Enantioconvergent Cu-catalyzed intramolecular C-C coupling at boron-bound C(sp3) atoms of α-aminoalkylboronates using a C1-symmetrical 2,2′-bipyridyl ligand attached to a helically chiral macromolecular scaffold

Article abstract of DOI:10.1021/jacs.0c09080

Enantioconvergent intramolecular coupling of α-(2-bromobenzoylamino)benzylboronic esters was achieved using a copper catalyst having helically chiral macromolecular bipyridyl ligand, PQXbpy. Racemic α-(2-bromobenzoylamino)benzylboronic esters were converted into (R)-configured 3-arylisoindolinones with high enantiopurity using right-handed helical PQXbpy as a chiral ligand in a toluene/CHCl3 mixed solvent. When enantiopure (R)- and (S)-configured boronates were separately reacted under the same reaction conditions, both afforded (R)-configured products through formal stereoinvertive and stereoretentive processes, respectively. From these results, a mechanism involving deracemization of organocopper intermediates in the presence of PQXbpy is assumed. PQXbpy switched its helical sense to left-handed when a toluene/1,1,2-trichloroethane mixed solvent was used, resulting in the formation of the corresponding (S)-products from the racemic starting material.

Full text of DOI:10.1021/jacs.0c09080

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Enantioconvergent Cu-Catalyzed Intramolecular C−C Coupling at
Boron-Bound C(sp3) Atoms of α‑Aminoalkylboronates Using a
C1‑Symmetrical 2,2′-Bipyridyl Ligand Attached to a Helically Chiral
Macromolecular Scaffold
Yukako Yoshinaga, Takeshi Yamamoto,* and Michinori Suginome*
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ABSTRACT: Enantioconvergent intramolecular coupling of α-(2-bromobenzoylamino)benzylboronic esters was achieved using a
copper catalyst having helically chiral macromolecular bipyridyl ligand, PQXbpy. Racemic α-(2-bromobenzoylamino)benzylboronic
esters were converted into (R)-configured 3-arylisoindolinones with high enantiopurity using right-handed helical PQXbpy as a
chiral ligand in a toluene/CHCl3 mixed solvent. When enantiopure (R)- and (S)-configured boronates were separately reacted under
the same reaction conditions, both afforded (R)-configured products through formal stereoinvertive and stereoretentive processes,
respectively. From these results, a mechanism involving deracemization of organocopper intermediates in the presence of PQXbpy is
assumed. PQXbpy switched its helical sense to left-handed when a toluene/1,1,2-trichloroethane mixed solvent was used, resulting in
the formation of the corresponding (S)-products from the racemic starting material.
Scheme 1. Asymmetric Cu-Catalyzed Intramolecular
Coupling of α-(o-Bromobenzoyl)aminobenzylboronic
Esters
ransition-metal-catalyzed reactions of organoboronic
Tacids have had a great impact on organic synthesis by
virtue of their characteristic chemical properties, which
differentiate them from other organometallic reagents.1
Although they are isolable, purifiable, configurationally stable,
and chemically stable, they become highly reactive in the
presence of basic activators. Of particular note is that a variety
of asymmetric C−C bond-forming reactions have been
achieved using organoboronic acids as essential reactants.2 In
many of these catalytic reactions, sp2-hybridized organo-
boronic acids play major roles because their transmetalation
is favored over that of sp3-hybridized derivatives. Recent
progress of boron-based transition metal catalysis has allowed
the utilization of unreactive sp3-hybridized organoboron
species, including chiral alkylboronic acids. The use of chiral
alkylboronic acids now allows asymmetric cross-coupling
reactions, which are classified into either stereospecific or
stereoconvergent processes. The former class of asymmetric
cross-coupling reactions utilize enantioenriched chiral organo-
boronic acids with achiral transition-metal catalysts, leading to
the formation of highly enantioenriched coupling products
either through stereoretentive or stereoinvertive reaction
pathways.3,4 The latter class, i.e., the stereoconvergent
process,5−7 utilizes racemic chiral organoboronic acids as a
starting material and is highly attractive because the
preparation of enantiomerically pure organoboronic acids can
be avoided. However, reports are limited to the Ni-catalyzed
coupling of secondary benzyltrifluoroborates with moderate
stereoselectivity (up to 65% ee) in the presence of chiral
bisoxazoline ligand under photoredox conditions.6 It is highly
desirable to accumulate more knowledge about stereo-
convergent coupling reactions, which have some related
precedents using chiral alkylmagnesium8 and alkylzinc9
reagents as coupling partners.
Our ongoing research interest has been focused on the
stereochemical course of the reactions of chiral α-amino-
alkylboronic acids.10 We reported Pd-catalyzed stereospecific
cross-coupling with aryl halides, which proceeds either with
stereochemical retention or inversion, depending on the
reaction conditions.4d Very recently, we reported stereospecific
Cu-catalyzed intramolecular coupling of α-aminoalkylboronic
acids bearing o-bromobenzoyl groups on the amino group
Received: August 24, 2020
https://dx.doi.org/10.1021/jacs.0c09080
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A

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(Scheme 1a).11 It was found that a slight modification of the
achiral bipyridyl ligand from unsubstituted 2,2′-bipyridyl used
in the original protocol of Dumas et al.12 allowed us to make
the reaction highly stereoinvertive. This study revealed that the
change of the substituents at 6- and 6′-positions of 2,2′-
bipyridyl ligand sharply alters not only the stereochemical
course, but also the rate of the reaction. We were particularly
interested in the result of the original report, in which a
racemic product was obtained from enantiopure α-amino-
alkylboronic acid.11,12 It has been proposed that racemization
of the organocopper intermediate is involved in the process. In
this paper, we report on the enantioconvergent intramolecular
coupling of α-(o-bromobenzoyl)aminobenzylboronic acids
using PQXbpy,13 which is a C1-symmetrical chiral 2,2′-
bipyridyl ligand attached at its 6-position to single-handed
helical poly(quinoxaline-2,3-diyl)s14,15 (Scheme 1b). Deracem-
ization of the organocopper intermediates is effectively
controlled by the chiral reaction space created by the helical
macromolecular ligand PQXbpy.16−18
polymer backbone at different positions on the bipyridyl
groups. PQXbpy P1, of which the bpy group is linked at its 6-
position, showed a significant enantioinduction of 85:15 in
favor of the (R)-product 2a (Table 2, entry 1). Ligands P2 and
Table 2. Cu-Catalyzed Reactions of Racemic 1a in the
a
Presence of PQXbpy P1−P13
As an initial test, reactions of racemic α-(o-bromobenzoyl)-
aminobenzylboronic acid pinacol ester (1a) was conducted in
the presence of a copper catalyst with several chiral dinitrogen
ligands including bipyridyl, pyridyloxazoline, and bisoxazoline
ligands (Table 1).19 The C1-symmetrical bipyridine and
Table 1. Cu-Catalyzed Reactions of Racemic 1a in the
a
Presence of Chiral Ligands
entry
PQXbpy
time/h
yield/%
er (R:S)
1
2
3
4
5
6
7
8
P1
P2
P3
P4
P5
P6
P7
P8
12
6
96
>99
81
85:15
27:73
22:78
52:48
79:21
80:20
66:34
83:17
58:42
56:44
78:22
71:29
77:23
18
72
24
12
48
12
48
96
24
6
11
>99
>99
58
82
49
9
P9
10
11
12
13
P10
P11
P12
P13
13
>99
>99
>99
12
a
1
The yield was determined by H NMR spectroscopic analysis using
entry
chiral ligand
time/h
yield/%
er (R:S)
dibenzyl ether as an internal standard. The enantiomeric excess was
determined by chiral SFC analysis. The progress of the reactions was
monitored at 6, 12, 18, 24, 48, 72, and 96 h.
1
2
3
4
L1
L2
L3
L4
12
24
48
48
>99
>99
7
43:57
55:45
59:41
29:71
12
P3, with linkages to the bpy group at the 4- and 3-positions,
respectively, gave moderate, but appreciable enantioselectiv-
ities, although the chiral macromolecular scaffold is not located
at the 6-position of the bpy groups (entries 2 and 3). We then
modified P1 by introducing substituents on the bpy groups
(entries 4−13). Although the enantioselectivity never exceeded
the result with P1, there were notable trends in the relationship
between their structure and reactivity/selectivity. First, among
the PQXbpy derivatives bearing a methyl group at different
positions (entries 4−8), P4 (R1 = Me), bearing a methyl group
at the 6′-position, showed much lower catalytic activity than
others (entry 4). This observation is in good agreement with
our previous report on the stereoinvertive system, in which an
achiral 6,6′-disubstituted bipyridyl ligand showed low catalytic
activity.11 Second, methyl substitution at the ortho-position of
the aryl−aryl axis in P7 (R4 = Me) gave low enantioselectivity,
probably because the methyl group reduces the planarity of the
a
1
The yield was determined by H NMR using dibenzyl ether as an
internal standard. The enantiomeric excess was determined by chiral
SFC analysis.
pyridyloxazoline ligands L120 and L221 gave the product 2a
in high yield, albeit with low enantiomeric ratio (er) (entries 1
and 2). The C2-symmetrical bisoxazoline ligands L322 and L423
resulted in low yields; however, a remarkable er value was
obtained in the reaction with L4 (entries 3 and 4). These
results suggested that an enantioconvergent or kinetic
resolution process is indeed operating and that the pyridyl
group is required to achieve reasonable chemical yields.
Derivatives of PQXbpy were then used as chiral ligands
under the same reaction conditions, except for the reduction of
catalyst loading to 5 mol%. We initially compared PQXbpy
P1−P3 having 2,2′-bipyridyl (bpy) groups linked to the
B
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bipyridyl group (entry 7). The others carrying methyl groups
at the 4- (R5), 4′- (R3), and 5′- (R2) positions showed
comparable catalytic activity and enantioselectivities (79:21−
83:17) (entries 5, 6, and 8). Third, electronic tuning at the
terminal pyridyl groups by introduction of R2 or R3
substituents had a remarkable effect on the catalytic activity
(entries 9−13). Introduction of electron-withdrawing sub-
stituents such as chloro and cyano groups to the terminal
pyridyl group significantly lowered both the catalytic activity
and enantioselectivity (entries 9 and 10). Based on these
results, we selected PQXbpy P1 for use in further study.
Under the optimized reaction conditions using P1′ as the
chiral catalyst, when the polymerization degree was increased
to 500, several substrates were subjected to the intramolecular
coupling reaction (Scheme 2). The reactions of 1a−e, bearing
phenyl groups containing different substituents at their para-
positions in the α-aminobenzylboron moiety, revealed that the
stereochemical course is remarkably affected by the electronic
nature of the substituents. The enantioselectivity increases with
a decrease in the electron density of the phenyl groups,
although introduction of a strongly electron-withdrawing
group resulted in low chemical yield (2e). Among the series
of substrates 1f−h bearing para-substituents in the phenyl
group of the benzoyl moiety, the presence of either an
electron-donating or an electron-withdrawing substituent was
found to lead to a deterioration of the enantioselectivity (1f
and 1h). In contrast, 1i−n bearing various functional groups at
the meta-positions of the benzoyl group generally showed high
enantioselectivities up to 94:6 er.
The macromolecular catalyst (R)-PQXbpy adopts >99%
right-handed helical conformation in most organic solvents,
including toluene and CHCl3 used as a reaction solvent.
However, the helix sense can be switched in some specific
solvents including 1,1,2-trichloroethane (TCE).13 Indeed, we
confirmed that (R)-PQXbpy P1′ adopted >99% left-handed
conformation in a mixture of 1,1,2-TCE and toluene (1:2)
after equilibration at room temperature for 135 h (Scheme 3).
Scheme 3. Copper-Catalyzed Reactions of Racemic 1 in the
Presence of Left-Handed Helical (R)-PQXbpy P1′
Scheme 2. Cu-Catalyzed Reactions of Racemic 1 in the
Presence of Right-Handed Helical (R)-PQXbpy P1′
a
Using the thus generated left-handed (M)-(R)-P1′, (S)-
configured 2a, 2k, and 2m were obtained in good yields with
high enantioselectivities. It should be noted that this result
clearly suggests that the enantioselectivity is governed by the
helical chirality of the catalyst.24,25
It is likely that a mechanism involving epimerization of an
organocopper intermediate is involved. Inclusion of the
epimerization step in this type of coupling was suggested in
reports by Dumas12 and by our group11 in the reaction of
enantiopure 1 in the presence of achiral 2,2′-bipyridyl as a
ligand. In the present system, the epimerization allows
deracemization at the stereogenic carbon center, leading to
the formation of the product in a stereoconvergent manner. To
confirm this assumption, we conducted reactions with
enantiopure (R)-1a and (S)-1a separately in the presence of
right-handed (P)-(R)-P1 at 10 °C (Scheme 4a). Both
enantiomers in fact afforded product (R)-2a in good yields,
albeit with different er. Whereas (R)-1a afforded an R/S ratio
of 96:4, (S)-1a gave an R/S ratio of 72:28. Under the same
reaction conditions (10 °C, 10 mol% catalyst), racemic 1a
provided (R)-2a with an R/S ratio of 84:16, which is the
average of the two reactions. In addition, it is apparent from
the high chemical yield that the high enantiomeric ratio is not
due to a major contribution of kinetic resolution. Indeed this
was confirmed by inspecting the enantiomer ratios in the
remaining starting material (46:54% er) and product (85:15
a
1
The yield was determined by H NMR using dibenzyl ether as an
internal standard. The enantiomeric excess was determined by chiral
SFC analysis.
C
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gives intermediate ent-A, which undergoes epimerization to A,
leading to the formation of (R)-2a. The greater erosion of
enantiopurity in the reaction of (S)-1a than of (R)-1a is likely
because the oxidative addition, although a slower process,
proceeds competitively with the epimerization process, leading
to minor, but significant levels of formation of (S)-2a.
In summary, we have established an enantioconvergent
intramolecular boron-based coupling of α-(2-bromobenzoyl-
amino)benzylboronic esters using copper catalysts bearing C1-
symmetrical chiral bipyridyl ligands attached to helical PQX.
Although the reaction is classified as a cyclization, amidation-
based preparation of the starting material 1 allows easy access
to various chiral isoindolinone derivatives. This study also
reveals that PQXbpy constitutes a new family of C1-
symmetrical 2,2′-bipyridyl ligands featuring a huge and
distinctive chiral reaction space, whereas the choice of the
corresponding low-molecular C1-symmetrical 2,2′-bipyridyl
ligands remains quite limited.
Scheme 4. Reactions of (a) (R)- and (S)-1a and (b) Racemic
1a in the Presence of Right-Handed PQXbpy P1
ASSOCIATED CONTENT
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er) at 25% conversion, indicating that the two enantiomers are
consumed in an almost parallel manner (kR/kS < 2) (Scheme
4b). It should be noted that we also conducted a series of
reactions of enantiomerically pure (S)-1 (See the SI, Table
S5). Notably, (S)-1b provided (S)-2b with formal stereo-
chemical retention, while (S)-1d,e afforded (R)-2d,e with
formal stereochemical inversion. These results may suggest
that the deracemization step is decelerated by electron-
donating groups at the benzyl group, leading to ineffective
enantioconvergent process.
Detailed experimental procedures and compound
characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Takeshi Yamamoto − Department of Synthetic Chemistry and
Biological Chemistry, Graduate School of Engineering, Kyoto
University, Kyoto 615-8510, Japan; orcid.org/0000-0002-
5184-7493; Email: suginome@sbchem.kyoto-u.ac.jp
Michinori Suginome − Department of Synthetic Chemistry and
Biological Chemistry, Graduate School of Engineering, Kyoto
University, Kyoto 615-8510, Japan; orcid.org/0000-0003-
3023-2219; Email: yamamoto@sbchem.kyoto-u.ac.jp
From these results, we propose a mechanism for this
stereoconvergent intramolecular coupling reaction (Scheme
5).11,12 The B-to-Cu transmetalation affords organocopper
Scheme 5. A Possible Reaction Mechanism Involving
Deracemization of Organocopper Intermediate A and ent-A
Using Right-Handed (P)-(R)-PQXbpy as a Chiral Ligand
Author
Yukako Yoshinaga − Department of Synthetic Chemistry and
Biological Chemistry, Graduate School of Engineering, Kyoto
University, Kyoto 615-8510, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09080
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI on Innovative
Areas (Grant Number JP15H05811 in Precisely Designed
Catalysts with Customized Scaffolding), KAKENHI (A)
(Grant Number 20H00377), and JST CREST (Grant Number
JPMJCR14L1 in Establishment of Molecular Technology
toward the Creation of New Function).
intermediate A, which undergoes oxidative addition of an aryl−
Br bond to form B and subsequent facile reductive elimination
to give product 2. It is assumed that intermediate A, which is
formed through invertive transmetalation, undergoes epimeri-
zation at the copper-bound stereogenic center directed by the
chiral ligand on the copper. The er is dependent on the relative
reaction rate of deracemization over oxidative addition, which
could be the rate-determining and stereodetermining step. The
right-handed helical scaffold of PQXbpy may make the
formation of A more favorable in the equilibrium over
diastereomeric ent-A. In the reaction of (R)-1a, invertive
transmetalation gave A directly, which is converted into the
product (R)-2a without significant erosion of the enantio-
purity. In contrast, the reaction of enantiomeric (S)-1a initially
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