acetal and glycosylation in one-pot or with alkylsilanes to promote 4,6-O-benzylidene reductive
transformations leads to a wide range of D-glucosamine building ring opening to the C-4 alcohol.10b,11
blocks for assembling oligomers.
Our study started with thiophenylglycosides, attractive
building blocks as both glycosyl donors or acceptors,12 with
The construction of complex carbohydrate oligomers is a challenging the participating amino protecting halogen acetamides 1 and 2
task as it often requires high degrees of functionalization.1 Synthesis and carbamates 313 and 4 (Fig. 1).
of both glycosyl donors and acceptors may be readily achieved by
It was completed by the N-protected b-thioarylglycosides 5–9
means of one-pot processes, decreasing the number of synthetic prepared from odorless 2-methyl-5-tert-butylthiophenol,14,15 as well
and purification steps.2 One-pot Lewis acid catalyzed reactions as by a-methyl glycoside 1016 and b-O-silyl compounds 11 and 12.
were developed by our group3 (Cu(OTf)2, FeCl3Á6H2O) and by The O-silylated substrates 1a–12a were obtained in high yield
Hung and coworkers4 (TMSOTf). These protocols have been (89–97%) from the triols 1–12 by treatment with hexamethyldisilazane
successfully applied to persilylated monosaccharides (glucose, (HMDS, 2 equiv.) and TMSOTf (10 mol%) in CH2Cl2 at rt.8b
mannose, galactose),3,5 disaccharides (trehalose, maltose),3b and
unprotected glucosides.6
The acetalation–etherification procedure, initially examined
on O-silylated trichloroacetamide 6a with benzaldehyde (3 equiv.)
Glucosamine containing oligosaccharides are in high and triethylsilane (1.1 equiv.) in the presence of 1 mol% of Cu(OTf)2
demand because of their wide biological properties.7 The above under the previously optimized solvent conditions (CH2Cl2 :CH3CN,
procedures, promoted by TMSOTf, are however presently limited.8 ratio of 4 : 1),3a afforded the expected 3-O-benzyl-4,6-O-benzylidene 6b
Our preliminary attempts using Cu(OTf)2 or FeCl3Á6H2O as a catalyst (66%) together with the 4,6-O-benzylidene 6c (33%, entry 1, Table 1).
on various N-protected substrates were either heterogeneous, This result is representative of the limitation observed with these
depending on the N-protecting group [Cu(OTf)2],3c or inefficient N-protected derivatives of glucosamine. The same loading of TfOH
(FeCl3Á6H2O).3b The major problem associated with these substrates (1 mol%) in CH2Cl2 provided similar results (entry 2). Increasing the
is that the catalysts are sequestrated by some of the N-containing amount of TfOH to 5 mol% (entry 3) enhanced significantly the
functionalities on carbohydrates, making the catalysis unproductive.
In our effort to explore complementary catalysts, we report here a
solution using trifluoromethanesulfonic acid as a catalyst, asso-
ciated with molecular sieves (Scheme 1).
Electrophilic activation of organic substrates by protic acids,
including triflic acid (TfOH), has been extensively studied.9
a
´
`
´
Universite Paris-Sud and CNRS, Laboratoire de Synthese de Biomolecules, Institut
´
´
de Chimie Moleculaire et des Materiaux d’Orsay, F-91405 Orsay, France.
E-mail: jean-marie.beau@u-psud.fr; Fax: +33 1 69 85 37 15;
Tel: +33 1 69 15 79 60
b Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du
CNRS, Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data and copies of 1H and 13C-NMR spectra of new
compounds. See DOI: 10.1039/c3cc48078j
Scheme 1 Selective one-pot transformations of glucosamine derivatives
catalyzed by triflic acid.
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Table
2
Triflic acid-catalyzed one-pot regioselective protection of
O-silylated 1a–12a
Entry
Substrate, R, X
T
Product, yielda (%)
1
2
3
4
5
6
7
8
1a, TFA, b-SPh
rt
1b, 92
5b, 85
10b, 80
11b, 92b
12b, 72
2b, 78
6b, 83
3b, 85
7b, 90
4b, 83
8b, 93
9b, 79
5a, TFA, b-SMbp
10a, TFA, a-OMe
11a, TFA, b-OTBDMS
12a, TFA, b-OTBDPS
2a, TCA, b-SPh
6a, TCA, b-SMbp
3a, Troc, b-SPh
7a, Troc, b-SMbp
4a, Alloc, b-SPh
8a, Alloc, b-SMbp
9a, CO2Me, b-SMbp
0 1C
0 1C
0 1C
rt
0 1C
rt
rt
rt
rt
rt
Fig. 1 Starting sugars for the one-pot regioselective protection of the
N-protected glycosides.
9
10
11
12
rt
Table 1 Copper triflate versus triflic acid-catalyzed transformation of
O-silylated trichloroacetamide 6a
a
11a and 11b were isolated after silica gel chromatography; other
b
products were isolated by precipitation in hexanes. The reaction was
carried out at a gram scale. Mbp = 2-methyl-5-tert-butylphenyl.
is well known for achieving this reaction,10b,11 with, however, no
example reporting catalytic amounts of the acid. The above ‘‘hetero-
geneous’’ acid catalysis was not favorable to effect this transforma-
tion as seen with the silylated substrate 10a. Treatment with the
above procedure (entry 1, Table 3), followed by further addition in
the same pot of Et3SiH (5 equiv.) and TfOH (10 mol%), induced only
partial opening of the 4,6-O-benzylidene, giving a mixture of 10b
(28%) and C4-alcohol 10d (24%) (entry 1, Table 3).
Entry Catalyst
Solvent
Time 6ba (%) 6ca (%)
1
2
Cu(OTf)2b, 1 mol% CH2Cl2 : CH3CN, 4 : 1 16 h
TfOH, 1 mol%
TfOH, 5 mol%
TfOH, 5 mol%
66
62
33
30
23
—
CH2Cl2
CH2Cl2
CH2Cl2
16 h
3
15 min 76
10 min 98
4c
a
Yields were determined by NMR spectroscopy with 4-nitro-
b
benzaldehyde as standard. Catalyst was added in solution in aceto-
Clear improvement occurred by adding CH3CN as a co-solvent
and using acid washed molecular sieves AW300.20 Under these
conditions, the reductive ring opening to 10d (67% yield, entry 2)
c
nitrile. With 3 Å molecular sieves. Mbp = 2-methyl-5-tert-butylphenyl.
conversion rate into 6b (15 min versus 16 h) but with a similar 6b/6c
ratio. Adding powdered 3 Å molecular sieves (3 Å MS, 1 g per g of
substrate) induced a remarkable improvement with the quick
formation (10 min) of only 6b (98%, entry 4).
Table 3 Regioselective one-pot transformations to 4-alcohol glucosamine
derivatives
This drastic change in the reaction course could be understood as
the in situ formation of an active solid-like catalyst.17 This was
1
confirmed by the H- and 19F-NMR spectra of a TfOH solution in
CD2Cl2 at the catalyst concentration (10 mM). The 1H-signal at
10.58 ppm and the 19F-signal at À79.9 ppm completely disappeared
after adding 3 Å MS to the NMR tube (see ESI†).18 This qualitatively
demonstrated that TfOH has been adsorbed at the surface of the
solid to provide an apparently better performing solid acid catalyst.
The transformation of the O-silylated substrates 1a–12a under
these optimized conditions proceeded fast and cleanly to the target
products (Table 2, entries 1–12).19 The silyl anomeric substituents in
11b (92%) and 12b (72%) were notably stable (entries 4 and 5),
showing the mildness of the reaction conditions.‡
Added TfOH
(mol%)
Product,
Entry Substrate, R, X
Time
yieldb (%)
1
2
3
4
5
6
7
8
9
10
10a, TFA, a-OMe
10a, TFA, a-OMe
5a, TFA, b-SMbp
6a, TCA, b-SMbp
7a, Troc, b-SMbp
8a, Alloc, b-SMbp
10
5
10
10
10
15
4 h 30 minc
2 he
10d, 24d
10d, 67
5d, 72
6d, 72
7d, 67
8d, 60
9d, 49
12d, 21
2 he
2 h 30 mine
4 h 30 min f
3 h 30 ming
5 hg
9a, CO2Me, b-SMbp 15
12a, TFA, b-OTBDPS 10
1 h 45 ming
12a, TFA, b-OTBDPS
12a, TFA, b-OTBDPS
—
—
1 h 10 minh,i 12d, 56
0.8 hi,j
12d, 68
Finally, persilylated a-methyl glucose3a subjected to this procedure
(20 min at 0 1C) provided the 3-O-benzyl-4,6-O-benzylidene product3a
in good yield (76%). This result underlines the ability of the triflic
acid–molecular sieves system to catalyze the one-pot transformation,
which could be applied to other carbohydrate series or polyol
compounds.
a
Procedure: PhCHO (3 equiv.), Et3SiH (1.2 equiv.), TfOH (5 mol%),
AW300 molecular sieves, CH2Cl2, 20 min. After completion of the
acetalation–etherification, CH3CN was added to give a final CH2Cl2/CH3CN
solvent ratio of 4/1. b Yields obtained after silica gel chromatography.
c
Conditions: PhCHO (3 equiv.), Et3SiH (1.2 equiv.), TfOH (5 mol%), 3 Å
molecular sieves, CH2Cl2, 4 h 30 min at 0 1C to rt. d 28% of the benzylidene
g
10b was also isolated. e At 0 1C. f At rt. At 0 1C to rt. h The reaction
We next examined a subsequent one-pot reductive ring opening
of the 4,6-O-benzylidene acetal. The triflic acid–triethylsilane system
i
was performed with 2.2 equiv. of benzaldehyde. Without CH3CN at
0 1C. Reductive ring opening was carried out with 2 equiv. of CF3CO2H.
j
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J. M. Palomo, Nat. Protocols, 2012, 7, 1783; (c) D. Lee and
M. S. Taylor, Synthesis, 2012, 3421M. Emmadi and S. S. Kulkarni,
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Scheme 2 One-pot synthesis of chitobiosyl building blocks 13 and 14
4 C.-C. Wang, J.-C. Lee, S.-Y. Luo, S. S. Kulkarni, Y.-W. Huang,
C.-C. Lee, K.-L. Chang and S.-C. Hung, Nature, 2007, 446, 896.
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Chem., 1985, 4, 141. Glycosylations combined with reductive opening:
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Acetates: (c) K. Sasaki, S. Matsumura and K. Toshima, Tetrahedron Lett.,
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catalyzed by triflic acid.
was complete. As seen with 3 Å MS, the 1H- and 19F-signals of TfOH
in solution in CD2Cl2 also disappeared in the presence of AW300
MS.18 These conditions, applied to the silylated 2-methyl-5-tert-
butylphenyl thioglycosides 5a–8a, gave good results but not with
the methyl carbamate 9a (entries 3–7).21 The anomeric O-TBDPS
product 12d was isolated in poor yield (21%, entry 8) due to the
competing cleavage of the anomeric silyl ether. However, without
additional TfOH, this conversion of 12a to 12d was increased to a
56% yield (entry 9) or by replacing TfOH by an excess of CF3CO2H22
(68% yield, entry 10).
In a further step, this could be combined, in a modular
approach, with an acid catalyzed glycosylation step, to prepare
N-differentiated chitobiosyl building blocks. Thus, silylated 6a and
7a were transformed to donors 6b and 7b under the optimized
conditions (Table 2) in CH2Cl2 at rt, after which acceptor 12d
(Table 3, 0.8 equiv.) and promoter N-iodosuccinimide (1.5 equiv.)
were added to the reaction mixture (Scheme 2). This gave the
disaccharides 13 and 14 (70–73% yield) with, as expected, only the
b-linkage due to the N-neighboring group participants.
In summary, it has been demonstrated that different trans-
formations, combined in one-pot procedures catalyzed by triflic
acid on molecular sieves,23 furnish various glucosamine building
blocks useful in oligosaccharide synthesis. This includes the
one-pot synthesis of N-differentiated chito-disaccharides and the
methodology can be further extended to other oligomers of interest.
Triflic acid in catalytic amounts combines with molecular sieves
providing in situ a valuable ‘‘solid’’ acid catalyst. It is to be expected
that, in large scale preparation, this procedure can be amenable to
the design of a continuous flow process.
´
12 J. D. C. Codee, R. E. J. N. Litjens, L. J. van den Bos, H. S. Overkleeft
and G. A. van der Marel, Chem. Soc. Rev., 2005, 34, 769.
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M. J. Schur and D. M. Whitfield, J. Org. Chem., 2003, 68, 2426;
(b) K. Miyajima and K. Achiwa, Chem. Pharm. Bull., 1997, 45, 312.
14 (a) H. Weiss and C. Unverzagt, Angew. Chem., Int. Ed., 2003, 42, 4261;
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D. Poulain and J.-M. Mallet, Bioorg. Med. Chem., 2012, 20, 1817.
15 Thioarylglycosides 5–8 were prepared from a–b mixtures of the
corresponding
peracetylated
derivatives
(2-methyl-5-tert-
butylthiophenol (1.2–1.5 equiv.), TMSOTf (1.2 equiv.), CH2Cl2, 0 1C
to rt; 52–85%; NaOMe, MeOH, rt for 5, 6, 8 or NaOMe, MeOH/
CH2Cl2, 0 1C for 7, 87–98%). Alternatively, thioarylglycoside 9 was
prepared from the acetylated, Troc-protected precursor of
(NaOMe, MeOH, rt, 95%).
7
We thank the French Agency for Research (grant no. ANR-10-
CD2I-0008) and the Institut Universitaire de France (IUF) for
the financial support of this study. The CHARM3AT program is
also acknowledged for its support.
16 B. Nilsson and S. Svensson, Carbohydr. Res., 1978, 62, 377.
17 For triflic acid supported on silica, see: (a) S. Yan, N. Ding, W. Zhang,
P. Wang, Y. Li and M. Li, Carbohydr. Res., 2012, 354, 6; (b) P. N. Liu,
F. Xia, Q. W. Wang, Y. J. Ren and J. Q. Chen, Green Chem., 2010,
12, 1049; (c) A. de Angelis, C. Flego, P. Ingallina, L. Montanari,
M. G. Clerici, C. Carati and C. Perego, Catal. Today, 2001, 65, 363.
18 1H and 19F NMR spectra were recorded for 10 mM TfOH in CD2Cl2
without and with the molecular sieves; C6F6 was used as standard
for the calibration of the 19F experiment (see ESI†).
19 Most of the products were conveniently isolated by precipitation in
hexanes in good to excellent yields (78 to 93%) with no contamina-
tion with benzaldehyde or benzyl alcohol.
20 Use of acid washed sieves AW300 in glycosylations: (a) M. Wilstermann
and G. Magnusson, Carbohydr. Res., 1995, 272, 1; (b) M. Adinolfi,
G. Barone, A. Iadonisi and M. Schiattarella, Tetrahedron Lett., 2002,
43, 5573; (c) M. Adinolfi, G. Barone, A. Iadonisi and M. Schiattarella,
Org. Lett., 2003, 5, 987.
Notes and references
‡ Representative procedure (synthesis of compound 11b): to a 0.2 M solution
of 11a (1.0 g, 1.65 mmol) in dry CH2Cl2, under an inert atmosphere,
benzaldehyde (500 mL, 4.97 mmol, 3 equiv.) and freshly activated 3 Å
molecular sieves (1 g per g of substrate) were added. The mixture was stirred
at rt for 15 min, then TfOH (7.5 mL, 0.083 mmol, 5 mol%) and Et3SiH (315 mL,
1.96 mmol, 1.2 equiv.) were added. After stirring for 10 min, the solution was
neutralized with triethylamine (1 mL), filtered through a celite pad and con-
centrated. The residue was purified by flash chromatography (cyclohexane/
AcOEt 9 : 1 to 4 : 1) to afford 11b (0.866 g, 92%) as a white foam.
1 (a) H. Paulsen, Angew. Chem., Int. Ed., 1982, 21, 155; (b) T. K. 21 These conditions were not suitable for the phenyl thioglycosides
Linhorst, Essentials of Carbohydrate Chemistry and Biochemistry, because of their poor solubility in the solvent mixture.
Wiley –VCH, Weinheim, 2nd edn, 2003; (c) T. J. Boltje, T. Buskas 22 M. P. DeNinno, J. B. Etienne and K. C. Duplantier, Tetrahedron Lett.,
and G.-J. Boons, Nat. Chem., 2009, 1, 611; (d) X. Zhu and
R. R. Schmidt, Angew. Chem., Int. Ed., 2009, 48, 1900.
2 (a) C.-H. Hsu, S.-C. Hung, C.-Y. Wu and C.-H. Wong, Angew. Chem.,
Int. Ed., 2011, 50, 11872; (b) M. Filice, J. M. Guisan, M. Terreni and
1995, 36, 669.
23 We prefer this expression to ‘‘adsorbed’’ or ‘‘supported’’ because we
have no evidence that TfOH forms a stable solid acid catalyst with
molecular sieves as shown previously with amorphous silica17
.
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Chem. Commun., 2014, 50, 1067--1069 | 1069