Intramolecular Pd-catalyzed anomeric C(sp3)-H activation of glycosyl carboxamides

Article abstract of DOI:10.1021/acs.orglett.7b02170

An expedient method for the synthesis of fused glycosylquinolin-2-ones and glycosylspirooxindoles through an unprecedented intramolecular Pd-catalyzed anomeric C-H activation of the sugar moiety of 2-bromophenyl glycosylcarboxamides is reported. The scope of the reaction is broad and tolerates a wide range of functional groups.

Full text of DOI:10.1021/acs.orglett.7b02170

Letter
pubs.acs.org/OrgLett
Intramolecular Pd-Catalyzed Anomeric C(sp3)−H Activation of
Glycosyl Carboxamides
Nicolas Probst,† Gwendal Grelier,‡ NourEddine Ghermani,§ Vincent Gandon,‡,∥ Mouad Alami,†
̂
and Samir Messaoudi*,†
†BioCIS, Univ Paris-Sud, CNRS, University Paris-Saclay, Chat
̂
enay-Malabry, France
‡Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ Paris-Sud, Universite
Gif-sur-Yvette, France
́
Paris-Saclay, 1, av de la Terrasse, 91198
§Institut Galien, Univ-Sud, CNRS, University Paris-Saclay, Chat
̂
enay-Malabry 92296, France
∥Institut de Chimie Molec
́
ulaire et des Mater
́
iaux d’Orsay, CNRS UMR 8182, Univ Paris-Sud, Universite Paris-Saclay, 91405 Orsay,
́
France
S
* Supporting Information
ABSTRACT: An expedient method for the synthesis of fused glycosylquinolin-2-ones and glycosylspirooxindoles through an
unprecedented intramolecular Pd-catalyzed anomeric C−H activation of the sugar moiety of 2-bromophenyl glycosylcarbox-
amides is reported. The scope of the reaction is broad and tolerates a wide range of functional groups.
Scheme 1. (A) Concept of the Intramolecular Csp3−H
he ability to synthesize complex molecules in a rapid and
Arylation of 2-Bromophenyl β-Glucosyl-1-carboxamides. (B)
Tefficient manner still represents a major challenge in organic
chemistry. In this context, C−H bond functionalization1 offers a
Natural Products Orixalone D and Zanthodiolone of
Glycosylquinolin-2-ones
unique opportunity to access compounds of synthetic interest
from readily available starting materials. Over the past decade,
transition-metal-catalyzed functionalization of seemingly inert
C(sp3)−H bonds has emerged as an efficient method for C−C
bond formation.2 In particular, substantial progress has been
achieved in the palladium-catalyzed activation of C(sp3)−H
bonds of challenging substrates (e.g., amino acids,3 peptides,4
cyclopropanes,5 amines,6 natural products,7 etc.). However, the
arylation of inert C(sp3)−H bonds in carbohydrates has never
been examined.8 From a conceptual point of view, this
methodology, if successful, would lead to greater scope in the
C(sp3)−H bond arylation, generating various motifs of syntheti-
cally useful fused glycosyl heterocycles. Moreover, the
modification of carbohydrate scaffolds has attracted tremendous
interest recently to investigate the complex nature of sugar-
mediated molecular recognition processes in biological systems.9
Inthis context, weinitiated aresearch programfocused ontheC−
H activation and functionalization10 of sugars and envisioned that
an intramolecular arylation of glycosylcarboxamides of type 1
(Scheme 1, A) could provide an efficient route for the preparation
of spirooxindole glycosides. Herein, we disclose our efforts to
develop the intramolecular direct arylation of glycosides
employing an amide-based tether that proceeds under palladium
catalysis, providing access to both spiro-glycosyloxindoles and
fused glycosylquinolin-2-ones structurally close to the natural
products zanthodiolone and orixalone D11 (an inhibitor of the
Received: July 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
production of nitric oxide in murine macrophage-like cells,11
Scheme1, B). Inaddition, this studydemonstrates thepivotalrole
played by the acetate group at C2 on the regioselectivity of the
C(sp3)−H bond cleavage. Additionally, we report experimental
observations and DFT calculations on the key C(sp3)−H
activation mechanism.
We decided on initial experiments to explore the feasibility of
the coupling of 2-bromophenyl β-glucosyl-1-carboxamide 1a by
investigating reaction product formation under fixed parameters:
Pd catalyst (Pd(OAc)2, 10 mol %), solvent (toluene), temper-
ature (150 °C), and time (3 h). Some representative examples are
listed in Table 1. Carrying out the reaction of 1a in the presence of
identification of new bioactive compounds. Thus, we continued
our investigations by fine-tuning the conditions of this novel
transformation, and we found that the efficiency of the reaction
was significantly affected by the choice of the base (entries 1−10).
In fact, weak bases such as K3PO4, AgOAc, and LiOAc were
ineffective as organic bases such as DIPEA (entries 1−4). On the
other hand, the use of Cs2CO3 led to total conversion of 1a and
furnished 2a in 76% isolated yield, combined with 8% of 3a (entry
5). In terms of metal carbonates, Cs2CO3 was superior to K2CO3,
while Ag2CO3 was ineffective. Strong bases such as NaOtBu or
KHMDS, which are usually used in the α-arylation of carbonyl
compounds,13 proved ineffective in our case. This last result may
suggest that the formation of a putative Pd-enolate is not
operative and the reaction proceeds via a C−H arylation pathway.
In another set of experiments, we showed that the nature of the
ligand also had a profound influence on the reaction yields
(entries 10−18). Among all phosphines, PCy3 used as its
phosphonium salt proved to be the optimal ligand, furnishing
2a in 76% yield (entry 5). The use of other bulky electron-rich
phosphines was less effective in this model reaction, except PPh3
and PhDavePhos, which afforded 67% HPLC yields in both cases
(entries 12 and 16). Finally, a 70% yield of 2a was obtained when
the reaction of 1a was carried out in the presence of PCy3 Pd-G2
precatalyst (5 mol %) instead of Pd(OAc)2/PCy3·HBF4 (entry
19). While one can note that the amount of the catalytic system
wasreducedto5mol%ofPd(OAc)2 and10mol%ofPCy3·HBF4,
the yield of 2a dropped to 53.9% (entry 20).
a
Table 1. Optimization of the Coupling Reaction of 1a
b
HPLC yield (%)
entry
ligand
base
2a
22.5
3a
1
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3
K3PO4
8.3
2.7
0.0
0.0
8.0
0.0
6.0
0.0
0.0
8.5
0.0
32.2
0.0
0.0
11.5
6.7
4.2
0.0
17.2
0.0
2
LiOAc
3.0
0.0
3
AgOAc
DIPEA
Cs2CO3
Ag2CO3
K2CO3
4
0.0
c
5
76.2 (76)
0.0
6
Motivated by these results, we next explored the scope of the
intramolecularcouplingofvariousβ-glycosylcarboxamides 1a−p,
4a, and 5a−f (Scheme 2). Remarkably, this reaction appeared to
be general with respect to different substituents on the aromatic
nucleusoftheglycosylcarboxamides(e.g., −F, −CF3,−CN,−Me,
7
7.9
8
LiHMDS
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0.0
9
0.0
10
11
12
13
14
15
16
17
18
19
20
52.9
39.2
67.0
20.2
15.8
12.8
67.0
14.0
12.3
70.3
PCp3·HBF4
PPh3
Scheme 2. C−H Activation of Anilide Glycosides 1a−p, 4a, or
5a−f*
dppp
XantPhos
Davephos
PhDavephos
Sphos
Cphos
PCy3·Pd G2
PCy3·HBF4
d
53.9
a
A sealable tube was charged with anilideglycoside 1a (0.06 mmol),
Pd(OAc)2 (10 mol %), ligand (20 mol %), base (3 equiv), 1,3,5-
trimethoxybenzene (0.5 equiv, internal standard), and toluene (0.08
M). The tube was flushed with argon and sealed. The reaction mixture
b
was heated at 150 °C during 3 h in an oil bath. Yields calculated by
HPLC with respect to 1,3,5-trimethoxybenzene as internal standard.
c
d
Yield of isolated product. 5 mol % of Pd(OAc)2 and 10 mol % of
PCy3·HBF4 were used.
PCy3·HBF4 (10 mol %) as ligand and K3PO4 (1.5 equiv) as base
led to a partial conversion of the starting material and provided
two new unexpected arylated compounds: compound 2a as the
major product (22.5% HPLC yield), and 3a12 as the minor one
(8.3% HPLC yield). Compound 2a could arise from Csp3−H
arylation at the C2-position followed by the loss of an ipso-acetate
group. This product, although obtained in a small amount,
showed the feasibility of the alluring conversion of 2-
bromophenyl β-glucosyl-1-carboxamide 1a into a fused glucosyl
quinolin-2-one 2a. With further optimization, such a trans-
formation could provide an expedient access to unprecedented
1,2-fused glycosylquinolin-2-one systems, thus allowing the
exploration of unknown chemical space which could lead to the
*
Reaction conditions: A sealable tube was charged with anilideglyco-
side 1a−p, 4a, or 5a−f (0.06 mmol), Pd(OAc)2 (10 mol %), PCy3·
HBF4 (20 mol %), Cs2CO3 (3 equiv) in toluene (0.08 M). The
reaction mixture was heated at 150 °C during the time indicated in
a
parentheses. Yield of isolated product.
B
DOI: 10.1021/acs.orglett.7b02170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Mechanistic Proposal (L = PCy3)
−OMe, −OCF3). Substrates bearing a substituent para to the
glycosylcarboxamide bond (substrates 1g−m) were reacted
under the optimized conditions to give the corresponding
glycosides 2g−m in moderate to good yields, regardless of their
electron-withdrawing or -donating nature. The exact structure of
3m was confirmed by the crystal structure analysis. In addition,
the cyclization of bromoglycosylcarboxamides bearing a sub-
stituent para to the bromine atom (substrates 1d−f) afforded the
corresponding products 2d−f in good yields. Importantly, the
sterically demanding ortho substitution pattern either ortho to the
carboxamide bond (substrate 1n) or ortho to the bromine atom
(substrate 1o,p) was tolerant toward the C−H arylation reaction,
leading to derivatives 2n−p in 90%, 39%, and 51% yields,
respectively. One can note that in all of the reactions shown
in Scheme 2 a trace amount of the side products 3a−p were
detected by LCMC, but these compounds have never been
isolated. Finally, alcohols of the sugar moiety had to be protected
as acetates since no reaction occurred when hydroxyl groups were
benzylated or left unprotected. This result suggests that the
acetate groups play an important role in the reaction mechanism.
To shed more light on this reaction, we examined the influence
of the acetate groups in this C−H activation process. As shown in
Scheme 2, this reaction is not limited to only β-glucosides 1a−p
since β-galactoside 4a and β-mannosides 5a−f were also valuable
substrates to give products 6a and 2a, 2d, 2f, 2g, 2k, and 2m in
yields ranging from 48% to 91%. These experimental data show
that mannosides 5a−f, which afforded products identical to those
obtained from glucosides 1a, 1d, 1f, 1g, 1k, and 1m, are more
reactive than their diastereoisomers, leading to better yields.
To probe whether the cyclization proceeds via a Heck-like
mechanism or through C(sp3)−H arylation followed by the loss
of the acetate group, we performed the reaction using glucal 8a
(Scheme 3, eq 1). This substrate failed to cyclize under our
with pyran carboxamide 12a occurred smoothly, furnishing,
again, the spirooxindole 2a in a moderate 36% yield14 (eq 3).
In light of the above observations, we suggest the mechanism
depictedinScheme4.ItstartswiththeoxidativeadditionofPd(0)
into the C−Br bond of typical substrates such as 9a, 1a, or 5a
followed by ligand exchange to give II. The intramolecular C−H
activation of the anomeric bond then occurs through a concerted
metalation deprotonation (CMD) mechanism to produce the
palladium C-enolate IIIa, which is in equilibrium with its
diastereomeric form IIIb through a putative O-enolate. Depend-
ing on the nature of the R group at the C2 position, the IIIa/IIIb
mixture may furnish the spirooxindole 10a when R = H by
reductive elimination or undergo a 1,2 Pd-migration15 when R =
OAc, followed by reductive elimination to produce V. This latter
intermediate, which is not enough stable under basic conditions,
evolves into 2a through an anti-HOAc elimination. It is important
to note that the intermediate V could be detected by LC−MS
analysiswitharetention timeof13.35mincorresponding the m/z
of 464.1556 ([M + H]+) and 386.1383 ([M + Na]+) (see the SI)
when the reaction of 2a was performed by using only 0.5 equiv of
the base. All of these results are in agreement with the mechanism
suggested here. In fact, C−H activation can occur in various ways,
including concerted or nonconcerted processes.16 To check the
validity of the proposed CMD mechanism, and also support the
hypothesis of type III complexes as common intermediates for
the two reaction products, DFT computations were carried out at
the M06/SDD-6-311+G(2df,2p) level.17,18 The only viable
pathway that could be found was indeed a CMD. Using 9a as
substrate forthecalculations(R=H), thefreeenergy ofactivation
was found to be +36.1 kcal/mol at C1.19,20 The corresponding
transition state is shown in Figure 1. By comparison, the CMD at
C2 is more energetically demanding by 1.2 kcal/mol (37.2 kcal/
mol). Using 1a (R = OAc down) or 5a (R = OAc up) as substrate,
the CMD at C1 was also always favored (+41.9 vs +44.5 kcal/mol
and +36.4 vs +43.5 kcal/mol, respectively). These values are
corroborated by the higher reactivity of 5a compared to 1a
observed experimentally. Thus, the spiro complexes III are
expected to be common intermediates for both product types.
Although not as yet elucidated, the reason for the ring expansion
from III to IV should be due to the increased acidity of the proton
Scheme 3. C−H Activation of Other Glycosides (Glucal 8a, 2-
a
Deoxyglucoside 9a), and Pyran 11a
a
Reaction conditions: A sealable tube was charged with an anilide
(0.06 mmol), Pd(OAc)2 (10 mol %), PCy3·HBF4 (20 mol %), Cs2CO3
(3 equiv), and toluene (0.08 M).
conditions, indicating that the Heck-like mechanism is unlikely.
We also explored the effect of the C2-acetate group. Surprisingly,
when the 2-deoxy-β-glucosyl carboxamide 9a was used as the
coupling partner, the C(sp3)−H activation occurred selectively at
ananomericpositionrather than attheC2position, providing, for
thefirsttime, thespirooxindole10ain78%yield(Scheme4,eq2).
This result indicates clearly that the C2 acetate group plays a
pivotal role in the regioselectivity of the C−H activation.
However, in this case, we noticed the reaction proceeded with
erosion of the diastereoselectivity (dr = 3:2). Moreover, reaction
C
DOI: 10.1021/acs.orglett.7b02170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4)SelectedarticlesonCsp3−Hactivationofpeptides:(a)Noisier, A.F.
M.; García, J.; Ionut,̧ I. A.; Albericio, F. Angew. Chem., Int. Ed. 2017, 56,
314. (b) Tang, J.; He, Y.; Chen, H.; Sheng, W.; Wang, H. Chem. Sci. 2017,
8, 4565.
(5) Selected articles on Csp3−H activation of cyclopropanes: (a) Ladd,
C. L.;Charette, A.B. Org.Lett. 2016,18,6046. (b)Ladd,C. L.;Belouin, A.
V.; Charette, A. B. J. Org. Chem. 2016, 81, 256. (c) Ladd, C. L.; Sustac
Roman, D.; Charette, A. B. Org. Lett. 2013, 15, 1350.
(6) Selected articles on Csp3−H activation of natural products:
(a) Yoshioka, S.; Nagatomo, M.; Inoue, M. Org. Lett. 2015, 17, 90.
(b) Dailler, D.; Danoun, G.; Baudoin, O. Chem. - Eur. J. 2015, 21, 9370.
(c) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders,
L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510.
Figure 1. CMD transition states corresponding to 9a and 1a (selected
distances in Å).
(7) For selected articles on Csp3−H activation of amines: (a) Millet, A.;
Dailler, D.; Larini, P.; Baudoin, O. Angew. Chem., Int. Ed. 2014, 53, 2678.
(b) Millet, A.; Larini, P.; Clot, E.; Baudoin, O. Chem. Sci. 2013, 4, 2241.
(c) Yang, L.; Melot, R.; Neuburger, M.; Baudoin, O. Chem. Sci. 2017, 8,
1344.
at C2 when R = OAc, which could allow a CMD after κ1-
20
−
coordination of a base (OAc−, HCO3 , or CO32−).
In conclusion, we report an unprecedented method for the
synthesis of fused glycosylquinolin-2-ones and glycosylspiroox-
indoles through an intramolecular Pd0-catalyzed anomeric
C(sp3)−H activation of glycosylcarboxamides. The method
tolerates a wide range of functional groups, and a variety of
substituted glcosylquinolinones were prepared in good yields.
(8) There is only one example report Rh(II) carbene-promoted
activation of the anomeric C−H bond of carbohydrates; see:
Boultadakis-Arapinis, M.; Lemoine, P.; Turcaud, S.; Micouin, L.;
Lecourt, T. J. Am. Chem. Soc. 2010, 132, 15477.
(9) (a) Feizi, T. Immunol. Rev. 2000, 173, 79. (b) Sharon, N. J. Biol.
Chem. 2007, 282, 2753. (c) Ke, C.; Destecroix, H.; Crump, M. P.; Davis,
A.P.Nat. Chem.2012,4,718.(d)Wang,A.C.;Jensen, E.H.;Rexach, J.E.;
Vinters, H. V.;Hsieh-Wilson, L. C. Proc. Natl. Acad. Sci. U.S. A. 2016, 113,
15120. (e) Pulsipher, A.; Griffin, M. E.; Stone, S. E.; Hsieh-Wilson, L. C.
Angew. Chem., Int. Ed. 2015, 54, 1466. (f)Spicer, C. D.;Davis, B. G. Chem.
Commun. 2013, 49, 2747. (g)Wibowo, A.;Peters, E. C.;Hsieh-Wilson, L.
C. J. Am. Chem. Soc. 2014, 136, 9528.
(10) (a) Bruneau, A.; Brion, J.-D.; Alami, M.; Messaoudi, S. Chem.
Commun. 2013, 49, 8359. (b) Brachet, E.; Brion, J.-D.; Messaoudi, S.;
Alami, M. Adv. Synth. Catal. 2013, 355, 477. (c) Brachet, E.; Brion, J.-D.;
Alami, M.; Messaoudi, S. Chem. -Eur. J. 2013, 19, 15276. (d) Bruneau, A.;
Roche, M.; Hamze, A.; Brion, J.-D.; Alami, M.; Messaoudi, S. Chem. - Eur.
J. 2015, 21, 8375. (e) Luong, T. H.; Brion, J.-D.; Lescop, E.; Alami, M.;
Messaoudi, S. Org. Lett. 2016, 18, 2126.
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b02170.
■
S
Experimental procedures, spectroscopic data, and NMR
spectra of new compounds(PDF)
X-ray crystallographic data for compound 3m (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: samir.messaoudi@u-psud.fr.
ORCID
(11) Ito, C.; Itoigawa, M.; Furukawa, A.; Hirano, T.; Murata, T.;
Kaneda, N.; Hisada, Y.; Okuda, K.; Furukawa, H. J. Nat. Prod. 2004, 67,
1800.
(12) The structure of 3a was determined by 1D and 2D NMR.
(13) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(b) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
Vincent Gandon: 0000-0003-1108-9410
Samir Messaoudi: 0000-0002-4994-9001
Notes
The authors declare no competing financial interest.
(14) For aclosed work, see: Lee, S.;Hartwig, J. F. J. Org. Chem. 2001, 66,
3402.
ACKNOWLEDGMENTS
■
(15) For 1,2-hydride shift in [M]-carbenoid intermediates, see:
(a) Qian, C.; Chen, J.; Fu, M.; Zhu, S.; Chen, W. H.; Jiang, H.; Zeng,
W. Org. Biomol. Chem. 2013, 11, 6013. (b)Furstner, A.;Stelzer, F.;Szillat,
We warmly thank Dr. P. Dauban (ICSN, CNRS UPR 2301) for
useful discussions. We acknowledge support of this project by
CNRS, University Paris-Sud, ANR (ANR-15-CE29-0002), IUF,
̈
H. J. Am. Chem. Soc. 2001, 123, 11863. (c)Mamane, V.;Gress, T.;Krause,
H.; Furstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (d) Mota, A. J.;
and by la Ligue Contre le Cancer through an Equipe Labellisee
2014 grant. Our laboratory is a member of the Laboratory of
Excellence LERMIT supported by a grant (ANR-10-LABX-33)
́
̈
Dedieu, A. Organometallics 2006, 25, 3130. (e)Dudnik, A. S.;Gevorgyan,
V. Angew. Chem., Int. Ed. 2007, 46, 5195. (f)Lee, J. H.;Toste, F. D. Angew.
Chem., Int. Ed. 2007, 46, 912.
(16) Roudesly, F.; Oble, J.; Poli, G. J. Mol. Catal. A: Chem. 2017, 426,
275.
(17) See the Supporting Information for details. Similar results were
obtained using the ωB97X-D functional.
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D
DOI: 10.1021/acs.orglett.7b02170
Org. Lett. XXXX, XXX, XXX−XXX