Stereoselective copper-catalyzed Chan-Lam-Evans N-arylation of glucosamines with arylboronic acids at room temperature

Article abstract of DOI:10.1039/c3cc44780d

An efficient and practical N-arylation of glycosylamines with substituted aryl boronic acids has been established. Using Cu(OAc)₂ and pyridine at room temperature under air atmosphere, the protocol proved to be general, and a variety of aryl N-glycosides have been prepared in good to excellent yields with exclusive β selectivity.

Full text of DOI:10.1039/c3cc44780d

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Stereoselective copper-catalyzed Chan-Lam-Evans N-arylation of
glucosamines with arylboronic acids at room temperature
Alexandre Bruneau, Jean-Daniel Brion, Mouad Alami* and Samir Messaoudi*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient and practical N-arylation of glycosylamines with
substituted aryl boronic acids has been established. Using
Cu(OAc)2 and pyridine at room temperature under air
atmosphere, the protocol proved to be general, and a variety
10 of aryl N-glycosides have been prepared in good to excellent
yields with exclusive  selectivity.
Substituted N-glycosides are valuable synthetic targets due to
their presence in compounds ranging from pharmaceuticals to
materials.1 One of the most important subfamilies of N-
15 glycosides is (hetero)aryl N-glycosides whose derivatives show
promising biological activities, including antiviral,2 and
anticancer3 properties. While these derivatives clearly hold great
potential in medicinal chemistry as well as in organic synthesis,
the synthesis of aryl N-glycosides has never been thoroughly
20 explored, since the stereoselective induction of nitrogen scaffolds
at the anomeric position remains a particularly difficult task.4
Usually, these derivatives are prepared by treating aniline
derivatives with glycosyl hydroxides at high temperature
(Scheme 1, path a).5 Alternative routes to N-glycosidic bond
25 formation consist on the use of N-H azoles as partners in (i) a
Mitsunobu coupling glycosylation with glycosyl hydroxides
50 this transformation is limited since the reaction required the use
of catalytic to stoichiometric amounts of Pd2dba3 (10 to 200
mol%), and a large excess of ligand (2.5 equiv) as well as aryl
bromide (2 to 15 equiv) to obtain satisfactory yields of coupling
products. Only per-O-benzylated D-glucopyranosylamine was
55 used as a sugar partner, thus limited the scope of the reaction.
Moreover, in all cases, a mixture of anomers (from 2:1 to 1:9
) was observed due probably to the instability of
glycosylamines at high temperature. Owing to the biological
significance and existing restricted synthetic methodologies, there
60 is an exigent need for a facile and efficient protocol to synthesize
aryl N-glycosides 3.
Since the initial reports of Chan and Lam,10 the copper promoted
coupling of amines with organoboronic acids has emerged as a
powerful tool for CN bond formation, and has found wide
65 applications in organic synthesis because of the mildness of the
reaction conditions. Although this coupling has been extensively
studied with various nitrogen nucleophiles, to the best of our
knowledge, there is no report describing the formation of aryl N-
glycosides from aminoglycosides and arylboronic acids.
70 Consequently, in continuation of our interest in C-heteroatom
bond formation,11 we report herein that N-arylation of
glucosamines can be realized efficiently and stereoselectively
using a catalytic amount of Cu(OAc)2 at room temperature under
air atmosphere (Scheme 1d).
(Scheme 1b),6 or (ii)
a nucleophilic substitution of the
acetohaloglycoside precursor under basic conditions (Scheme
1b).7 These procedures however, are cruelly limited in substrate
30 scope with respect to nitrogen nucleophile8 and (hetero)aryl N-
glycosylamines were obtained in variable yields depending on the
reactivity of the nitrogen nucleophile. In addition, reactions can
be lengthy and undesired mixture of epimers  is occasionally
observed.4,5a An appealing option to access aryl N-glycosides 3
35 would be the use of glycosylamines as nucleophiles in transition
metal-catalyzed reactions. To our knowledge, only one report
described the preparation of aryl N-glycosides by coupling of per-
O-benzylated D-glucopyranosylamine with activated bromoarenes
(Scheme 1c).9 This report is very interesting since
40 glycosylamines can act as a nucleophile in transition metal-
catalyzed reactions. Unfortunately, the preparative interest of
Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique,
LabEx LERMIT, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-
92296, France. Fax:
+ (33) 0146835828; Tel: + (33) 0146835887; E-mail:
45 samir.messaoudi@u-psud.fr, mouad.alami@u-psud.fr
†
Electronic Supplementary Information (ESI) available: General, experimental
procedures for starting materials and 1H and 13C spectra for all new compounds.
See DOI: 10.1039/b000000x/
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[journal], [year], [vol], 00–00 | 1

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Page 2 of 3
Table
1 Survey of reaction conditions for the N-arylation of
entries 6 and 7-10), and the use of only 1 equivalent was
aminoglucose 1a with 2aa
sufficient, giving rise to 3a in a good 72% yield (entry 11). One
can note that under catalytic amount of pyridine (40VmiewolA%rt)ic,lethOenline
DOI: 10.1039/C3CC44780D
45 reaction conversion drops down until 66% (entry 12). With
respect to copper catalyst, no significant improvement of the
yield of 3a was observed (entries 13-15). Pleasingly, the yield of
3a was improved up to 85% by employing 2.5 equivalent of
phenylboronic acid added in three portions (entry 17). Under
50 these optimal conditions, 3a was formed as a single -isomer
without any anomerization.
entry
[Cu]
Base
[c]
Conv.
(%)b
51d
45
65
yield
(%)c
19
21
53
57
65
72
49
-
-
-
72
-
-
Mol/L
0.07
0.07
0.14
0.29
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.58
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Collidine
Lutidine
Et3N
68
85
86 e
Motivated by these results, we next explored the scope of the
coupling reaction of β-aminoglucose 1a with various arylboronic
acids.13 Gratifyingly, all the arylations proceeded cleanly and
55 selectively in excellent yields. As depicted in Table 2, 1a was
readily coupled with aryl boronic acids having para and meta
electron-donating or electron-withdrawing substituents to give N-
glycosylated products in good to excellent yields with complete
β-selectivity.
28 e
40 e
9
40e
10
11
12
13
14
15
16
17
K2CO3
54 e
Pyridine
Pyridine
Pyridine
82 e, f
66 e, g
52 e, f
37 e, f
65 e, f
95 e, f
100 e, f
CuSO4.5H2O Pyridine
CuTC
Cu(OAc)2
Cu(OAc)2
-
-
Pyridine
Pyridine
Pyridine
80h
85i
60 Table 2 Scope of arylboronic acids 2 for Cu-catalyzed N-arylation of
aminoglucose 1aa
a 1a (1 equiv), phenylboronic acid 2a (2 equiv), [Cu] (20 mol %), base (2
b
5 equiv), molecular sevies, CH2Cl2, 24 h, 20 °C.
Conversion was
determined by 1H NMR in the crude reaction mixture based on the
chemical shift of the proton signal (ppm) at the C5-position of the sugar
moiety (1a: δ = 3.69, 3a: δ = 3.82). c Yield of isolated 3a. d 1.5 equiv. of
e
Cu(OAc)2 were used. The reaction was performed without molecular
10 sieves as the additives. Reaction with 1 equiv. of pyridine. Reaction
with 40 mol% of pyridine. PhB(OH)2 (2 equiv) were added in two
portions at t = 0 and 3.5 h. PhB(OH)2 (2.5 equiv) were added in three
f
g
h
i
portions at t = 0 (1 equiv), 3.5 h (0.75 equiv) and 7 h (0.75 equiv).
At the outset, we examined the coupling of peracetylated β-
15 aminoglucose 1a with phenylboronic acid 2a under various
source of copper catalysts, bases and solvents. Representative
results from this study are summarized in Table 1. The reaction of
1a (1 equiv) with 2a (2 equiv) was first investigated under Chan
and Lam’s original procedure10a,b [Cu(OAc)2 (1.5 equiv), pyridine
20 (2 equiv), molecular sieves, CH2Cl2, 24 h at 20 °C] (Table 1,
entry 1). Unfortunately, this protocol afforded an inseparable
mixture of the expected β-aryl N-glycoside 3a, together with
diphenyl byproduct arising from an oxidative homo-coupling of
phenylboronic acid12. After a tedious separation, 3a was isolated
25 in a low 19% yield. Next, we examined the catalytic version
using 20 mol% of Cu(OAc)2 under otherwise identical conditions.
Although the reaction conversion was low compared to the
stoichiometric version, the desired product 3a was isolated in a
similar yield (21%, entry 2). Increasing the concentration of β-
30 aminoglucose 1a from 0.07 to 0.29 M largely favors the
formation of 3a (entries 2-4) and the concentration c = 0.58 M
was found to be the best compromise between solubility and
efficiency of the reaction with the yield of 3a increased up to
65% (entry 5). These results indicate clearly that the
35 concentration of 1a plays a critical role in the outcome of the
CN bond formation. Further optimization revealed that the
presence of molecular sieves proved to be deleterious for the
coupling of 1a with 2a since performing the reaction without
molecular sieves led to the desired product 3a in a good 72%
40 yield (entry 6). The screening reaction was continued with respect
to the base. Pyridine was found to be the best choice (compare
a Reactions of 1a (1 equiv) with ArB(OH)2 (2.5 equiv) were performed in
flask at r.t. in CH2Cl2 by using Cu(OAc)2 (20 mol %), Pyridine (1 equiv).
It was soon discovered that substitution ortho to boron had a
65 dramatic influence on the reaction rate. The relatively hindered 2-
methoxyphenylboronic acid gave only a 15% yield of the desired
compound 3c, while 2-chlorophenylboronic acid did not furnish
3n even using
a
stiochiometric amount of Cu(OAc)2.
Interestingly, C-halogen bonds (e.g., I, Br, Cl, F) were tolerated
70 in the N-glycosylation reaction affording compounds 3g-k in
yields ranging from 75 to 87%. The presence of halogen
substituents in 3g-k provided a handle for further structural
diversifications using metal-catalyzed cross coupling reactions.
In a further set of experiments, we investigated the scope and
75 generality of the method with respect to mono- and
aminodisaccharides. As depicted in Table 3, coupling reactions
proceeded cleanly in high yields without any side reaction such as
anomerization of the resulting aryl-N-glycosides. The reaction is
general with respect to the sugar configuration as O-acetylated 1-
80 aminoD-galactose, O-acetylated 1-aminoD-mannose14
2
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Table 3 Scope of glucosamines 1b-g for N-arylation with 2a
was formed, for the first time, directly by using N-glycosides as
nucleophile partners in the presence of Cu(OAc)2 as the catalyst
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35 system. Because of the mildness of the DreOaIc: t1i0o.n10c3o9n/dCi3tCioCn4s4,78th0eD
protocol developed is diastereoselective, functional-group
tolerant, and proceeds in good to excellent yields. We believe that
this methodology will find broad applications in organic synthetic
chemistry as well as in combinatorial and pharmaceutical
40 sciences.
Notes and references
1
2
(a) R. A. Dwek, Chem. Rev.1996, 96, 683; (b) A. H. Adel, R. Abdel,
S. H. El, A. El, R. S. Richard, Carbohydr. Res. 1999, 315, 106; (c)
D.M. Huryn, Okabe, M. Chem. Rev. 1992, 92, 1745.
(a) A. L. Hopkins, J. Ren, J. Milton, R. J. Hazen, J. H. Chan, D. I.
Stuart, D. K. Stammers, J. Med. Chem. 2004, 47, 5912. (b) E. de
Clerq, Antiviral Res. 2005, 67, 56. (c) C. Mathe, G. Gosselin,
Antiviral Res. 2006, 71, 276.
3
(a) H. J. Knölker, K. R. Reddy, Chem. Rev. 2002, 102, 4303; (b) F.
Anizon, P. Moreau, M. Sancelme, A. Voldoire, M. Prudhomme, M.
Ollier, D. Severe, J.-F. Riou, C. Bailly, D. Fabbro, T. Meyer, A.-M.
Aubertin, Bioorg. Med. Chem. 1998, 6, 1597; (c) C. Marminon, F.
Anizon, P. Moreau, S. Leonce, A. Pierre, B. Pfeiffer, P. Renard, M.
Prudhomme, J. Med. Chem. 2002, 45, 1330.
a Reactions of 1a (1 equiv) with ArB(OH)2 (2.5 equiv) were performed in
flask at r.t. in CH2Cl2 by using Cu(OAc)2 (20 mol %), Pyridine (1 equiv).
and 1-amino-Nacetyl-D-glucosamine give the corresponding
products 4a-c, 4e and 4g,h in moderate to good yields. The
coupling procedure is not only limited to monoaminosaccharides
but also works successfully with peracetylated D-disaccharide
derived from Dcellobiose octaacetate. The exclusive 1,2-trans
N-glycosides 4d,f were obtained in 70% and 68% yields,
10 respectively, and the stereochemistry of the 14’ glycosidic bond
remained intact. Importantly, there is no significant impact of
protecting groups on the reactivity of the aminosugar derivatives
since benzyl- or pivaloyl- protected carbohydrate react similarly
than O-acetylated derivative 1a furnishing the coupling products
15 4i-l in yields ranging from 47 to 75%. Noteworthy, the coupling
of unprotected 1-aminoglucose with phenylboronic acid
failed, and the starting material was recovered unchanged.
5
4
5
M. Y. Fosso, V. P. N. Nziko, C. W. T. Chang, J. Carbohydr. Chem.
2012, 31, 603.
(a) W. Du, Y. Hu, Synth. Commun. 2004, 34, 2987. (b) N. Bridiau,
M. Benmansour, M. D. Legoy, M. Maugard, Tetrahedron, 2007, 63,
4178, (b) F. Erben, D. Kleeblatt, M. Sonneck, M. Hein, H. Feist, C.
Fischer, A. Matin, J. Iqbal, M. Ploetz, J. Eberle, P. Langer, Org.
Biomol. Chem., 2013, 11, 3963.
(a) S. Messaoudi, F. Anizon, S. Léonce, A. Pierré, B. Pfeiffer, M.
Prudhomme, Eur. J. Med. Chem. 2005, 40, 961; (b) S. Messaoudi, F.
Anizon, S. Léonce, A. Pierré, B. Pfeiffer, M. Prudhomme,
Tetrahedron 2005, 61, 7304; (c) H. Henon, S. Messaoudi, B. Hugon,
F. Anizon, B. Pfeiffer, M. Prudhomme, Tetrahedron 2005, 61, 5599.
(a) M. Ohkubo, T. Nishimura, H. Jona, M. Nakano, T. Honma, H.
Morishima, Tetrahedron 1996, 52, 8099; (b) M. Ohkubo, H.
Kawamoto, T. Ohno, M. Nakano, H. Morishima, Tetrahedron 1997,
53, 585; (c) S. Messaoudi, F. Anizon, B. Pfeiffer, R. Golsteyn, M.
Prudhomme, Tetrahedron Lett. 2004, 45, 4643.
6
7
8
9
Glycosyl amines are not stable enough to act as nucleophiles in SNAr
to make N-glycosyl compounds.
N. Chida, J. Synt. Org. Chem. Jpn. 2008, 66, 1105.
With substantial amounts of 3g in hand (Table 2), we focused our
attention on demonstrating whether our method could be
20 employed as a platform for molecular diversity. As shown in
Table 4, the significant increase in molecular complexity
achieved by otherwise simple and reliable transformations is
quite appealing, thus giving access to structures that are difficult
10 (a) D. M. T. Chan, K. L. Monaco, R. P. Wang , M. P. Winters,
Tetrahedron Lett., 1998, 39 , 2933; (b) P. Y. S. Lam, C. G. Clark, S.
Saubern, J. Adams, M. P. Winters, D. M. T. Chan, A. Combs,
Tetrahedron Lett. 1998, 39, 2941; (c) D. A. Evans, J. L. Katz, T. R.
West, Tetrahedron Lett. 1999, 39, 2937; For review, see: (d) J. X.
Qiao, P. Y. S. Lam, Synthesis, 2011, 829; (e) K. S. Rao, T.-S. Wu,
Tetrahedron 2012, 68, 7735.
11 (a) D. Audisio, S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami,
Tetrahedron Lett. 2007, 48, 6928; (b) S. Messaoudi, D. Audisio, J.-D.
Brion, M. Alami, Tetrahedron 2007, 63, 10202; (c) D. Audisio, S.
Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, J. Org. Chem. 2011,
76, 4995; (d) S. Messaoudi, J.-D. Brion, M. Alami, Adv. Synth. Catal.
2010, 352, 1677; (e) E. Brachet, J.-B. Brion, S. Messaoudi, M.
Alami, Adv. Synth. Catal. 2013, 355, 477.
to
obtain
by
other
means.
Notably,
N-glycosyl
25 phenylthioglycosides 5a-c15 bearing both CN and CS
glycosidic bonds could easily be prepared via a Pd-catalyzed
coupling reaction of 3g with various thioglycosides.11e
Table 4 Pd-catalyzed S-glycosidation of 3g with various thioglycosides 2a
12 The arylboronic acids are well-known to dimerize under similar
conditions, see: A. S. Demir, O. Reis, M. Emrullahoglu, J. Org.
Chem. 2003, 68, 10130.
13 The coupling of 1a with heteroarylboronic acids (pyridin-3-ylboronic
acid or benzofuran-2-ylboronic acid and thiophen-2-ylboronic acid)
or with an aliphatic boronic acid (butylboronic acid) failed.
14 Attempts to prepare 1-amino-glucose failed. This later is unstable
and isomerizes into the thermodynamically stable -anomer. See: Y.
Ichikawa, T. Nishiyama, M. Isobe, J. Org. Chem. 2001, 66, 4200.
15 For recent reviews on glycoconjugates and applications see: a) Y. M.
Chabre, R. Roy, Chem. Soc. Rev. 2013, 42, 4657; b) M. Gingras, Y. M.
Chabre, R. Roy, Chem. Soc. Rev. 2013, 42, 4823; and references
therein.
a
For experimental conditions see reference (11e) or (ESI).
In summary, we have succeeded in achieving the coupling of
30 N-glycosylamine derivatives with functionalized arylboronic acid
at room temperature to furnish aryl N-aminoglycosides. To the
best of our knowledge the C(sp2)N bond of aryl N-glycosides
This journal is © The Royal Society of Chemistry [year]
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