Nickel-catalyzed reductive coupling of glucosyl halides with aryl/vinyl halides enabling β-selective preparation of C-aryl/vinyl glucosides

Article abstract of DOI:10.1007/s11426-019-9501-4

This work describes stereoselective preparation of β-C-aryl/vinyl glucosides via mild Ni-catalyzed reductive arylation and vinylation of C1-glucosyl halides with aryl and vinyl halides. A broad range of aryl halides and vinyl halides were employed to yield C-aryl/vinyl glucosides in 42%–93% yields. Good to excellent β-selectivities were obtained for C-glucosides by using tridentate ligand.

Full text of DOI:10.1007/s11426-019-9501-4

SCIENCE CHINA
Chemistry
•COMMUNICATIONS•
SPECIAL ISSUE: Organic Free Radical Chemistry
https://doi.org/10.1007/s11426-019-9501-4
Nickel-catalyzed reductive coupling of glucosyl halides with
aryl/vinyl halides enabling β-selective preparation of C-aryl/vinyl
glucosides
Jiandong Liu, Chuanhu Lei* & Hegui Gong*
School of Materials Science and Engineering, Center for Supramolecular Chemistry and Catalysis, Department of Chemistry,
Shanghai University, Shanghai 200444, China
Received April 11, 2019; accepted May 13, 2019; published online June 18, 2019
This work describes stereoselective preparation of β-C-aryl/vinyl glucosides via mild Ni-catalyzed reductive arylation and
vinylation of C1-glucosyl halides with aryl and vinyl halides. A broad range of aryl halides and vinyl halides were employed to
yield C-aryl/vinyl glucosides in 42%–93% yields. Good to excellent β-selectivities were obtained for C-glucosides by using
tridentate ligand.
nickel-catalyzed, reductive coupling, β-selective preparation, C-aryl/vinyl glucosides
Citation:
Liu J, Lei C, Gong H. Nickel-catalyzed reductive coupling of glucosyl halides with aryl/vinyl halides enabling β-selective preparation of C-aryl/vinyl
glucosides. Sci China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-9501-4
C-glycosides embody an important class of bioactive com-
pounds found in nature and commercial drugs [1]. The
prestigious examples of natural products include (+)-varitriol
(anticancer activities) [2], Aspalathin (antimutagenic and
antioxidant properties) [3] and Salmochelins (e.g., Sal-
mochelin S1 as a metabolite of the ferric-binding side-
rophores) (Figure 1) [4]. C-glycosides are inert towards the
metabolic processes as compared to their O-counterparts,
where a plethora of C-glycosides were synthesized as potent
therapeutic agents [5]. Among them, canagliflozin (In-
vokana), empagliflozin (Jardiance) and dapagliflozin (Far-
xiga) have been widely used for the treatment of type-2
diabetes (Figure 1) [6].
which delivered high β-selectivities for C-aryl glucosides
(Reaction (1)) [7,8]. Knochel et al. [9] employed Ar2Zn as
the organometallic nucleophiles under catalyst-free condi-
tions to react with glucosyl bromide (Reaction (1)). The re-
action generates C-aryl glucosides with excellent β-
selectivities. By contrast, Walczak et al. [12,13] disclosed
that C1-glycosyl stannanes underwent an excellent stereo-
retentive cross-coupling reaction with aryl halides (Reaction
(2)). Recently, our group [14] developed a method employ-
ing pyridine/DMAP as ligand to prepare α-C-vinyl/aryl
glycosides via nickel-catalyzed reductive coupling of gly-
cosyl halides with vinyl and aryl halides in mild conditions.
Such a method adds a new entry to α-selective preparation of
C-glycosides as compared to the concurrent protocols that
generally produce moderate α-selectivities for arylation of
C1-glucosyl bromide [10,11].
The cross-coupling methods to access fully oxygen satu-
rated β-C-glycosides, in particular β-C-glucosides, often re-
quire transition-metal-catalysis (Scheme 1) [7–16]. Gagné
first utilized Ni-catalyzed Negishi strategy for the coupling
of C1-glycosyl halides with alkyl- and aryl-Zn reagents,
Herein, we report efficient preparation of β-C-aryl and
-vinyl glucosides and galactosides using Ni-catalyzed cross-
electrophile coupling strategy (Reaction (3), Scheme 1) [17].
This work features a ligand-controlled β-selective construc-
*Corresponding authors (email: chlei@shu.edu.cn; hegui_gong@shu.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

2
Liu et al. Sci China Chem
Table 1 Optimization for the formation of 2a
a), b)
a)
b)
Entry
1
Variation from the standard method A
None
Yield
c)
85% (1:12)
Figure 1 The representative examples of natural-occurring C-glycosides
and drugs for type II diabetes (color online).
2
Ni(ClO4)2∙6H2O instead of Ni(acac)2
L1 instead of tBu-Terpy
L2 instead of tBu-Terpy
L3 instead of tBu-Terpy
DMAinstead of THF
DMFinstead of THF
w/o Ni(acac)2, w/o tBu-Terpy
Without tBu-Terpy
MgCl2 (100 mol%)
0 °C
32% (1:11)
trace
3
4
N.D.
5
trace
6
trace
7
N.D.
8
N.D.
9
N.D.
10
11
12
13
80% (1:3)
N.D.
21 °C
74% (1:12)
25 °C
66% (1:12)
a) Method A as in entry 1; b) yield determined by 1H NMR spectroscopy
using 2,5-dimethylfuran as an internal reference, and ratio in parenthesis
refers to α/β ratio; c) isolated yields.
high yields (entries 11–13).
Scheme 1 β-Selective preparation of C-aryl/vinyl-glucosides (color on-
line).
To further probe the applicability of the present method,
coupling of a range of substituted aryl iodides with Ac-
protected glucosyl bromide 1 was carried out using method
A. As shown in Figure 2, compounds 2b–2e were obtained in
good to excellent yields with high β-selectivities. Compound
2f bearing less electron deficient substituents was obtained in
a good yield and high β-selectivity, which is the Ac-protected
commercial drug empagliflozin for type-2 diabetes [6]. Use
of 3-iodothiophene as coupling partner gave 2g in a moderate
yield and excellent β selectivity. Aryl iodides decorated with
meta-bomo furnished 2h with good yield and selectivity,
which is useful for further functionalization. For electron-
rich and -neutral arenes, method A also yielded moderate to
good yields and high β-selectivities by employing 15 mol%
MgCl2, as exemplified by 2i–2m. For the low-yielding re-
actions, we observed that the formation of glucal accounted
for the mass balance for glucosyl bromides, whereas hy-
drodehalogenation by-products did for aryl halides. We
reason that MgCl2 is required to activate Zn and reduce
Ni(II) to Ni(0), particularly in the cases of electron-rich aryl
halides (Figure 2). We performed an experiment using
Ni(COD)2 as the precatalyst without addition of MgCl2
tion of C-glucosides and represents a rare example for
transition metal-catalyzed stereoselective preparation of C-
vinyl glucosides/galactosides. The application of this method
was manifested by expeditious access to the intermediates of
Salmochelin derivatives and a commercial anti-diabetes drug
canagliflozin [4,6].
We commenced our work with the reaction of Ac-pro-
tected glucosyl bromide 1 and methyl 4-iodobenzoate. Ex-
tensive examination revealed a combination of Ni/tBu-
Terpy/Zn in tetrahydrofuran (THF) at 15 °C to be optimal,
with which C-aryl glucoside 2a was obtained in 85% yield
with an α/β ratio of 1:12 (Table 1, entry 1) [18]. Other nickel
sources and ligands, as well as solvents did not give a better
result (entries 2–7). Without nickel catalyst and ligand, or
without the ligand only no desired product was detected
(entries 8 and 9). When one equivalent of MgCl2 was used,
similar yield but lower β-selectivity was observed, indicating
MgCl2 can interfere β-selectivity, likely due to halide ex-
change within the aryl-Ni intermediates (entry 10) [14].
Keeping the temperature at 15 °C appeared to be crucial to

3
Liu et al. Sci China Chem
Figure 2 Scope of the aryl iodides. Yield refers to as isolated yield, and
ratio in parenthesis refers to α/β ratio (color online).
Figure 3 Selective preparation of β-C-aryl-glycosides. Yield refers to as
isolated yield, and ratio in parenthesis refers to α/β ratio (color online).
(Scheme S3, Supporting Information online), and similar
results for 2j were obtained. Without MgCl2, a control ex-
periment showed that no reaction occurred for 2j using
method A.
The utility of this work was further showcased by the
synthesis of β-2n and β-2o (Figure 3), which served as key
intermediates of Salmochelin derivatives (Fe3+-side-
rophores) and the precursor of a commercial drug canagli-
flozin for type-2 diabetes, respectively (Figure 4) [4,6,19].
Saponification of the latter provided canagliflozin in 90%
yield. Finally, a brief investigation of the scope of other
glycosyl halides for the coupling with 4-iodoanisole and 4-
iodobenzoate was explored. Arylation of benzyl-protected
glucosyl chloride with 4-iodoanisole in the presence of
15 mol% MgCl2 delivered 3 in 60% yield with a 1:5 of α/β
ratio. Galactosyl bromide displayed similar selectivities to
the glucosyl analogs (e.g., 4); high β selectivities were also
observed in 2-phthalimido glucosyl bromide (α/β=1:19) and
2,3,5-tri-O-aceto-D-ribofuranosyl chloride (e.g., 5 and 6).
We also investigate the preparation of β-C-vinyl glyco-
sides using the same coupling protocol. It was noted that
vinyl halides are generally more prone to dimerization as
compared to aryl counterparts [20]. Thus, coupling of Piv-
protected glucosyl bromide 7 with E-8 under Ni(acac)2/tBu-
Terpy/Zn/MgCl2/THF conditions provided 9a in an optimal
65% yield with an α/β ratio of 1:8 (Figure 4, method B). By
contrast, the acetyl-protected glucosyl bromide 1 gave 78%
yield with an α/β ratio of 1:3 (Table S2, Supporting In-
formation online) [18]. The aryl moiety bearing 4-CO2Me
within the styrene resulted in an enhanced yield, whereas a
MeO-group was slightly inferior without eroding the ste-
Figure 4 Selective preparation of β-C-vinyl-glycosides. Yield refers to as
isolated yield, and ratio in parenthesis refers to α/β ratio (color online).

4
Liu et al. Sci China Chem
reoselectivity, as evidenced by 9b and 9c (Figure 4). Method
B was also effective for the construction of Piv-protected β-
C-galactosides (e.g., 10a–10c), but not for β-mannoside 11.
Only the α-anomer was isolated, suggesting that substrate-
controlled stereochemistry dictates in this case. With slight
modifications, method B was suited for alkyl-substituted
vinyl and dienyl bromides furnishing β-selective preparation
of 12a–12c (Figure 4). In these cases, 1 was more effective
than 7, possibly due to enhanced reactivity of the former
arising from less steric hindrance. A quick application of the
vinyl product β-12a was conducted by hydrogenation to af-
ford the reduction product 13. It was noted that the pre-
paration of C-alkyl glucosides with good control of α- and β-
selectivities remains a challenge [7].
According to previously reported Ni-catalyzed reductive
cyclization/coupling of alkyl halides [11,14], coupling of 14
and methyl 4-iodobenzoate using method A produced 15 in
64% yield (Reaction (4)). Thus, we proposed this glycoside
forming protocol involves a radical mechanism, wherein an
aryl-NiII intermediate may intercept a glucosyl radical gen-
erated from halide abstraction by a NiI intermediate [8,17].
using the boat conformer is possible, and it favors β site due
to the bulkiness of Terpy-Ni(II) intermediate (Reaction (6)).
In contrast to our previous report, the use of labile pyridine
and DMAP resulted in good α selectivities under similar
reaction conditions [14]. In those cases, α-attack is favoured
possibly due to reduced steric interactions between Ni-Py
complex and the α-site of the glucosyl scaffold, in addition to
the anomeric stabilization of σ*(α-Ni–C) by p-lone electron
pair of the oxygen atom [25].
In summary, we have described an efficient Ni-catalyzed
cross-electrophile coupling method for stereoselective pre-
paration of β-C-aryl/vinyl glucosides. A unique tBu-Terpy
ligand-controlled diastereoselectivity was observed. We en-
visage that this method is synthetically practical for acces-
sing the relevant bioactive compounds containing β-
glucosides and -galactosides by using readily available gly-
cosyl and aryl/vinyl halides, and by avoiding the preparation
of organometallic reagents.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (21871173, 21572140, 21372151).
Conflict of interest The authors declare that they have no conflict of
interest.
To further understand the reaction mechanism, a tridentate
NiII complex 16 was obtained by reaction of methyl 4-io-
dobenzoate with Ni0 in the presence of tBu-Terpy [18]. 1H
NMR studies indicated it was paramagnetic and cationic in
polar solvents (Scheme S2) [18,21,22]. No appreciable 2a
was detected for the reactions of 16 with 1 (Reaction (5)),
regardless of the presence of MgCl2. With Zn, 2a was ob-
tained in 55% yield with high β-selectivity. We reason that it
is likely that complex 16 was reduced by Zn to tBu-Terpy-
NiI-Ar, to which oxidative addition of 1 leads to Ar-NiIII-
alkyl prior to the reductive elimination giving 2a (Scheme
S1), similar to Vicic’s proposal for Ni-catalyzed Negishi
mechasim [23,24].
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
1
2
For a recent review, see: Yang Y, Yu B. Chem Rev, 2017, 117:
12281–12356
(a) Zeng J, Vedachalam S, Xiang S, Liu XW. Org Lett, 2011, 13: 42–
45; (b) Malmstrøm J, Christophersen C, Barrero AF, Oltra JE, Justicia
J, Rosales A. J Nat Prod, 2002, 65: 364–367
3
4
5
Han Z, Achilonu MC, Kendrekar PS, Joubert E, Ferreira D, Bonnet
SL, van der Westhuizen JH. J Nat Prod, 2014, 77: 583–588
Fischbach MA, Lin H, Liu DR, Walsh CT. Proc Natl Acad Sci USA,
2005, 102: 571–576
(a) Compain P, Martin OR. BioOrg Medicinal Chem, 2001, 9: 3077–
3092; (b) Hultin P. Curr Top Med Chem, 2005, 5: 1299–1331; (c) Zou
W. Curr Top Med Chem, 2005, 5: 1363–1391; (d) Stambaský J, Hocek
M, Kocovský P. Chem Rev, 2009, 109: 6729–6764; (e) Koester DC,
Holkenbrink A, Werz DB. Synthesis, 2010, 19: 3217–3242; (f) Leclerc
E, Pannecoucke X, Ethève-Quelquejeu M, Sollogoub M. Chem Soc
Rev, 2013, 42: 4270–4283
The origin of β selectivity in this C-glucoside forming
approach is explained by a favourable β-attack of the Ac-
protected glucosyl radical to a Terpy-Ni(II)-Ar intermediate
(e.g., 17). It was known that Ac-protected glucosyl radical
adopts a boat-like B2,5-comfomer which is more stable than
the chair-like one with a free energy (ΔG) difference by
0.57 kcal/mol (Reaction (6)) [10,25]. Thus, radical attack
6
(a) Sadurní A, Kehr G, Ahlqvist M, Wernevik J, Sjögren HP, Kank-
konen C, Knerr L, Gilmour R. Chem Eur J, 2018, 24: 2832–2836;
(b) Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S,
Espadero RM, Woerle HJ, Broedl UC, Johansen OE. Diabetes Vas-
cular Dis Res, 2015, 12: 90–100
7
8
9
Gong H, Sinisi R, Gagné MR. J Am Chem Soc, 2007, 129: 1908–1909
Gong H, Gagne MR. J Am Chem Soc, 2008, 130: 12177–12183
Lemaire S, Houpis IN, Xiao T, Li J, Digard E, Gozlan C, Liu R,

5
Liu et al. Sci China Chem
Gavryushin A, Diène C, Wang Y, Farina V, Knochel P. Org Lett,
2012, 14: 1480–1483
10 Adak L, Kawamura S, Toma G, Takenaka T, Isozaki K, Takaya H,
Orita A, Li HC, Shing TKM, Nakamura M. J Am Chem Soc, 2017,
139: 10693–10701
11 Nicolas L, Angibaud P, Stansfield I, Bonnet P, Meerpoel L, Reymond
S, Cossy J. Angew Chem Int Ed, 2012, 51: 11101–11104
12 Zhu F, Rodriguez J, Yang T, Kevlishvili I, Miller E, Yi D, O’Neill S,
Rourke MJ, Liu P, Walczak MA. J Am Chem Soc, 2017, 139: 17908–
17922
A, Martin R. Chem Eur J, 2014, 20: 8242–8258; (d) Wang X, Dai Y,
Gong H. Top Curr Chem, 2016, 374: 43; (e) Xiao J, Cong XW, Yang
GZ, Wang YW, Peng Y. Chem Commun, 2018, 54: 2040–2043; (f)
Xiao J, Cong XW, Yang GZ, Wang YW, Peng Y. Org Lett, 2018, 20:
1651–1654; (g) Luo L, Zhai XY, Wang YW, Peng Y, Gong H. Chem
Eur J, 2019, 25: 989–992
18 See the Supplementary Information for details
19 Synthetic Strategies toward SGLT2 Inhibitors: Aguillón AR, Mas-
carello A, Segretti ND, de Azevedo HFZ, Guimaraes CRW, Miranda
LSM, de Souza ROMA. Org Process Res Dev, 2018, 22: 467–488
20 Liu J, Ren Q, Zhang X, Gong H. Angew Chem Int Ed, 2016, 55:
15544–15548
13 Yi D, Zhu F, Walczak MA. Org Lett, 2018, 20: 1936–1940
14 Liu J, Gong H. Org Lett, 2018, 20: 7991–7995
15 (a) Badir SO, Dumoulin A, Matsui JK, Molander GA. Angew Chem
Int Ed, 2018, 57: 6610–6613; (b) Dumoulin A, Matsui JK, Gutiérrez-
Bonet Á, Molander GA. Angew Chem Int Ed, 2018, 57: 6614–6618
16 For representative examples for de novo synthesis of C-glycosides:
(a) Balachari D, O’Doherty GA. Org Lett, 2000, 2: 4033–4036; (b)
Balachari D, O’Doherty GA. Org Lett, 2000, 2: 863–866; (c) Ahmed
MM, O’Doherty GA. Tetrahedron Lett, 2005, 46: 4151–4155
17 (a) Knappke CEI, Grupe S, Gärtner D, Corpet M, Gosmini C, Jacobi
von Wangelin A. Chem Eur J, 2014, 20: 6828–6842; (b) Everson DA,
Weix DJ. J Org Chem, 2014, 79: 4793–4798; (c) Moragas T, Correa
21 Klein A, Kaiser A, Wielandt W, Belaj F, Wendel E, Bertagnolli H,
Zalis S. Inorg Chem, 2008, 47: 11324–11333
22 Hamacher C, Hurkes N, Kaiser A, Klein A. Z Anorg Allg Chem, 2007,
633: 2711–2718
23 Schley ND, Fu GC. J Am Chem Soc, 2014, 136: 16588–16593
24 Jones GD, Martin JL, McFarland C, Allen OR, Hall RE, Haley AD,
Brandon RJ, Konovalova T, Desrochers PJ, Pulay P, Vicic DA. J Am
Chem Soc, 2006, 128: 13175–13183
25 Abe H, Shuto S, Matsuda A. J Am Chem Soc, 2001, 123: 11870–
11882