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Journal Name
COMMUNICATION
Table 3: Glycals scope for the C-H functionalisation
Conclusions
DOI: 10.1039/C9CC05993H
RO
RO
BnO
RO
RO
BnO
Pd(cod)Cl2 (20 mol%)
AgOAc (1.5 equiv.)
K CO (3.6 equiv.)
A Pd-catalyzed directed C-H functionalisation of the anomeric
position on C2-amidoglycals was presented as a novel route to
C-aryl/alkenylglycosides. Diverse aryl/alkenyl iodides and
glycals could be successfully engaged leading to good to
excellent yields. Application of the methodology to the
synthesis of glycosylated (mono- and disaccharide) amino acids
and to the synthesis of an analogue of Dapagliflozin is depicted.
Mechanistic investigation is undergoing to understand the role
of each reagent.
O
O
H
2
3
Ar
O
NH
Citric acid (85 mol%)
Ar-I (6 equiv.)
toluene, 130 °C, 16 h
O
NH
N
N
3-5
OBn
O
OBn
BnO
BnO
BnO
BnO
OMe
O
OMe
OMe
O
AQ
O
AQ
CO2Me
3
a 72%
3b 53%
This work has benefited from the facilities and expertise of the
Agence Nationale de la Recherche for financial support
(SuCH_Fun, JCJC ANR-18-CE07-0030-01).
O
O
O
O
OMe
O
O
BnO
BnO
OMe
OMe
CF3
O
AQ
O
AQ
4
a 73%
4b 60%
OBn
O
BnO
BnO
BnO
O
O
BnO
OBn
O
AQ
Conflicts of interest
There are no conflicts to declare.
CO2tBu
5
41%
BocHN
This effect could explain the absence of reactivity in our
methodology and give us clue about the mechanism. Indeed, in
concerted metalation-protonation mechanism proposed in
some C-H functionalisation literature, the acidity of the proton
Notes and references
1
3
is crucial to observe reactivity. Following this postulate, a
disarming effect should increase the acidity of the anomeric
proton and thus promote the reactivity. This type of mechanism
is thus unlikely. On the contrary, it was proved that C-H bond
energy is an important parameter to explain some reactivities.
Indeed, in transition-metal catalyzed processes, activation of a
strong C-H bond leads to a favorable strong metal-carbon
1
(a) P. M. Rudd, T. Elliott, P. Cresswell, I. A. Wilson and R. A.
Dwek, Science, 2001, 291, 2370; (b) P. H. Seeberger and D. B.
Werz, Nature, 2007, 446, 1046; (c) B. Ernst and J. L. Magnani,
Nat. Rev. Drug Discov., 2009, 8, 661; (d) H. Liao, J. Ma, H. Yao
and X.-W. Liu, Org. Biomol. Chem., 2018, 16, 1791.
2
3
(a) F. Nicotra, Top. Curr. Chem., 1997, 187, 55; (b) M. de
Robichon, A. Bordessa, N. Lubin-Germain and A. Ferry, J. Org.
Chem. 2019, 84, 3328.
(a) K.-S. Song, S. H. Lee, M. J. Kim, H. J. Seo, J. Lee, S.-H. Lee,
M. E. Jung, E.-J. Son, M. W. Lee, J. Kim and J. Lee, ACS Med.
Chem. Lett., 2011, 2, 182; (b) X.-J. Wang, L. Zhang, D. Byrne, L.
Nummy, D. Weber, D. Krishnamurthy, N. Yee and C. H.
Senanayake, Org. Lett., 2014, 16, 4090.
1
3
bond. C-H bond energy could be, in our case, the crucial point.
Further investigations will be performed to explore this
hypothesis. Our methodology was scaled up by submitting 800
mg of 1 with phenyl iodide as coupling partner. Satisfyingly, the
corresponding C-arylglycoside 2b is obtained in a similar yield
than in the 50 mg scale (57% versus 61%). Finally, we applied
our method to the synthesis of an analogue of the Dapagliflozin
drug, commercialized (FORXIGA®) to treat type 2 diabetes
4
(a) L. Adak, S. Kawamura, G. Toma, T. Takenaka, K. Isozaki, H.
Takaya, A. Orita, H. C. Li, T. K. M. Shing and M. Nakamura, J.
Am. Chem. Soc., 2017, 139, 10693; (b) Y. Yang and B. Yu,
Chem. Rev., 2017, 117, 12281; (c) K. Kitamura, Y. Ando, T.
Matsumoto and K. Suzuki, Chem. Rev. 2018, 118, 1495; (d) E.
Bokor, S. Kun, D. Goyard, M. Tόth, J.-P. Praly, S. Vidal and L.
(Scheme 2). Compound 1 was thus reacted in the optimised
conditions in presence of diaryl iodide 6 leading successfully to
the desired Dapagliflozin analogue 2o in an excellent 85% yield.
5
6
3
2
43; (b) G. Rouquet and N. Chatani, Angew. Chem. Int. Ed.,
013, 52, 11726; (c) N. Kuhl, M. N. Hopkinson, J. Wencel-
Pd(cod)Cl2 (20 mol%)
BnO
BnO
BnO
AgOAc (1.5 equiv.)
K2CO3 (3.6 equiv.)
BnO
BnO
BnO
O
O
Delord and F. Glorius, Angew. Chem. Int. Ed., 2012, 51, 10236.
(a) T. G. Frihed, M. Bols, C. M. Pedersen, Eur. J. Org. Chem.,
2016, 2740; (b) M. Boultadakis-Arapinis, C. Lescot, L. Micouin,
T. Lecourt, Synlett, 2013, 24, 2477; (c) N. Probst, G. Grelier, N.
Ghermani, V. Gandon, M. Alami, S. Messaoudi, Org. Lett.,
2017, 19, 5038.
Citric acid (85 mol%)
OEt
toluene, 130 °C, 16 h
Cl
O
AQ
O
AQ
I
1a
2o 85%
Cl
OEt
6
(6 equiv.)
Dapagliflozin
OEt
7
8
Selected works: (a) M.-C. Belhomme, T. Poisson and X.
Pannecoucke, Org. Lett., 2013, 15, 3428; (b) B. Wang, D.-C.
Xiong and X.-S. Ye, Org. Lett., 2015, 17, 5698; (c) T. Kikuchi, J.
Takagi, H. Isou, T. Ishiyama and N. Miyaura, Chem. Asian, J.,
2008, 3, 2082.
HO
HO
HO
Cl
O
OH
Scheme 2: Application of the developed methodology to the synthesis of a
Dapagliflozin analogue
A. Yokota, Y. Aihara and N. Chatani, J. Org. Chem., 2014, 79,
1
1922.
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