Stereoselective Preparation of C-Aryl Glycosides via Visible-Light-Induced Nickel-Catalyzed Reductive Cross-Coupling of Glycosyl Chlorides and Aryl Bromides

Article abstract of DOI:10.1002/adsc.202100343

A nickel-catalyzed cross-coupling reaction of glycosyl chlorides with aryl bromides has been developed. The reaction proceeds smoothly under visible-light irradiation and features the use of bench-stable glycosyl chlorides, allowing the highly stereoselective synthesis of C-aryl glycosides. (Figure presented.).

Full text of DOI:10.1002/adsc.202100343

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DOI: 10.1002/adsc.202100343
Very Important Publication
Stereoselective Preparation of C-Aryl Glycosides via Visible-Light-
Induced Nickel-Catalyzed Reductive Cross-Coupling of Glycosyl
Chlorides and Aryl Bromides
Ze-Dong Mou,+a Jia-Xi Wang,+a Xia Zhang,a,* and Dawen Niua,*
a
Department of Emergency, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital,
and
School of Chemical Engineering, Sichuan University, Chengdu, 610041, People’s Republic of China
E-mail: zhang-xia@scu.edu.cn; niudawen@scu.edu.cn
+
These authors contributed equally.
Manuscript received: March 18, 2021; Revised manuscript received: May 7, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100343
metal catalysis.[7] The use of glycosyl bromides as
donors to synthesize aryl glycosides via a nickel-
Abstract: A nickel-catalyzed cross-coupling reac-
tion of glycosyl chlorides with aryl bromides has
been developed. The reaction proceeds smoothly
under visible-light irradiation and features the use of
bench-stable glycosyl chlorides, allowing the highly
stereoselective synthesis of C-aryl glycosides.
catalyzed reductive coupling strategy was also reported
by the Gong group.[8] In addition, Walczak synthesized
aryl glycosides via a palladium-catalyzed stereoreten-
tive coupling of glycosyl-Sn with aryl electrophiles.[9]
Molander explored 1, 4-dihydropyridines as glycosyl-
based radical precursors to realize the synthesis of
reversed C-acyl glycosides through Ni/photoredox dual
Keywords: Carbohydrates; Photoredox catalysis;
Nickel; Reductive cross-coupling; Stereoselectivity;
catalysis.[10] More recently, the Diao group reported
decarboxylative coupling between glycosyl esters and
Aryl glycosides
aryl bromides.[11]
Our group has been interested in the development
of methods to make analogues and derivatives of
Aryl C-glycosides have important medicinal values carbohydrates. We reported a nickel-catalyzed Suzuki-
due to their significant biological activities and Miyaura cross-coupling to prepare C-aryl glycals from
resistance to metabolic degradation.[1] For excellent bench-stable α-oxo-vinylsulfones.[12] This reaction
examples, several C-aryl glucosides have been ap- demonstrates high generality to make C-aryl glycals.
proved by FDA for the treatment of type 2 diabetes However, the conversion of C-aryl glycals to β-C-aryl
(Scheme 1).[2] However, efficient stereoselective con- glucosides was inefficient. We then became intrigued
struction of C-aryl glycosidic bonds has been a if glycosyl chlorides could be used as the electrophilic
technical challenge in the synthesis of such drugs.[3] cross-coupling partner. Glycosyl chlorides are readily
Many industrialized routes involve the nucleophilic available. More importantly, per-acetylated glycosyl
attack of aryl metal reagents to glycosyl chlorides demonstrate significant stability toward long-
electrophiles.[1b] Recently, synthesis of aryl C-glyco- term storage. However, the use of glycosyl chlorides in
sides by cross-coupling strategies has attracted signifi- cross-coupling reactions has been underdeveloped. The
cant attention.[4] For example, Gagné reported the Nakamura group achieved the synthesis of aryl glyco-
synthesis of aryl glycosides from glycosyl bromides sides from glycosyl chlorides via iron-catalyzed free
and aryl zinc reagents through a nickel-catalyzed radical reactions.[13] Grignard reagents were used as the
Negishi coupling reaction.[5] Cossy described a cobalt- nucleophilic partner. In this work, we report reductive
catalyzed reaction of glycosyl bromides with aryl cross-coupling between glycosyl chlorides and aryl
metal reagents to synthesize aryl glycosides.[6] Knochel bromides to afford C-aryl glycosides. This reaction
revealed the use of aryl zinc reagents as nucleophiles occurs under photocatalytic conditions in the presence
to achieve the construction of aryl glycosides without of Ni-based catalysts. Various C-aryl glycosides were
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Table 1. Condition Optimization for Cross-Coupling of 13 and
14.
[a] Conditions: 13 (0.05 mmol), 14 (4 equiv.), photocatalyst
(2 mol%), NiBr2·diglyme (30 mol%), dtbbpy (30 mol%),
Hantzsch ester (HE) (2 equiv.), base (4 equiv.).
1
[b] Yields were determined by H NMR spectroscopy with
1,1,2,2-Tetrachloroethane as internal standard.
lowered the coupling efficiency (entry 8). Switching
the nickel source to Ni(COD)2 delivered 15 in reduced
yield (entry 9). The pre-formed NiBr2·diglyme/dtbbpy
complex could also be used (entry 10). Other transition
metals such as Pd, Cu, and Co were also attempted,
but no aryl glycoside products were detected (en-
try 11). Employing TTMSS instead of Hantzsch ester
afforded 15 in only 11% yield (entry 12). If Zn was
used instead of Hantzsch ester, no detectable amount
Scheme 1. Significance of C-aryl glycosides and their synthesis
by cross-coupling approaches.
obtained with high selectivities. This method was of 15 was formed (entry 13). The use of K2CO3 instead
successfully applied in the synthesis of canagliflozin. of TMG gave trace amounts of 15 (entry 14). Notably,
We commenced our study by investigating the β-glycosyl chloride could also serve as glycosyl donor
model reaction between acetyl-protected glycosyl in this reaction, furnishing 15 as the predominant
chloride 13 and 1-bromo-4-methoxybenzene 14 (Ta- product in slightly lower yield (entry 15).
ble 1). After screening reaction parameters, we found
With satisfactory reaction conditions established,
the desired reaction could be achieved under photo- the scope of the reaction was explored (Table 2). We
catalytic conditions in the presence of Ni-catalysts. found that the glycosyl chlorides derived from
Recently, the visible-light transition-metal co-catalysis galactose and mannitol underwent clean conversion
has emerged as a novel type of catalytic mode.[14–16] In into the corresponding C-aryl glycosides with moder-
our case, product 15 was obtained with high β- ate yields and high selectivities (17a, 17b). Similarly,
selectivity when NiBr2·diglyme and dtbbpy were the glycosyl chlorides derived from fucose affording
employed
(dFCF3ppy)2dtbbpy]PF6 as a photocatalyst, Hantzsch (17c). 1-Cl-2-deoxyglucose known for easy β-H
ester (HE) as terminal reductant, tetrameth- elimination of C2 can afford aryl glycoside product
as
catalyst
precursors,
[Ir- the aryl glycosides in excellent yield and α/β ratio
a
ylguanidine (TMG) as a base, acetonitrile (ACN) as 17d smoothly under the optimized conditions. Sub-
solvent, and a 10 W blue LED lamp as an irradiation strates derived from rhamnose also proceeded well,
°
source at 25 C for 24 h (entry 1). Control experiments and it can undergo stereoselective preparation of
revealed some key factors for the success of this corresponding aryl glycoside with high selectivity,
reaction. Without Ni catalyst, the photocatalyst, or leading to product 17e in 52% yield. Likewise, the
hantzsch ester, no desired product was detected substrate derived from arabinose could participate in
(entries 2–4). No reaction took place when the blue the reaction and resulted in the generation of aryl
LED lamp was removed (entry 5). Without base, only glycoside with moderate yield and β-selectivity (17f).
trace amounts of 15 were generated (entry 6). The To our delight, the catalytic system also showed
ligands diNH2bpy and diOMebpy could also be reactivity toward the glycosyl chloride derivatives
employed (entries 7–8), but the use of diOMebpy made from xylose and lyxose (17g, 17h).
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Table 2. Substrate Scope for Glycosyl Chlorides.[a]
19f). Polysubstituted aryl bromides could also be
readily incorporated (19g–m). Furthermore, heteroaryl
bromides including those containing indole (19q),
benzothiophene (19r), thiophene (19s), benzodioxole
(19t), or benzodioxane (19u) could be employed with
our method to provide the desired aryl glycoside
products in moderate to good yields and with good β-
selectivities (19q–u).
In order to further explore the utility of this method,
the synthesis of a pharmaceutically important molecule
canagliflozin was performed (Scheme 2). The cross-
coupling reaction of acetyl-protected glucosyl chloride
13 with an aryl bromide bearing a heteroaromatic ring
20 furnished the corresponding product in good yield
with excellent β-selectivity under the optimized con-
ditions. Subsequently, the acetyl groups of the arylation
product were cleanly removed under mild conditions
and provided 21 in 48% overall yield.
A plausible reaction mechanism was proposed for
this transformation based on literature precedence
(Scheme 3). The initial step is the reductive quenching
of the excited photocatalyst by HE to give the HE
[a] Conditions: 16 (0.2 mmol), Aryl bromide (4 equiv.) as
arylation reagent, [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mol%),
NiBr2·diglyme (30 mol%), dtbbpy (30 mol%), Hantzsch ester
(HE) (2 equiv.), TMG (4 equiv.). Unless otherwise noted,
isolated yields were reported. The reported isolated yields are
average of two runs. See supporting information for
experimental details.
The scope with respect to aryl bromides was also radical cation.[14] Subsequent deprotonation of the HE
investigated (Table 3). Various commercially available radical cation by base generates the HE radical, which
aryl bromides derivatives could partake in this reac- could undergo either a SET process with the photo-
tion. For example, the electron-rich and electron- catalyst or the direct electron transfer to glycosyl
neutral aryl bromides were found to be suitable chloride 36 to yield the glycosyl radical 37.[15] At the
substrates (19a–d, 19n-p). Substituents at the para- or same time, Ni0 complex 26 readily undergo oxidative
meta-position of aryl bromides were tolerated (19e, addition into aryl bromide 22 to furnish intermediate
23, which would be rapidly intercepted by the glycosyl
radical 37 to form the glycosyl-NiIII complex 24.[16]
Thereafter, reductive elimination would afford the
desired aryl glycoside 39 and NiI species 25.[17] Lastly,
single-electron transfer from the available IrII species
Table 3. Substrate Scope for Aryl Bromides.[a]
Scheme 2. Synthetic Application.
[a] Conditions: 13 (0.2 mmol), Aryl bromide (4 equiv.) as
arylation reagent, [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mol%),
NiBr2·diglyme (30 mol%), dtbbpy (30 mol%), Hantzsch ester
(HE) (2 equiv.), TMG (4 equiv.). Unless otherwise noted,
isolated yields were reported. The reported isolated yields are
average of two runs. See supporting information for
experimental details.
Scheme 3. Proposed Mechanism.
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1H NMR spectra were calibrated using 1,1,2,2-tetra-chloro-
ethane as an internal standard.
29 to complex 25 can reduce the metal catalyst back to
the starting Ni0 catalyst while simultaneously regener-
ating the ground-state photocatalyst 27, effectively
closing the catalytic cycles.[18] Notably, the high β-
selectivity might be due to the formation of the dimeric
NiI-ligand species, which would occupy the equatorial
position for steric reasons.[19]
In conclusion, we have developed a catalytic
system that achieves the stereoselective preparation of
C-aryl glycosides via visible-light-induced nickel-
catalyzed cross coupling of glycosyl chlorides with
aryl bromides. Mild conditions and the ability to
couple readily available, easy-to-handle starting mate-
rials and reagents to afford aryl glycosides with high β-
selectivity are attractive features of this process. We
believe that these advantages will enable the rapid
access to diverse aryl glycosides for drug discovery
and chemical biology studies.
Acknowledgements
This work is supported by funding from National Key Research
and Development Program (2018YFA0903300), National Natu-
ral Science Foundation of China (Nos. 21922106, 21772125,
and 81803359), and start-up funding from Sichuan University.
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Experimental Section
General information
Flash chromatography was performed manually, using silica gel
purchased from Qingdao Haiyang, and mixtures of petroleum
ether/ethyl acetate as eluting solvents. Acetonitrile was pur-
chased from J&K scientific and used as received. NiBr2 and
NiBr2·diglyme were purchased from Energy Chemicals and
used as received. All bipyridine ligands were purchased from
Energy Chemicals and used as received. Hantzsch ester was
purchased from Meryer Chemicals and used as received.
1,1,3,3-tetramethylguanidine (TMG) was purchased from En-
ergy Chemicals and used as received. All aryl bromides were
purchased from Energy Chemicals and used as received. The
photocatalyst and glycosyl chlorides were prepared following
the reported procedures.
General procedure
The [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mmol%) and hantzsch ester
(2.0 equiv.) were weighed into a screw capped vial containing a
stir bar. The vial was loosely capped and transferred into a N2-
filled glovebox. Glycosyl chloride (1.0 equiv.), NiBr2·diglyme
(30 mmol%) and dtbbpy (30 mmol%) were then added sequen-
tially, followed by addition of acetonitrile (1.2 mL unless
otherwise noted). Then, 1,1,3,3-tetramethylguanidine (TMG)
(4.0 equiv.) and aryl bromide (4.0 equiv.) were sequentially
added. The vial was tightly capped, taken out of the glovebox,
stirred (500 rpm stirring) and irradiated with a 10 W blue LED
lamp (with cooling fan to keep the reaction temperature at
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Stereoselective Preparation of C-Aryl Glycosides via Visible-
Light-Induced Nickel-Catalyzed Reductive Cross-Coupling
of Glycosyl Chlorides and Aryl Bromides
Adv. Synth. Catal. 2021, 363, 1–6
Z.-D. Mou, J.-X. Wang, X. Zhang*, D. Niu*