Nickel-Catalyzed Radical Migratory Coupling Enables C-2 Arylation of Carbohydrates

Article abstract of DOI:10.1021/jacs.1c03563

Nickel catalysis offers exciting opportunities to address unmet challenges in organic synthesis. Herein we report the first nickel-catalyzed radical migratory cross-coupling reaction for the direct preparation of 2-Aryl-2-deoxyglycosides from readily available 1-bromosugars and arylboronic acids. The reaction features a broad substrate scope and tolerates a wide range of functional groups and complex molecular architectures. Preliminary experimental and computational studies suggest a concerted 1,2-Acyloxy rearrangement via a cyclic five-membered-ring transition state followed by nickel-catalyzed carbon-carbon bond formation. The novel reactivity provides an efficient route to valuable C-2-Arylated carbohydrate mimics and building blocks, allows for new strategic bond disconnections, and expands the reactivity profile of nickel catalysis.

Full text of DOI:10.1021/jacs.1c03563

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Nickel-Catalyzed Radical Migratory Coupling Enables C‑2 Arylation
of Carbohydrates
Gaoyuan Zhao, Wang Yao, Ilia Kevlishvili, Jaclyn N. Mauro, Peng Liu,* and Ming-Yu Ngai*
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ABSTRACT: Nickel catalysis offers exciting opportunities to address unmet challenges in organic synthesis. Herein we report the
first nickel-catalyzed radical migratory cross-coupling reaction for the direct preparation of 2-aryl-2-deoxyglycosides from readily
available 1-bromosugars and arylboronic acids. The reaction features a broad substrate scope and tolerates a wide range of functional
groups and complex molecular architectures. Preliminary experimental and computational studies suggest a concerted 1,2-acyloxy
rearrangement via a cyclic five-membered-ring transition state followed by nickel-catalyzed carbon−carbon bond formation. The
novel reactivity provides an efficient route to valuable C-2-arylated carbohydrate mimics and building blocks, allows for new strategic
bond disconnections, and expands the reactivity profile of nickel catalysis.
arbohydrates, the most abundant biomolecules, play vital
roles in a wide array of biological processes, including
C
cell−cell recognition, protein folding, neurobiology, inflamma-
tion, and infection.1 The modification of carbohydrate
structure(s) to enhance or alter the physiological properties
of the parent molecule is therefore an attractive strategy for the
development of novel pharmaceuticals. Indeed, carbohydrates
and their mimics are present in a range of commercially
available therapeutics and vaccines, and the evolving methods
for carbohydrate synthesis and modification continue to
influence the drug discovery landscape.2 Over the past few
decades, tremendous progress has been made toward C-1
modification of carbohydrates, such as O-glycosylation3 and C-
glycosylation.4 Nevertheless, a general catalytic strategy for the
preparation of diverse and valuable C-2-functionalized 2-deoxy
sugars from readily available sugar precursors remains
elusive.5,6 In view of the fact that C-2-functionalized 2-deoxy
sugars are ubiquitous in nature and are found in medicine,
molecular imaging, cell engineering, and catalysis,7 the
establishment of a versatile catalytic approach for the
preparation of this class of sugars is highly attractive.
Figure 1. Ni-catalyzed migratory cross-coupling enables the catalytic
synthesis of challenging 2-aryl-2-deoxy sugars.
Nickel catalysis has advanced as a general technology for
chemical synthesis.8 Recently, significant progress has been
made in nickel-catalyzed migratory cross-coupling (MCC)
reactions9 that enable a range of remote functionalization
reactions of alkyl halides (Figure 1A). These include
hydroarylation,10 hydroalkylation,11 alkenylation,10d acyla-
tion,12 and carboxylation.13 In such reactions, the nickel
catalyst typically migrates from the activation site to the cross-
coupling site via a two-electron β-hydrogen elimination/
migratory insertion sequence (Figure 1B).9 In contrast, Ni-
catalyzed MCC reactions that proceed through a radical
migratory pathway such as a 1,2-spin-center shift (SCS)14 are
rare.15 Inspired by the seminal work of Surzur and Tanner,
who showed that β-(acyloxy)alkyl radical could undergo a 1,2-
SCS with concomitant acyloxy migration,16 we hypothesized
that such a reactivity could serve as the basis of a nickel-
catalyzed radical MCC reaction via a 1,2-SCS pathway (Figure
1C). The success of such a reaction could (i) provide new
strategic bond formations that lead to otherwise difficult or
unobtainable molecular architectures; (ii) expand the reactivity
profile of Ni catalysis; (iii) advance fundamental knowledge in
radical chemistry; and (iv) promote new reaction design and
Received: April 5, 2021
Published: June 4, 2021
https://doi.org/10.1021/jacs.1c03563
J. Am. Chem. Soc. 2021, 143, 8590−8596
© 2021 American Chemical Society
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development. Herein we report the establishment and
application of such a reaction platform for the preparation of
synthetically challenging C-2-arylated carbohydrates from
readily available 1-bromosugars and arylboronic acids (Figure
1C).17
known to promote transmetalation in the nickel-catalyzed
Suzuki−Miyaura cross-coupling reaction,24 also diminished the
efficiency of the reaction (entry 5). The use of 1,4-dioxane as a
solvent resulted in the formation of hydrodebromination side
products, lowering the product yield (entry 6). Finally, control
experiments showed that NiBr2·DME, Cs2CO3, elevated
reaction temperature, and an oxygen-free environment were
critical for the success of the reaction (entries 7−10).
It is noteworthy that catalytic C-2 arylation of readily
available sugar precursors for the preparation of saturated, fully
oxygenated 2-aryl-2-deoxy sugars has not been reported.18 The
existing approaches to this class of sugar derivatives involve
either the construction of carbon skeletons by homologation of
chiral aldehydes using the carbonyl ene cyclization strategy19
or epoxide ring opening of 2,3-epoxy sugars with arylmagne-
sium iodides or lithium diarylcuprates.20 However, these
methods require the multistep synthesis of advanced
intermediates, involve harsh reaction conditions, and have
limited substrate and reaction scopes. Thus, the work
described here offers rapid access to novel 2-aryl-2-deoxy
sugars and serves as the first example of a nickel-catalyzed
radical MCC reaction that proceeds through a 1,2-SCS
pathway.
We commenced our investigation by examining the reaction
of α-glucosyl bromide 1a and phenylboronic acid (2a) in the
presence of Ni catalysts and found that when a mixture of 1a
(1.00 equiv), 2a (2.00 equiv), NiBr2·DME (5.00 mol %), 4,4′-
di-tert-butyl-2,2′-dipyridyl (dtbbpy) (10.0 mol %), isopropanol
(i-PrOH) (0.75 equiv), and Cs2CO3 (2.00 equiv) in benzene
(0.100 M) was heated at 80 °C for 20 h, the desired C-2-
arylated 2-deoxyglucoside 3a was produced in 84% yield with
3.6:1 axial to equatorial selectivity together with a small
amount of the C-1-arylated byproduct (Table 1, entry 1).21,22
The nature of the ligand is critical for the success of the
reaction, as replacing dtbbpy with other classes of N,N-
bidentate ligands such as phenanthroline (L1), pyridine−
pyrazole (L2), and bisoxazoline (L3) greatly reduced the
reaction yield (entries 2−4).23 Removal of i-PrOH, which is
Next, we explored the scope of aryl- and heteroarylboronic
acids (Table 2A). The reaction tolerates a range of arylboronic
acids with different substituents such as methyl, tert-butyl,
phenyl, methoxy, diphenylamino, methyl sulfide, and methyl
ester, forming the corresponding products 3b−i in 46−86%
yield with moderate axial/equatorial selectivity. 2-Naphthyl-
boronic acid and heteroarylboronic acids, including 9-phenyl-
9H-carbazol-3-yl- and 2-benzofuranylboronic acids, were viable
substrates and gave the desired products 3j−l in moderate
yields. Examination of the generality of 1-bromosugars revealed
that an array of sugar derivatives bearing different protecting
and migratory groups were competent under this protocol
(Table 2B).25 D-Galactoside and L-fucoside derivatives reacted
smoothly and formed the corresponding products 3m, 3n, and
3p in yields of 40−74%. It is noteworthy that these substrates
gave the products with the opposite stereoselectivity. Steric
interaction between the nickel catalyst and the axial C-4 OAc
appears to favor the formation of the equatorial product.
Protecting groups such as tert-butyldimethylsilyl, benzyl, acetyl,
pivaloyl, and benzoyl are well-tolerated. A substrate with a
fused ring structure was compatible, producing 3q. We also
investigated the effect of structural modification of the
migratory ester group on the reaction efficiency and found
that C-2 esters substituted with alkyl, aryl, or heteroaryl groups
successfully migrated, delivering the corresponding products
3r−x in 38−85% yield.
The synthetic utility of the reaction is further highlighted by
its amenability to the late-stage modification of functionally
dense natural-product- and drug-conjugated sugar derivatives
(Table 2C). For instance, a melibiose derivative and an
oleanolic acid-derived α-glucosyl bromide reacted under the
standard conditions, affording the desired products 5a and 5b
in 52% and 77% yield, respectively. 1-Bromoglucosyl
derivatives of the uricosuric agent probenecid, the anti-
inflammatory drug zaltoprofen, and the antihyperuricemic
drug febuxostat all underwent C-2 arylation to give the
corresponding products 5c−e in good yields, demonstrating
that the method can be used in the preparation of
pharmaceutically relevant compounds. With the antiacne
agent adapalene (4f) as a migratory group, the desired product
5f was obtained in 56% yield with 10:1 axial/equatorial
selectivity. This and earlier results, such as the formation of 3r,
indicated that increasing the size of the migratory group
enhances the axial selectivity. It is worth noting that our
protocol (i) affords the α-2-aryl-2-deoxy glycosides exclusively,
with none of the corresponding β isomers; (ii) enables access
to previously inaccessible C-2-arylated carbohydrate deriva-
tives and building blocks; and (iii) expands chemical and
patent spaces for drug discovery.
a
Table 1. Selected Optimization Experiments
While a detailed understanding of the reaction mechanism
awaits further investigation, preliminary mechanistic studies
suggested a radical process. The addition of a radical scavenger
such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) com-
pletely inhibited the reaction (Figure 2A),8b,15b and when the
1,2-trans- and 1,2-cis-2-iodosugars 6a and 6b were subjected to
a
See the Supporting Information for experimental details. Yields of 3a
and axial:equatorial (ax:eq) ratios were determined by 1H NMR
analysis using dibromomethane as the internal standard.
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a
Table 2. Scope of C-2 Arylation of α-Glycosyl Bromides via Ni-Catalyzed 1,2-SCS Strategy
a
See the Supporting Information for experimental details. The isolated yield and axial:equatorial (ax:eq) ratio are indicated below each entry.
the reaction conditions, they both formed the desired product
3a in excellent yields with the same level of stereoselectivity
(Figure 2B). This stereoselectivity was similar to that observed
in the standard reaction using α-glucosyl bromide 1a as the
substrate, suggesting that these reactions proceed through a
common C-2 radical intermediate. Crossover experiments
using substrates 1a and 1u afforded only the non-crossover
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Figure 2. Mechanistic studies and proposed reaction mechanism. See the Supporting Information for experimental and computational details. s.d.s.
= stereoselectivity-determining step.
products 3a and 3u, indicating that the acyloxy migration likely
takes place through a concerted mechanism (Figure 2C).
On the basis of these results, the known acyloxy
migration,17,26 the nickel-catalyzed Suzuki−Miyaura cou-
pling,8b,d and DFT calculations (see Figure S4 for the
computed reaction energy profiles),27 a plausible catalytic
cycle is shown in Figure 2D. The active catalyst [NiI]Br (I)28 is
presumably generated under the standard conditions through
(i) transmetalation of the [NiII]Br2 precatalyst with 2 equiv of
dihydroxyisopropoxyarylborate 2′, (ii) reductive elimination of
the resulting [NiII]Ar2 complex to liberate diaryl side products
and a [Ni0] species, and (iii) comproportionation of [Ni0] with
[NiII]Br2.29 [NiI]Br could undergo transmetalation with an
arylborate to form [NiI]Ar species II. Bromine atom
abstraction of α-glycosyl bromide 1 by complex II generates
the [NiII](Br)Ar species and chair 1-glycosyl radical (III). This
radical intermediate could directly recombine with [NiII](Br)
Ar and then undergo reductive elimination to form C-1-
arylated side products (3′).22 However, DFT calculations
showed that the conversion of III to its B2,5 boat conformation
IV followed by a concerted 1,2-acyloxy rearrangement is more
favorable under our reaction conditions (see Figures S6 and
S7). The 1-glucosyl radical prefers the B2,5 boat conformation
IV by 0.6 kcal/mol, which stems from the extended anomeric
interaction between the lone-pair electrons of the endocyclic
O, the singly occupied molecular orbital (SOMO), and the
σC*−O orbital of the C-2 OAc group.30 This interaction weakens
the C-2 OAc bond and promotes the 1,2-SCS through a
concerted 1,2-acyloxy rearrangement via a cyclic five-
membered-ring transition state (TS5),26c,30 affording deoxy-
pyranosan-2-yl radical V.31 Although a typical secondary alkyl
radical would be less stable than an anomeric radical, in this
case the molecular stability gained from the formation of an
anomeric C−O bond in V drives the desired 1,2-SCS32 and
makes this step (IV → V) exergonic by 2.0 kcal/mol. DFT
calculations suggested that the stereoselectivity-determining
step (s.d.s.) is the addition of the [NiII](Br)Ar species to
deoxypyranosan-2-yl radical, where the axial addition is more
favorable than the equatorial addition because the equatorial
addition to square-planar Ni complex is hindered by
unfavorable steric interactions with the cis C-1 acetoxy group
(Figures S4 and S5). These results agree with the
experimentally observed preference for the 1,2-trans product.
Once intermediate VI is formed, it undergoes reductive
elimination, liberating the desired C-2-arylated product 3 and
regenerating the [NiI]Br catalyst I. At this stage, we cannot rule
out an alternative mechanism involving bromine atom
abstraction of α-glycosyl bromide by [NiI]Br, transmetalation
of the resulting [NiII]Br2 with arylborate to form [NiII]Br(Ar),
and then recombination of [NiII]Br(Ar) with 2-glycosyl radical
followed by reductive elimination to give 2-arylated carbohy-
drates and regenerate [NiI]Br (see Figure S8 for details).
In conclusion, we have developed the first nickel-catalyzed
1,2-SCS cross-coupling reaction that enables the direct
synthesis of saturated, fully oxygenated 2-aryl-2-deoxy glyco-
sides. The reaction features a broad substrate scope, is
amenable to late-stage functionalization of natural-product-
and drug-conjugated sugar derivatives, and allows for the
formation of C-2-arylated glycosides that cannot otherwise be
easily accessed. Preliminary mechanistic studies suggest a
radical reaction pathway with a concerted acyloxy migration. It
is anticipated that this reaction will serve as the basis for the
development of Ni-catalyzed radical migratory coupling
reactions and a broadly useful C-2 functionalization of
carbohydrates. This approach will eventually allow for the
preparation of a wide array of novel carbohydrate mimics and
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building blocks for synthesis, medicinal chemistry, and
materials science. A myriad of exciting studies and extensions
of this chemistry can be envisaged, including detailed
mechanistic studies, the identification of factors that govern
the regio- and diastereoselectivities, the introduction of
different functional groups at C-2, alternative transition metal
catalysts, and reaction development beyond carbohydrate
functionalization. These are the subjects of an ongoing
investigation.
Brook University. We also thank all of the reviewers for their
insightful comments and suggestions.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03563.
Experimental details and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Peng Liu − Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, United States; Department
of Chemical and Petroleum Engineering, University of
Pittsburgh, Pittsburgh, Pennsylvania 15261, United States;
orcid.org/0000-0002-8188-632X; Email: pengliu@
pitt.edu
Ming-Yu Ngai − Department of Chemistry and Institute of
Chemical Biology and Drug Discovery, State University of
New York, Stony Brook, New York 11794, United States;
orcid.org/0000-0002-3055-6662; Email: ming-yu.ngai@
stonybrook.edu
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Authors
Gaoyuan Zhao − Department of Chemistry, State University
of New York, Stony Brook, New York 11794, United States
Wang Yao − Department of Chemistry, State University of
New York, Stony Brook, New York 11794, United States
Ilia Kevlishvili − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Jaclyn N. Mauro − Department of Chemistry, State University
of New York, Stony Brook, New York 11794, United States
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03563
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Shunichi Fukuzumi on the
occasion of his 70th birthday. The research reported herein
was supported by the National Institutes of General Medical
Sciences (NIGMS, R35-GM119652 to M.-Y.N. and R35-
GM128779 to P.L.). DFT calculations were performed at the
Center for Research Computing at the University of
Pittsburgh, the TACC Frontera supercomputer, and the
Extreme Science and Engineering Discovery Environment
(XSEDE) supported by the National Science Foundation
(Grant ACI1548562). The Shimadzu UPLC/MS used for
portions of this work was purchased with funds from an
NIGMS equipment administrative supplement (R35-
GM119652-04S1), a Shimadzu Scientific Instruments grant,
and the Office of the Vice President for Research at Stony
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pubs.acs.org/JACS
Communication
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