Intramolecular Pd-Catalyzed Arylation of 1-Amidosugars: A New Route to N-Glycosyl Quinolin-2-ones

Article abstract of DOI:10.1021/acs.orglett.6b00752

The synthesis of N-glycosylated quinolin-2-ones via an intramolecular N-arylation of glycosylamides is reported. The coupling involves the use of only Pd(OAc)₂ as the catalyst and nBu₄NOAc as the base in 1,4-dioxane. This versatile approach allows the synthesis of various N-glycosylated quinolin-2-ones with exclusive α or β selectivity.

Full text of DOI:10.1021/acs.orglett.6b00752

Letter
pubs.acs.org/OrgLett
Intramolecular Pd-Catalyzed Arylation of 1‑Amidosugars: A New
Route to N‑Glycosyl Quinolin-2-ones
Thi Thanh Huyen Luong, Jean-Daniel Brion, Ewen Lescop, Mouad Alami,* and Samir Messaoudi*
†
†
‡
,†
,†
†
BioCIS, Univ. Paris-Sud, CNRS, University Paris-Saclay, Chat
̂
enay-Malabry, France
Institut de Chimie des Substances Naturelles ICSN-CNRS, Gif-sur-Yvette, France
S Supporting Information
‡
*
ABSTRACT: The synthesis of N-glycosylated quinolin-2-ones via an intramolecular N-arylation of glycosylamides is reported.
The coupling involves the use of only Pd(OAc) as the catalyst and nBu NOAc as the base in 1,4-dioxane. This versatile
2
4
approach allows the synthesis of various N-glycosylated quinolin-2-ones with exclusive α or β selectivity.
he 1-aminosugar moiety is a privileged unit in
pharmaceutical science due to its unique properties.
Scheme 1. Synthesis of N-Glycosyl Quinolin-2-ones
1
T
This group has been increasingly used to address many of the
issues that are commonly encountered in the process of drug
2
discovery and optimization such as ADMET parameters. The
attachment of glycosyl units to a biologically active quinolin-2-
3
one core can cause several changes in its features, including its
chemical, physical, and biochemical properties such as oral
2
absorption and bioavailability. While N-glycosylated quinolin-
2-one derivatives 3 are of wide interest, their synthesis has been
problematic due to the difficulty in stereoselectively introducing
a nitrogen scaffold at the anomeric position of the sugar
4
moiety. Only two reports have dealt with the synthesis of these
target compounds, and both have involved the same basic
5
strategy. Mustafa et al. have described, as a single example, the
use of 2-methoxyquinoline as aglycon and tetra-O-acetyl-α-D-
glucopyranosyl bromide as the glycosyl donor (Scheme 1, eq
6
1
). In a similar approach, Niedballa et al. have disclosed a
single example of the conversion of trimethylsilyloxy quinolin-
-one into the corresponding glycosyl quinolin-2-one, in the
2
presence of a glycosyl donor and tin tetrachloride (Scheme 1,
eq 2). However, both methods are limited in substrate scope
with respect to the quinolinone partner and the sugar unit.
As part of our continuing effort in the functionalization of
To establish appropriate conditions for the selective
intramolecular arylation of 1-amidosugars of type 2 (Scheme
), (2-iodophenyl)acrylamidoglycopyranose 2a was initially
selected as the model substrate (Scheme 2). This compound 2a
was prepared by coupling the acrylic acid 1a as a mixture of
isomers (Z/E = 93:7) with the tetraacetylated 1-amino-β-
1
7
heterocycles via metal-catalyzed reactions, combined with our
interest in functionalizing sugars under transition-metal
8
catalysis, we report herein that N-glycosyl quinolin-2-ones 3
can be synthesized efficiently and stereoselectively via the
intramolecular N-arylation of 1-amidosugars using a catalytic
Received: March 15, 2016
amount of Pd(OAc) (Scheme 1, eq 3).
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of the Model Substrate 2-
Iodophenyl)acrylamidoglycopyranose 2a
revealed that stirring the reaction for only 30 min under
otherwise the same conditions led to a mixture of the desired
products β-3a and α-3a in an 85:15 ratio and the same yield for
the isolated β-3a (62%, entry 2). The screening reaction was
optimized with respect to the amount of the base. The use of
1
.5 equiv of n-Bu NOAc was found to be sufficient, giving rise
4
to β-3a in a good 62% yield (compare entries 2 and 4, 5).
Pleasingly, the yield of β-3a improved to 69% by omitting
TBAB as an additive (entry 6). In the next set of experiments,
pure (2-iodophenyl)-Z-acrylamide-β-glycopyranose (Zβ)-2a
was used as starting material. Under the optimal conditions,
N-glycosyl quinolin-2-one β-3a was formed in 76% yield as a
single β-isomer without any anomerization (entry 7). This
result suggested that α-3a was formed from (Zα)-2a. To clarify
this hypothesis, the coupling of pure (Zα)-2a was further
investigated under the optimized conditions. Accordingly, only
α-3a was isolated as a single anomer, and the coupling constant
between H and H (J = 6.3 Hz) reflected the α-glycosides
structure (entry 8; see Supporting Information). Moreover, to
verify the hypothesis that the (Eβ)-2a isomer does not react or
isomerize into the more reactive (Zβ)-2a, we carried out the
reaction with the pure (Eβ)-2a isomer. Under the optimized
conditions, no reaction occurred and the formation of
compound 3a was never detected (entry 9). Of note,
performing the reaction using the (2-bromophenyl)acrylamido-
glycopyranose instead of the iodinated derivative 2a furnished
the desired product 3a in 46% yield; however, the same
reaction with the (2-chlorophenyl)acrylamidoglycopyranose
failed.
a
Isomer ratios were measured by integration of well-resolved signals in
the 300 MHz 1H NMR (CDCl3).
9
glycopyranose employing Xu’s conditions (Scheme 2). In
contrast to Xu’s results, the expected coupling product (Zβ)-2a
was isolated together with two other byproducts in 75% yield
1
2
1,2
(
Scheme 2). After a tedious separation, 1D- and 2D-NMR
analysis revealed that these byproducts corresponded to the
Eβ)-2a and (Zα)-2a-isomers. The final ratio between the three
(
isomers Zβ/Zα/Eβ was 1:0.2:0.06 (see Supporting Informa-
tion) (Scheme 2).
Next, we continued our study by exploring the feasibility of
2
the intramolecular key step C(sp )−N bond formation of the 1-
amidosugar Zβ-2a contaminated with a small amount of its Eβ-
and Zα-isomers (Zβ/Zα/Eβ = 1:0.2:0.06). To our surprise,
heating the mixture in the presence of Pd(OAc) (5 mol %),
2
tetrabutylammonium acetate (3 equiv) as the base, and
tetrabutylammonium bromide (3 equiv) in dioxane at 130 °C
for 4 h led to N-β-glycosyl quinolin-2-one β-3a (J1,2 = 9.9 Hz)
in 63% yield (entry 1, Table 1) together with its anomer α-3a
derived from this cyclization of (Zα)-2a. Further optimization
With this encouraging result in hand, we next turned our
attention to examining the scope and limitations of the
coupling reaction of various β- or α-substituted (2-iodophenyl)-
Z-acrylamidosugars. As shown in Scheme 3, the amidosugars 2
were prepared from the coupling of substituted 3-(2-
iodophenyl)acrylic acids 1 as a mixture of Z/E-isomers (Z/E
Table 1. Survey of Reaction Conditions for the
Intramolecular N-Arylation of Tetraacetyl β-Amidoglucose
2
a
=
93:7) with 1-aminosugar derivatives. In all cases studied, the
a
desired coupling amidosugars Zβ-2 were obtained as the major
product contaminated by their isomers Eβ and Zα (see
Supporting Information for the ratios), and this mixture was
used crude for the next step. Gratifyingly, various substituted
(
2-iodophenyl)-Z-acrylamido-β-glycopyranoses reacted effi-
ciently to give the N-glycosylated quinolin-2-ones 3a−n as a
mixture of β and α anomers in ratios ranging from 1:0.1 to
1
:0.27 and yields up to 76%. Interestingly, this cross-coupling
tolerated the presence of C−halogen bonds (e.g., −Br, −Cl,
−F) which offers a platform for further metal-catalyzed cross-
coupling reactions (compounds 3b−e, 3h, 3k, and 3m,n). In
addition, the protocol was compatible with different amidosu-
gars such as galactoside and mannoside giving the correspond-
ing products 3g−i in 76%, 55%, and 68% yields, respectively.
This coupling is not limited to monoamidosaccharides, but also
works with peracetylated β-D-disaccharides derived from D-
cellobiose octaacetate. The N-glycosylated quinolin-2-ones 3j,k
were obtained in 64% and 60% yields, respectively.
Interestingly, this study was extended successfully to
unprotected amidosugars. As shown in Scheme 3, derivatives
ratio of 2a
Zβ/Zα/Eβ
temp
ratio
yield ofd
b
c
entry
(°C)
t (h) additive β-3a/α-3a
β-3a(%)
1
2
3
4
5
6
7
8
9
1:0.2:0.06
1:0.2:0.06
1:0.2:0.06
1:0.2:0.06
1:0.2:0.06
1:0.2:0.06
1:0:0
130
130
130
130
130
100
100
100
100
4
TBAB
TBAB
TBAB
TBAB
TBAB
−
85:15
85:15
−
85:15
85:15
85:15
100:0
0:100
−
63
62
0.5
0.25
0.5
0.5
1
e
−
f
63
g
62
69
1
−
76
h
0:1:0
1
−
72
0:0:1
1
−
00
a
2
a (1 equiv), Pd(OAc) (5 mol %), base (3 equiv), additive (3
2
b
2
l−n reacted efficiently under our optimized conditions leading
equiv), anhydrous dioxane (0.1 M). TBAB = nBu NBr (tetrabutyl-
4
c
1
to the product 3l−n bearing unprotected sugar moieties. Of
note in all cases, the β and α anomers were separated by SiO
amonium bromide). Ratio was determined by H NMR in the crude
reaction mixture based on the chemical shift (ppm) of the proton
2
d
flash chromatography or preparative HPLC and the NMR of
pure single anomers has been reported (see Supporting
Information).
signal H2 for β-3a (δ = 5.90) and H3 for α-3a (δ = 6.15). Yield of
e
f
isolated β-3a. Only 25% of conversion of 2a. 2 equiv of base were
g
h
used. 1.5 equiv of base were used. Yield of isolated α-3a.
B
DOI: 10.1021/acs.orglett.6b00752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Substituted Amidosugars 2 for the
Intramolecular Pd-Catalyzed N-Arylation
Scheme 4. Pd-Catalyzed Suzuki Arylation of β-3b
a
a
Conditions: reactions of β-3b (1 equiv) with arylboronic acids (1.25
equiv) were performed in a Schlenk tube at 80 °C in dioxane by using
b
Pd dba (2 mol %), Sphos (5 mol %), Cs CO (3 equiv). Yield of
2
3
2
3
isolated product.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00752.
Experimental procedures, spectroscopic data, and NMR
spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: samir.messaoudi@u-psud.fr.
E-mail: mouad.alami@u-psud.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CNRS is gratefully acknowledged for financial support of
this research. We also thank ARC (association pour la
recherche sur le cancer), for their financial support of this
research and for a Ph.D. grant to T.T.H.L. Our laboratory
BioCIS-UMR 8076 is a member of the Laboratory of
Excellence LERMIT supported by a grant from ANR (Agence
Nationale de la Recherche, ANR-10-LABX-33).
a
Conditions: reactions of 2 (1 equiv) were performed in a Schlenk
tube by using Pd(OAc) (5 mol %), nBu NOAc (1.5 equiv) in dioxane
2
4
b
(
0.1 M) at 100 °C. Yield of isolated mixture of both anomers β-3 and
α-3. Ratio was determined by H NMR of the mixture of 3-β/α after
flash chromatography purification.
c
1
In a further set of experiments, we tested whether multiple
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DOI: 10.1021/acs.orglett.6b00752
Org. Lett. XXXX, XXX, XXX−XXX