Ni/Photoredox-Dual-Catalyzed Functionalization of 1-Thiosugars

Article abstract of DOI:10.1021/acs.orglett.9b01730

A general protocol for functionalization of glycosyl thiols has been reported. This protocol is based on a single-electron Ni/photoredox dual-catalyzed cross coupling between 1-thiosugars and a broad range of aryl bromides and iodides as well as alkenyl and alkynyl halides. This base-free method gives access to a series of functionalized thioglycosides in moderate to excellent yields with a perfect control of the anomeric configuration. Moreover, it has been shown that this methodology may be transposed successfully to the continuous-flow photoredox chemistry.

Full text of DOI:10.1021/acs.orglett.9b01730

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni/Photoredox-Dual-Catalyzed Functionalization of 1‑Thiosugars
Mingxiang Zhu,† Guillaume Dagousset,‡ Mouad Alami,† Emmanuel Magnier,‡
and Samir Messaoudi*,†
†
́
̂
BioCIS, Universite Paris-Sud, CNRS, University Paris-Saclay, Chatenay-Malabry, France
‡
́
Institut Lavoisier de Versailles, UMR 8180, Universite de Versailles Saint-Quentin, 78035 Cedex Versailles, France
S
* Supporting Information
ABSTRACT: A general protocol for functionalization of glycosyl thiols has been reported. This protocol is based on a single-
electron Ni/photoredox dual-catalyzed cross coupling between 1-thiosugars and a broad range of aryl bromides and iodides as
well as alkenyl and alkynyl halides. This base-free method gives access to a series of functionalized thioglycosides in moderate to
excellent yields with a perfect control of the anomeric configuration. Moreover, it has been shown that this methodology may be
transposed successfully to the continuous-flow photoredox chemistry.
1-Thioglycosides are of great interest in pharmaceutical
science.1 These derivatives are considered as mimetics of
biologically relevant O-glycosides as they are known to be
resistant toward enzymatic hydrolysis.2 Some biologically
active 1-thioglycosides are represented in Figure 1, including
the hSGLT1 inhibitor, ligand of lectine A, cytotoxic Hsp90
inhibitor, galactosidase and glycosidase inhibitors, as well as
antimicrobial agents. In addition, thioglycosides are considered
as versatile intermediates in organic synthesis.3
Despite their potential interest in medicinal chemistry, only
few methods report their synthesis. Usually, they are prepared
by reaction of thiophenol with per-O-acetylated glycosyl
donors in the presence of a Lewis acid.4 They also could be
prepared by substituting the halogen atom at the anomeric
position of the sugar by a thiolate anion.5 These approaches
however suffer from the harsh reaction conditions and are
limited in substrate scope with thiophenols. Various Pd-,6 Ni-,7
or Cu-catalyzed8 S arylations of glycosyl thiols with aryl iodides
were developed independently by Sticha,8a Xue,8c and our
group (Figure 2 Ia,b).9 However, demanding reaction
conditions such as high catalyst loadings (30 mol % in the
case of Ni catalysis), specialized phosphine ligands for the Pd
catalysis, elevated reaction temperatures (80−120 °C cases of
Pd or Cu catalysis), and long reaction times often limit the
practicability or the scope of substrates. Moreover, in all these
cases the coupling is effective with only aryl iodides; however,
the cross coupling with aryl bromides is rather unexplored.
Figure 1. Example of biologically active thioglycosides.
Owing to the high importance of thioglycosides, there is a
strong impetus to develop mild and general reactions for their
efficient synthesis.
Dual nickel photocatalysis has emerged as a powerful
strategy and a remarkably efficient tool for organic cross-
coupling reactions in recent years.10 Although this approach
Received: May 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01730
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Letter
Figure 2. (Ia and b) Traditional metal-catalyzed cross-coupling methods for the synthesis of thioglycosides. (Ic) Dual nickel photocatalyzed
approach. (II) Proposed mechanism.
was used successfully for the C−C bond construction, the
formation of a C−heteroatom bond through Ni-photoredox
processes is less explored. Moreover, methods which use
photoredox dual catalysis to form a thiyl radical and promote it
through cross coupling with aryl halides to form C−S bonds
are rare. Johannes and co-workers developed an Ir/Ni dual-
photoredox-mediated cross-coupling reaction of thiols with
aryl iodides.11 Very recently, Molander et al. reported the first
Ni/photoredox cross-coupling reaction for the S-arylation of
cysteine-containing unprotected peptides.12 The authors
showed elegantly that the mildness of this approach allows
late-stage functionalization of complex biomolecules. However,
the S-arylation of the anomeric bond of thiosugars under Ni-
photoredox dual catalysis has never been examined, probably
due to the inherent complexity of carbohydrates.
In continuation of our study on the reactivity of thiosugars
under transition metal catalysis, we became interested in
whether the S-(hetero)arylation of 1-thiosugars could be
realized by the single-electron dual Ni/photocatalysis (Figure
2Ic). We considered that 1-thiosugars may be suitable
substrates for such a strategy, keeping in mind that a practical
synthetic method should work not only with aryl iodides but
also with aryl bromides as well as alkenyl- and alkynyl-
bromides. We could assume that the catalytic cycle may be
initiated by photon absorption, generating excited state Ru
photocatalyst, followed by oxidation of the HAT reagent via
single electron transfer (SET) (Figure 2, II). In this context,
ammonium bis(catechol)alkylsilicates were recently found to
be effective hydrogen atom transfer (HAT) reagents for Csp2−
S coupling under the Ni/photoredox processes.13 Rapid H
atom abstraction from the glycosyl sulfhydryl group generates a
glycosyl thiyl radical. This later adds to Ni(II) which arises
from Ni(0) oxidative addition with the aglycon halide. In a
possible alternative of the catalytic cycle, Molander, Kozlowski,
and co-workers reported that the thiyl radical metalation may
precede the oxidative addition step.14 Reductive elimination
from Ni(III) affords the desired thioglycoside, and the dual
catalytic cycles are closed by a final SET.
In the first set of experiments, we examined the coupling of
tetra-O-acetylated 1-thio-β-D-glucopyranose 1a with 1-bromo-
benzonitrile 2a as a model study under various reaction
conditions. Representative results from this study are
summarized in Table 1. The reaction of 1a (1 equiv) with
2a (1 equiv) was first investigated under Molander’s conditions
B
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Table 1. Optimization of the Coupling Reaction of 1a with
2a
Scheme 1. Scope of Coupling of Thioglucose 1a with
a
Halo(hetero)arenes, Alkenyl Halides, and Alkynyl Bromides
c
2
b
entry
X
equiv of 2a
solvent
3a (%)
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
Br
I
1
DMF
DMF
DMF
DMF
DMA
DMSO
MeCN
THF
59
79
85
81
32
54
40
19
90
1.3
1.5
2
2
2
2
2
1.5
1.5
c
DMF
DMF
d
10
I
95
a
A sealable tube was charged with thiosugar 1a (1 equiv, 0.2 mmol),
1-bromo-4-benzonitrile 2a (xx equiv), [Ni(dtbbpy)(H2O)4]Cl2
precatalyst (5 mol %), [Ru(bpy)3](PF6)2 (2 mol %), and HAT
reagent (diisopropylammonium bis(catechol)isobutylsilicate) (1.3
b
equiv) in dry and degassed DMF (1.0 mL). Yield of isolated
c
d
product. 70% of 3a when 3 mol % of Ni catalyst was used. 150 mg
of molecular sieves was added.
using 5 mol % of [Ni(dtbbpy)(H2O)4]Cl2 and 2 mol % of a
commercially available [Ru(bpy)3(PF6)2] photocatalyst in the
presence of ammonium bis(catechol)alkyl silicate (1.3 equiv)
as a HAT reagent under blue-light-emitting diode (LED)
irradiation (Table 1, entry 1). Pleasingly, this protocol afforded
the desired thioglycoside 3a in a moderate 59% yield as a
single β-anomer (J1,2 = 9 Hz). Increasing the amount of the
bromide partner 2a from 1 equiv to 1.3 equiv furnished 3a in a
good 79% yield (entry 2). Moreover, the yield was increased
up to 85% when 1.5 equiv of 2a was used (entry 3). The
optimization of the reaction conditions was continued with
respect to solvent; however, no significant improvement of the
yield of 3a was observed with DMA, DMSO, MeCN, and THF
(entries 5−8). Finally, performing the coupling reaction with
the iodobenzonitrile instead of the bromide led to 3a in 90%
yield (entry 9). Extensive examinations of the other reaction
parameters revealed that the use of molecular sieves plays an
important role in this reaction. The yield of 3a was improved
up to 95% with complete retention of the anomeric
configuration when the reaction was conducted in the presence
of molecular sieves (entry 10). A control experiment showed
that all parameters (Ni catalyst, Ru photocatalyst, HAT
reagent, and light) were essential for the reaction to proceed.
Without one of them, the reaction do not occur.
With these encouraging results, we investigated next the
scope for this dual Ni/photocatalysis process by systematically
varying the nature of the electrophile partner 2 and the
thiosugar substrates 1a−e (Scheme 1). All the couplings
proceeded cleanly and selectively in good yields. As shown in
Scheme 1, various electron-deficient and electron-rich aryl
iodides having para- and meta-substitution effectively under-
went reaction with tetra-O-acetylated 1-thio-β-D-glucopyranose
1a in yields up to 96% (products 3a−o).
Various reactive functional groups were tolerated, such as
nitrile (3a), ester (3g), halogens (3b−d, 3h), isopropyl (3n),
and amino acid (3o). In addition, the presence of an ortho
substitution at the aromatic ring of the coupling partner does
a
b
Yield of isolated product. Comparison with results obtained by Pd
c
catalysis reported in refs 8a, 8b, and 8c. Reaction conditions: A
sealable tube was charged with thiosugar 1a (1 equiv, 0.2 mmol), aryl,
alkenyl, or alkynyl halides 2 (1.5 equiv), [Ni(dtbbpy)(H2O)4]Cl2
precatalyst (5 mol %), [Ru(bpy)3](PF6)2 (2 mol %), and HAT
reagent (diisopropylammonium bis(catechol)isobutylsilicate) (1.3
equiv) in dry and degassed DMF (1.0 mL).
C
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not affect the coupling process as compounds 3d, 3l , and 3m
having ortho substituent groups were obtained in 88%, 73%,
and 85% yields, respectively.
Scheme 2. Scope of Thiosugars 1b−e Coupling with
b
Iodoarenes
Aside from aryl iodides, aryl bromides can also serve as
coupling partners under Ni photocatalysis. For example, cross
coupling of aryl bromides bearing various functions (−CN, −
Cl, −F, and − OMe) have been successfully achieved under
room temperature to afford the corresponding thioglycosides
(3a−b, 3h, 3i, 3k,l) in moderate to good yields with no
changes to the standard reaction conditions. However, we can
note that aryl bromides are less reactive than their iodide
congeners in this cross-coupling protocol. Interestingly,
couplings with heteroaryl halides derived from quinolinone,
pyridine, and indole have also been successful, furnishing 3p−r
in excellent yields (87%−95%). In addition, para-iodopheny-
lalanine (NHBoc) can be employed as a coupling partner
(compound 3o).
One can be note that across a number of substrates coupling
products were afforded in comparable yields to those obtained
under palladium-catalyzed (thermal) conditions.
In the aim to further push the limit of this Ni-photocatalysis
protocol, we examined the coupling of 1a with halogenated
alkenes and alkynes. Delightfully, when E-β-styryl bromide was
employed, the coupling with 1a afforded stereoselectively the
desired alkenyl thioglycoside derivative 3t in 87% yield. In
addition, reaction of 4-(bromoethynyl)thiophene with 1a
furnished the desired alkynyl-thioether 3u in 58% yield.
Interestingly, when (E)-1,2-diiodoethene was used, the
coupling reaction with 1a furnished selectively the mono-
coupling product 3s in a moderate 30% yield, while the
formation of dicoupling product has never been observed.
Finally, this methodology was applied with success to the
synthesis of the compound 3v (85% yield), an hSGLT1
inhibitor used for the control of hyperglycemia in patients with
diabetes.
a
b
Yield of isolated product. Reaction conditions: A sealable tube was
charged with thiosugar 1b−e (1 equiv, 0.2 mmol), aryl halides 2 (1.5
equiv), [Ni(dtbbpy)(H2O)4]Cl2 precatalyst (5 mol %), [Ru(bpy)3]-
(PF6)2 (2 mol %), and HAT reagent (diisopropylammonium
bis(catechol)isobutylsilicate) (1.3 equiv) in dry and degassed DMF
(1.0 mL).
Scheme 3. Continuous-Flow Coupling of Thioglucose 1a
with 2a
In a next step, we examined the scope of this method with
respect to the glycosyl thiols. As depicted in Scheme 2, this
coupling reaction tolerates different glycosylthiols 1b−e: O-
benzoylated 1-thio-β-D-glucopyranose 1b, O-acetylated 1-thio-
β-D-galactopyranose 1c, and O-acetylated 1-thio-β-D-fucopyr-
anose 1d, all coupled with the 4-iodobenzonitrile 2a to give
thioglycosides 4a−c in good yields. In addition, this coupling
could be applied to the complex disaccharide 1-thio-β-D-
cellobiose 1e which was efficiently reacted with 2a to give 4d
in 64% yield.
Recently, continuous-flow synthetic methodologies com-
bined to photochemistry have become an emerging field.15
This combination could allow the development of a fully
automated process with an increased efficiency and, in many
cases, improved sustainability. The great peculiarity of a flow
photoredox system is a very efficient irradiation that allows us
to speed the reaction rate up so that productivity is generally
greatly improved with respect to the batch system. Indeed,
reaction scale up is usually easy to perform with high yields. In
order to accelerate our coupling process, we attempted to
transport the continuous-flow techniques to our reaction. We
were pleased to see that the thioarylation of 1a with 2a in a
large-scale version (0.8 mmol scale, 4-fold), could be carried
out under the same conditions at a residence time of 20 min at
25 °C. Remarkably, the reaction runs smoothly with complete
conversion, and the desired product was isolated in 79% yield
(Scheme 3).
In summary, we have shown that 1-thiosugars are competent
nucleophile partners in the Ni/photoredox-dual-catalyzed
cross-coupling reactions and developed a general method for
the synthesis of thioglycosides in batch or in flow. The method
tolerates a wide range of functional groups such as aryl,
heteroaryl, alkenyl, and alkynyl bromides and iodides. In
addition, a variety of glycosyl thiols could be used. This
method opens news opportunities for using thiosugars in
synthetic methodology.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01730.
Experimental procedures, spectroscopic data, and NMR
spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: samir.messaoudi@u-psud.fr.
D
DOI: 10.1021/acs.orglett.9b01730
Org. Lett. XXXX, XXX, XXX−XXX

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ORCID
Letter
Dynamic Drug Design: Identification and Optimization of β-
Galactosidase Inhibitors from a Dynamic Hemithioacetal System.
ChemBioChem. 2010, 11, 1600.
Guillaume Dagousset: 0000-0001-8720-3828
Emmanuel Magnier: 0000-0003-3392-3971
Samir Messaoudi: 0000-0002-4994-9001
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge support of this project by CNRS,
University Paris-Sud, ANR (CarNuCat, ANR-15-CE29- 0002),
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■
́
and by la Ligue Contre le Cancer through an Equipe Labellisee
2014 grant. We also thank the China Scholarship Council for a
fellowship (CSC) to Mingxiang Zhu. The laboratory of
̂
Chatenay-Malabry is a member of the Laboratory of Excellence
LERMIT supported by a grant (ANR-10-LABX-33). The
laboratory of Versailles is a member of the Laboratory of
Excellence CHARMMMAT which is acknowledged for the
funding of the flow chemistry device.
DEDICATION
In memory of Professor Franco
■
̧
is COUTY.
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DOI: 10.1021/acs.orglett.9b01730
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