Copper-mediated O-arylation of lactols with aryl boronic acids

Article abstract of DOI:10.1016/j.cclet.2019.06.014

An efficient and novel methodology to access phenolic glycosides has been established by using copper-mediated coupling reaction of aryl boronic acids with hemiacetals. The reaction takes place normally in the presence of Cu(OAc)₂ (1.0 equiv.) and pyridine (2.0 equiv.) at 40 °C. This protocol distinguishes itself by wide substrate scope, operational simplicity and giving rise to a myriad of phenolic glycosides in good to excellent yields.

Full text of DOI:10.1016/j.cclet.2019.06.014

G Model
CCLET 5045 No. of Pages 5
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Copper-mediated O-arylation of lactols with aryl boronic acids
a,b,
Jing-Jing Suia,b, De-Cai Xiongb,c, , Xin-Shan Ye
*
*
a
National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
b
c
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient and novel methodology to access phenolic glycosides has been established by using copper-
mediated coupling reaction of aryl boronic acids with hemiacetals. The reaction takes place normally in
the presence of Cu(OAc)2 (1.0 equiv.) and pyridine (2.0 equiv.) at 40 ꢀC. This protocol distinguishes itself
by wide substrate scope, operational simplicity and giving rise to a myriad of phenolic glycosides in good
to excellent yields.
Received 7 May 2019
Received in revised form 3 June 2019
Available online xxx
Keywords:
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Phenolic glycoside
O-Arylation
Lactol
Aryl boronic acid
Phenolic glycosides such as vancomycin [1], seenoside A [2] and
camellianin B [3] (Scheme 1a), refer to molecules containing a
sugar unit bound to a phenol aglycone. These compounds are
widely distributed in nature and play numerous important roles in
living organisms. Phenolic glycosides have also received special
attention owing to their vital pharmaceutical potentials, such as
antitumor [4], antidiabetic [5] and anti-inflammatory effects [6]. A
major obstacle in the development of pharmacological characteri-
zation of phenolic glycosides is their extremely trace content in
natural sources.
Chemical synthesis enables facile access to phenolic glycosides
in pure and large quantities. There has been a growing emphasis
on investigating the synthesis of phenolic glycosides. A great deal
of efforts has been devoted to the development of effective
methods for the synthesis of phenolic glycosides. O-Glycosylation
of phenols is the main strategy for the formation of these
compounds. A large variety of glycosyl donors such as glycosyl
halides [7], glycosyl trichloroacetimidates [8], glycosyl N-phenyl
trichloroacetimidates [9], glycosyl acetates [10], thioglycosides
[11], alkynyl glycosides [12], 1,2-anhydrosugar [13], and hemi-
acetals [14], have been used for the assembly of phenolic
glycosides either through an SN2 type mechanism under basic
conditions or through an SN1 type mechanism under acidic
conditions (Scheme 1b). However, when using these methods, the
anomerization, formation of C-glycoside by-products, and low
functional-group tolerance usually hamper the versatility and
utility of phenolic glycoside synthesis.
O-Arylation of hemiacetals represents another route to afford
phenolic glycosides. The Olofsson group developed a novel method
for anomeric O-arylation using bench-stable iodonium (III)
reagents [15]. Xiao group revealed a new coupling reaction of
sugar lactols with aryl bromides to form phenolic glycosides via
dual photoredox/Ni catalysis [16]. As part of our continuous studies
on the preparation of carbohydrate derivatives by the coupling
reactions with aryl boronic acids [17], we herein report the
synthesis of phenolic glycosides via copper-mediated O-arylation
of lactols with aryl boronic acids (Scheme 1c).
We started our investigations on the coupling reaction of
2,3,4,6-tetra-O-acetyl-D-glucopyranose (1a) with commercially
available 4-methoxyphenylboronic acid (2a) (Table
1
and
Tables S1-S3 in Supporting information). We anticipated that a
stoichiometric amount of copper salt would be necessary for the
formation of the C–O bond. Indeed, the desired product 3aa was
obtained in 8% isolated yield by the use of CuCl2 (1.0 equiv.) in the
presence of pyridine (3.0 equiv.) (entry 1). The reaction appeared
completely inert to Cu(OTf)2, CuSO4 5H2O, CuCl and CuBr (entries
Á
2–5). Gratifyingly, the use of Cu(OAc)2 instead of CuCl2 afforded
the desired product 3aa in 62% yield (entry 6). Increasing the
reaction temperature to 40 ꢀC improved the reaction efficiency
(Table S3). It was observed that pyridine was the proper base and
the amount of pyridine also influenced the reaction yield (the best
amount was 2.0 equiv.) (entries 7–11 and 14–15, and Tables S1 and
S3). Further studies indicated that dichloromethane would be the
best solvent (Table S2). The omission of molecular sieves failed to
* Corresponding authors at: State Key Laboratory of Natural and Biomimetic
Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
E-mail addresses: decai@bjmu.edu.cn (D.-C. Xiong), xinshan@bjmu.edu.cn
(X.-S. Ye).
https://doi.org/10.1016/j.cclet.2019.06.014
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: J.-J. Sui, et al., Copper-mediated O-arylation of lactols with aryl boronic acids, Chin. Chem. Lett. (2019), https://
doi.org/10.1016/j.cclet.2019.06.014

G Model
CCLET 5045 No. of Pages 5
2
J.-J. Sui et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Scheme 1. Phenolic glycosides and their synthetic methods.
give the product (entry 16, Table S4 in Supporting information).
Therefore, the optimized conditions are as follows: lactol (1.0
equiv.), aryl boronic acid (3.0 equiv.), Cu(OAc)2 (1.0 equiv.),
pyridine (2.0 equiv.) and activated 4 Å molecular sieves, in CH2Cl2
at 40 ꢀC for 24 h (entry 15).
Table 1
Screening of optimal conditions.a
Under the optimized conditions, the reaction of lactol 1a with
different aryl boronic acids were surveyed, as shown in Table 2. The
results showed that aryl boronic acids bearing both electron-
donating substituents and electron-withdrawing substituents
underwent the reaction smoothly, affording the phenolic glyco-
sides in moderate to excellent yields. The reaction of ortho-, meta-
and para-substituted aryl boronic acid substrates gave good yields
(entries 8 and 9). Interestingly, the reaction of vinyl-, chloro- and
iodo-substituted aryl boronic acids with compound 1a also
proceeded very well, providing the desired coupled products,
which could be used for further transformations. The reaction of
disubstituted 3,5-dimethoxyphenylboronic acid gave the desired
product 3ak in moderate yield (52%, entry 10).
Entry
Conditions
Yield (%)b
1
2
3
4
5
6
7
8
CuCl2
Cu(OTf)2
8
trace
N.R.c
N.R.
N.R.
62
N.R.
12
trace
N.R.
trace
71
CuSO4
CuCl
Á
5H2O
Next, the scope of lactols was explored under the optimized
conditions and the results are summarized in Table 3. The
CuBr
Cu(OAc)2
reaction of 2,3,4,6-tetra-O-acetyl-
O-acetyl- -mannose (1c), 2,3,4-tri-O-acetyl-
2,3,4-tri-O-acetyl- -xylose (1e) with both electron-rich p-methox-
D
-galactose (1b), 2,3,4,6-tetra-
Cu(OAc)2, 2,6-lutidine
Cu(OAc)2, Et3N
Cu(OAc)2, DMAP
Cu(OAc)2, K2CO3
Cu(OAc)2, Cs2CO3
Cu(OAc)2, 40 ꢀ
Cu(OAc)2, 50 ꢀ
Cu(OAc)2, pyridine (1.0 equiv.), 40 ꢀ
Cu(OAc)2, pyridine (2.0 equiv.), 40 ꢀ
Cu(OAc)2, no 4 Å MS
D
L-arabinose (1d) and
9
D
10
11
12
13
14
15
16
ybenzeneboronic acid (2a) and electron-deficient p-nitrobenze-
neboronic acid (2 h), proceeded in good yields (entries 1–5). 2,3,4-
C
C
Tri-O-benzyl- -fucose (1f) also tolerated in this transformation,
L
68
77
90
N.R.
generating product 3fa in 65% isolated yield (entry 6). Similarly,
the benzylated/benzoylated counterpart of glucose/galactose/
mannose, underwent the reaction smoothly in satisfactory yields
(entries 7–16). It is noteworthy that the reaction of the mannose-
derived 1c and 1k provided an exclusive α-product (entries 3, 15
and 16). In all the reactions, no C-glycoside byproducts were
detected. Most of the produced phenolic glycosides were lack of
C
C
a
Reaction conditions: 1a (1.0 equiv.), 2a (3.0 equiv.), Cu salt (1.0 equiv.), pyridine
(3.0 equiv.), 4 Å MS (0.10 g), CH2Cl2 (1.0 mL), r.t., under air atmosphere for 24 h.
b
Isolated yield.
N.R.: no reaction.
c
Please cite this article in press as: J.-J. Sui, et al., Copper-mediated O-arylation of lactols with aryl boronic acids, Chin. Chem. Lett. (2019), https://
doi.org/10.1016/j.cclet.2019.06.014

G Model
CCLET 5045 No. of Pages 5
J.-J. Sui et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
3
Table 2
The scope of aryl boronic acids.a
Entry
1
Aryl boronic acid
Product
Yield (α/β)b
2b
2c
2d
3ab
93%, (1:1.5)
2
3
4
5
6
3ac
3ad
3ae
3af
3ag
94%, (1:1)
91%, (1:1)
92%, (1:1)
90%, (1:1)
66%, (1:2)
2e
2f
2g
7
8
9
2 h
2i
3ah
3ai
3aj
71%, (1:1)
95%, (1:1)
94%, (1:1)
2j
10
2k
3ak
52%, (1:1)
a
Reaction conditions: 1a (0.037 mmol), aryl boronic acid (0.111 mmol), Cu(OAc)2 (0.037 mmol), pyridine (0.074 mmol), 4 Å MS (0.15 g), CH2Cl2 (1.5 mL), 40 ꢀC, under air
atmosphere for 24 h.
b
Isolated yield.
stereoselectivity, and the anomeric ratio of the obtained glycosides
was not identical with that of the corresponding lactols in CDCl3. It
might be because that the anomeric ratio of lactols could vary as
the change of temperature, basicity, and solvent.
Based on the literature report [18], a plausible reaction mechanism
is depicted in Scheme 2. Initially, the aryl boronic acid reacts with Cu
(OAc)2 to generate CuII(Ar)OAc, which is oxidized with another Cu
(OAc)2 to form CuIII(Ar)(OAc)2. Finally, the ligand exchange and the
latter reductive elimination furnishes the phenolic glycosides.
In conclusion, we have developed an efficient and practical
copper-mediated coupling reaction of lactols with aryl boronic
acids for the preparation of phenolic glycosides. The O-
arylation of the anomeric oxygen in sugar moiety proceeded in
moderate to excellent yields under mild reaction conditions. A
broad range of lactols and aryl boronic acids with various
functional groups were tolerated. The disclosed approach may
find wide applications in the synthesis of many phenolic glyco-
sides with biological importance.
Please cite this article in press as: J.-J. Sui, et al., Copper-mediated O-arylation of lactols with aryl boronic acids, Chin. Chem. Lett. (2019), https://
doi.org/10.1016/j.cclet.2019.06.014

G Model
CCLET 5045 No. of Pages 5
4
J.-J. Sui et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Table 3
The scope of lactols.a
Entry
1
Lactol
1b
Aryl boronic acid
Product
Yield (α/β)b
2a
3ba
77%, (1:2)
2
3
2 h
2a
3bh
3ca
64%, (1:2)
1c
83%, α only
4
5
6
1d
1e
1f
2a
2a
2a
3da
3ea
3fa
74%, (1: 1)
84%, (1:1)
65%, (1:1)
7
8
9
1g
2a
2 h
2a
3ga
3gh
3ha
90%, (1.5:1)
58%, (1.5:1)
73%, (1:1)
1h
10
2 h
3hh
69%, (1:1)
11
12
13
1i
2a
2 h
2a
3ia
3ih
3ja
82%, (2:1)
56%, (1.5:1)
72%, (2: 1)
1j
14
15
2 h
2a
3jh
53%, (2: 1)
1k
3ka
75%, α only
Please cite this article in press as: J.-J. Sui, et al., Copper-mediated O-arylation of lactols with aryl boronic acids, Chin. Chem. Lett. (2019), https://
doi.org/10.1016/j.cclet.2019.06.014

G Model
CCLET 5045 No. of Pages 5
J.-J. Sui et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
5
Table 3 (Continued)
Entry
Lactol
Aryl boronic acid
Product
Yield (α/β)b
16
2 h
3kh
56%, α only
a
Reaction conditions: lactol (0.037 mmol), 2a or 2 h (0.111 mmol), Cu(OAc)2 (0.037 mmol), pyridine (0.074 mmol), 4 Å MS (0.15 g), CH2Cl2 (1.5 mL), 40 ꢀC, under air
atmosphere for 24 h.
b
Isolated yield.
[3] W. Li, R.J. Dai, Y.H. Yu, et al., Biol. Pharm. Bull. 30 (2007) 1123–1129.
[4] (a) R. Riccio, K. Nakanishi, J. Org. Chem. 47 (1982) 4589–4592;
(b) B. La Ferla, C. Airoldi, C. Zona, et al., Nat. Prod. Rep. 28 (2011) 630–648;
(c) C. Mendez, J. Gonzalez-Sabin, F. Moris, et al., Planta Med. 81 (2015) 1326–
1338;
(d) H. Murase, T. Noguchi, S. Sasaki, Bioorg. Med. Chem. Lett. 28 (2018) 1832–
1835;
(e) B.T. Scroggins, J. Burkeen, A.O. White, et al., Int. J. Radiat. Oncol. Biol. Phys.
100 (2018) 344–352;
(f) N. Tatematsu, Y. Waguri-Nagaya, Y. Kawaguchi, et al., Mod. Rheumatol. 28
(2018) 495–505.
[5] (a) S. Burda, W. Oleszek, J. Agric. Food Chem. 49 (2001) 2774–2779;
(b) Y.S.R. Elnaggar, E.M.M. Shehata, S. Galal, Nanomedicine 12 (2017) 893–910.
[6] C.S. Kim, L. Subedi, K.J. Park, et al., Fitoterapia 106 (2015) 147–152.
[7] (a) W. Koenigs, E. Knorr, Ber. Dtsch. Chem. Ges. 34 (1901) 957–981;
(b) K. Mohri, Y. Watanabe, Y. Yoshida, et al., Chem. Pharm. Bull. 51 (2003)
1268–1272.
[8] (a) R.R. Schmidt, J. Miche, Angew. Chem. Int. Ed. 19 (1980) 731–732;
(b) D.A. Burnett, M.A. Caplen, M.S. Domalski, et al., Bioorg. Med. Chem. Lett. 12
(2002) 311–314;
Scheme 2. The proposed mechanism for the O-arylation of lactols.
(c) P.W. Qin, J. Wang, H. Wang, et al., J. Agric. Food Chem. 62 (2014) 4521–4527.
[9] (a) M. Li, X.W. Han, B. Yu, J. Org. Chem. 68 (2003) 6842–6845;
(b) C. Menozzi-Smarrito, C.C. Wong, W. Meinl, et al., J. Agric. Food Chem. 59
(2011) 5671–5676.
Acknowledgments
[10] Y.S. Lee, E.S. Rho, Y.K. Min, et al., J. Carbohydr. Chem. 20 (2001) 503–506.
[11] (a) S.G. Duron, T. Polat, C.H. Wong, Org. Lett. 6 (2004) 839–841;
(b) G.J. Liu, C.Y. Li, X.T. Zhang, et al., Chin. Chem. Lett. 29 (2018) 1–10.
[12] (a) Y. Hu, Y.H. Tu, D.Y. Liu, et al., Org. Biomol. Chem. 14 (2016) 4842–4847;
(b) J.F. Zhou, X. Chen, Q.B. Wang, et al., Chin. Chem. Lett. 21 (2010) 922–926.
[13] C.F. Liu, D.C. Xiong, X.S. Ye, Tetrahedron Lett. 57 (2016) 1372–1374.
[14] (a) W.R. Roush, R.A. Hartz, D.J. Gustin, J. Am. Chem. Soc.121 (1999) 1990–1991;
(b) L. Petersen, K.J. Jensen, J. Org. Chem. 66 (2001) 6268–6275;
(c) J.P. Issa, C.S. Bennett, J. Am. Chem. Soc. 136 (2014) 5740–5744.
[15] (a) G.L. Tolnai, U.J. Nilsson, B. Olofsson, Angew. Chem. Int. Ed. 55 (2016) 11226–
11230;
(b) N. Lucchetti, R. Gilmour, Chem. - Eur. J. 24 (2018) 16266–16270.
[16] H. Ye, C. Xiao, Q.Q. Zhou, et al., J. Org. Chem. 83 (2018) 13325–13334.
[17] (a) D.C. Xiong, L.H. Zhang, X.S. Ye, Org. Lett. 11 (2009) 1709–1712;
(b) C.F. Liu, D.C. Xiong, X.S. Ye, J. Org. Chem. 79 (2014) 4676–4686;
(c) S.B. Tang, Q.N. Zheng, D.C. Xiong, et al., Org. Lett. 20 (2018) 3079–3082.
[18] (a) S.V. Ley, A.W. Thomas, Angew. Chem. Int. Ed. 42 (2003) 5400–5449;
(b) A.E. King, T.C. Brunold, S.S. Stahl, J. Am. Chem. Soc. 131 (2009) 5044–5045.
This work was financially supported by the National Key R&D
Program of China (No. 2018YFA0507602), the National Natural
Science Foundation of China (Nos. 21572012, 21772006) and the
State Key Laboratory of Drug Research (No. SIMM1803KF-02).
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.06.014.
References
[1] D. Kahne, C. Leimkuhler, L. Wei, et al., Chem. Rev. 105 (2005) 425–448.
[2] S.Y. Lee, W. Kim, Y.G. Lee, et al., Pharmacol. Res. 119 (2017) 422–430.
Please cite this article in press as: J.-J. Sui, et al., Copper-mediated O-arylation of lactols with aryl boronic acids, Chin. Chem. Lett. (2019), https://
doi.org/10.1016/j.cclet.2019.06.014