Enantioselective Synthesis of Atropisomeric Anilides via Pd(II)-Catalyzed Asymmetric C-H Olefination

Article abstract of DOI:10.1021/jacs.0c09400

Atropisomeric anilides have received tremendous attention as a novel class of chiral compounds possessing restricted rotation around an N-aryl chiral axis. However, in sharp contrast to the well-studied synthesis of biaryl atropisomers, the catalytic asym

Full text of DOI:10.1021/jacs.0c09400

pubs.acs.org/JACS
Article
Enantioselective Synthesis of Atropisomeric Anilides via Pd(II)-
Catalyzed Asymmetric C−H Olefination
Qi-Jun Yao,† Pei-Pei Xie,† Yong-Jie Wu, Ya-Lan Feng, Ming-Ya Teng, Xin Hong,* and Bing-Feng Shi*
Cite This: https://dx.doi.org/10.1021/jacs.0c09400
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Atropisomeric anilides have received tremendous
attention as a novel class of chiral compounds possessing restricted
rotation around an N-aryl chiral axis. However, in sharp contrast to
the well-studied synthesis of biaryl atropisomers, the catalytic
asymmetric synthesis of chiral anilides remains a daunting
challenge, largely due to the higher degree of rotational freedom
compared to their biaryl counterparts. Here we describe a highly
efficient catalytic asymmetric synthesis of atropisomeric anilides via
Pd(II)-catalyzed atroposelective C−H olefination using readily
available L-pyroglutamic acid as a chiral ligand. A broad range of
atropisomeric anilides were prepared in high yields (up to 99%
yield) and excellent stereoinduction (up to >99% ee) under mild
conditions. Experimental studies indicated that the atropostability
of those anilide atropisomers toward racemization relies on both steric and electronic effects. Experimental and computational
studies were conducted to elucidate the reaction mechanism and rate-determining step. DFT calculations revealed that the amino
acid ligand distortion is responsible for the enantioselectivity in the C−H bond activation step. The potent applications of the anilide
atropisomers as a new type of chiral ligand in Rh(III)-catalyzed asymmetric conjugate addition and Lewis base catalysts in
enantioselective allylation of aldehydes have been demonstrated. This strategy could provide a straightforward route to access
atropisomeric anilides, one of the most challenging types of axially chiral compounds.
in 2002.9,10 Although the stereoinduction was low at that time
INTRODUCTION
■
In a chiral molecule, an sp3-hybridized carbon atom connected
to four different substituents is a well-recognized asymmetric
element known as central chirality. Axially chiral compounds
lack stereogenic centers but exist as enantiomers, due to the
restricted rotation around a chiral axis, which are known as
“atropisomers”.1 To date, biaryl atropisomers, a kind of
stereoisomer arising from a restricted rotation around the single
bond between two aromatic rings, have been extensively
investigated.2 In sharp contrast, the catalytic asymmetric
synthesis of axially chiral anilides, an interesting class of
atropisomeric compounds bearing an N−C chiral axis first
reported by Curran,3 has been overlooked.4 Despite the fact that
these atropisomers are becoming increasingly prevalent and
important in medicinal chemistry,5 asymmetric synthesis,6 and
peptoid chemistry (Figure 1a),7 the main hurdle is largely due to
that chiral anilides are conformationally more flexible and have a
higher degree of rotational freedom compared to the biaryl
counterparts (Figure 1b, multiple rotations around N−Ar and
N−CO bonds vs one single rotation around the Ar−Ar bond,
which also distinguish those cyclic anilides with carbonyl
trapped in a rigid ring),4a,8,9 rendering the enantiocontrol much
more complicated and challenging. Catalytic asymmetric
approaches to access these synthetically challenging chiral
skeletons were first reported by the Curran and Taguchi groups
(24−56% ee), these pioneering works inspired further efforts in
this cutting-edge area,4b including (a) distinguishing the
substituents R2 and R3 on aromatic rings through enantiose-
lective N-functionalization, such as the Tsuji−Trost reaction,11
metal-catalyzed N-arylation,12 phase-transfer catalyzed N-
alkylation,13 and the N-allylation Morita−Baylis−Hillman
reaction14,15 (Figure 1c, I); (b) the enantioselective con-
struction of the Ar−N axis via organocatalytic nucleophilic
addition16 (Figure 1c, II); (c) de novo aromatic ring formation
via asymmetric [2 + 2 + 2] cycloaddition17 (Figure 1c, III).
Despite these remarkable advances, the research is still in its
infancy with regard to efficiency, generality, and diversity.
Therefore, further development of economic and facile
strategies that can efficiently deliver highly enantiopure chiral
anilides is highly warranted.
Received: September 3, 2020
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 1. Strategies for the enantioselective synthesis of atropisomeric anilides. (a) The importance of chiral anilides in pharmaceuticals and
asymmetric synthesis. (b) Challenges of the asymmetric synthesis of chiral anilides: different modes of rotation between chiral biaryls (top, Ar−Ar
rotation) and chiral anilides (bottom, N−Ar and N−CO rotations). (c) Previous approaches to the enantioselective synthesis of chiral anilides. (d)
This work: a new strategy for the enantioselective synthesis of atropisomeric anilides via an atroposelective C−H olefination strategy.
In light of the unique features and significance of this
structural motif, we assumed that an asymmetric C−H
functionalization/dynamic kinetic resolution (DKR) strategy
might enable the diverse and straightforward access of these
chiral skeletons. In the past decade, transition metal-catalyzed
asymmetric C−H functionalization has become one of the most
efficient strategies in the construction of stereochemically
complex molecules.18 In particular, the atroposelective C−H
functionalization/DKR has been realized to be a straightforward
and practical tool to access axially chiral biaryls,2d,f,19,20 showing
great potential in natural products syntheses20b,c and ligand
elaborations.20g However, the synthesis of chiral anilides via
catalytic asymmetric C−H functionalization strategy remains an
unsolved problem. We posit that the following daunting
challenges need to be addressed to achieve the goal: (1) the
mode of asymmetric induction during the C−H cleavage step is
poorly understood due to the relatively complicated rotational
freedom. (2) the C−H activation reaction has to be conducted
under mild conditions in order to ensure good asymmetric
induction and maintain the chirality due to the relatively low
atropostability of the resulting products; thus, the judicious
choice of types of substrates and transformation would be crucial
for the success. Moreover, to merit the goal of high
enantiocontrol and economy, the chiral ligand must be readily
available and inexpensive. As a continuation of our long-
standing efforts to synthesize axially chiral compounds via C−H
activation,20 herein we report the discovery of a novel catalytic
system that overcomes those challenges and enables the
synthesis of chiral anilides via Pd(II)-catalyzed C−H olefina-
tion/DKR using readily available L-pGlu-OH as an inexpensive
chiral ligand (Figure 1d). A wide range of chiral anilides were
obtained in excellent yields and enantioselectivities (50
examples, up to 99% and >99% ee). This strategy opens up a
straightforward route to access chiral anilides via a highly
efficient and atom-economical approach.
RESULTS AND DISCUSSION
■
Optimizing Reaction Conditions. Initial exploratory
studies of the reaction were commenced by exploring the
enantioselective C−H olefination/DKR of N-benzyl-N-(2-
isopropylphenyl) picolinamide (rac-1a) with methyl acrylate
(4a). We expected that the use of pyridine-type DG would
enable the challenging C−H olefination to occur under mild
conditions, guaranteeing high atroposelectivity during the
stereoselectivity-determining step and atropostability of the
products. The presence of the bulky isopropyl group at the
ortho-position ensures the configurational stability of the newly
formed atropoisomers. To our delight, we found that in the
presence of 10 mol % Pd(OAc)2 as catalyst and 20 mol % L-
pGlu-OH (L1) as the chiral ligand, the atroposelective C−H
B
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: rac-1a (0.10 mmol, 1.0 equiv), methyl acrylate 4a (0.25 mmol, 2.5 equiv), ligand (20 mol %), and Pd(OAc)2 (10 mol %) in
b
c
solvent (1.0 mL). Isolated yields. The ee values were determined by chiral HPLC.
olefiantion of rac-1a affords the desired product 1aa in 84% yield
with 53% ee (Table 1, entry 1). We then screened a variety of
solvents and found that TFE was the optimal (entry 2, 92%, 84%
ee, see Table S2 for details). N-monoprotected α-amino acids
(MPAAs) have been widely used as a class of privileged chiral
ligands in Pd(II)-catalyzed enantioselective C−H activation,21
since the groundbreaking work by Yu and co-workers.21a
Various MPAAs were then investigated, and L-pGlu-OH (L1)
proved to be the best (entries 2−8).22 Further tuning of a
mixture of solvents revealed that the ee value of 1aa could be
improved to 91% without significantly affecting the reactivity in
TFE/DME (entry 9). As expected, the reaction temperature
could be reduced to 50 °C, giving 1aa in high yield and improved
enantioselectivity (entry 12, 98% yield, 97% ee). Notably, both
the racemic starting material rac-1a and the enantiopure product
1aa exist as couples of Z/E rotamers as observed in 1H NMR.
Conformational analysis of anilides rac-1a and 1aa by NOESY
experiments in CDCl3 indicated that E-rotamers were formed
Ha. This similar phenomenon was also observed in 1aa (see the
Supporting Information for details).
Scoping the Substrates. With the optimal reaction
conditions in hand, the scope of the anilides was examined
(Table 2). We first investigated the substituents on the pyridine
ring (Table 2a). Both electron-withdrawing groups (EWGs:
1ba, 5′-NO2; 1ca, 5′-CF3; 1da, 5′-CO2Me; 1ea, 4′-Cl; 1fa, 5′-F)
and electron-donating groups (EDGs: 1ga, 4′-OMe; 1ha, 5′-
OMe) were compatible and gave the desired products in
excellent enantioselectivities (91% ee to >99% ee), albeit
anilides with EWGs were less reactive and prolonged reaction
time was needed to ensure good yields. 3′-Methyl-substituted
pyridine anilide rac-1i reacted smoothly to give chiral anilide 1ia
in good yield and enantioselectivity, but with a low E/Z ratio
(85%, 91% ee, E:Z = 2.3:1), largely due to the steric repulsion
between Me and 2,6-substituents on the aryl ring (i-Pr and
olefin). Control experiments using 1k−1m as substrates
revealed that (1) pyridine rather than carbonyl group acted as
the coordinating site; (2) the coordination of palladium is very
sensitive to steric hindrance, as 6′-Me and even 6′-F could
prevent the coordination.
1
predominantly. These conclusions were also supported by H
NMR directly. In the E-rotamer, Ha of rac-1a is located in the
shielding area of the aromatic ring, rendering the chemical shift
of Ha in the Z-rotamer smaller than that in the E-rotamer. The
ratio of Z/E rotamers could be determined by the integration of
Then we investigated the substituents on the aryl ring (Table
2b). The steric hindrance of ortho-substituents is important for
C
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Table 2. Substrate Scope of Atropoisomeric Anilides
a
Standard reaction conditions: anilides rac-1, rac-2, or rac-3 (0.1 mmol), methyl acrylate 4a (0.3 mmol), Pd(OAc)2 (0.01 mmol), L1 (0.02 mmol),
b
c
d
AgOAc (0.25 mmol), TFE/DME (1/1, 1 mL), 50 °C, 48 h. Isolated yields. Ees were determined by chiral HPLC analysis. 72 h. 40 °C. 96 h. s =
ln[(1 − C)(1 − ee2n)]/ln[(1 − C)(1 + ee2n)], C = ee2n/(ee2n + ee2na). PA = picolinoyl.
D
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Table 3. Substrate Scope of Olefins
a
Reaction conditions: 1a (0.1 mmol), 4 (0.3 mmol), Pd(OAc)2 (0.01 mmol), L1 (0.02 mol), AgOAc (0.25 mmol), TFE/DME (1/1) (1 mL), 50
b
°C, 48 h. Yields are based on 1a, Isolated yields. Enantiomeric excess (ee) were determined by chiral HPLC analysis. Reaction performed for 60 h.
c
Reaction performed with 1.1 equiv of olefin (0.11 mmol). Boc, tert-butyloxycarbonyl.
the atropostability, and as a result, rac-2b with a smaller methoxy
group led to completely racemized product 2ba even at reduced
temperature (40 °C), while those with larger substituents, such
as chloro (rac-2c), methyl (rac-2d-2j), ethyl (rac-2k),
tetrahydronaphthyl (rac-2l), and naphthyl (rac-2m), gave the
corresponding products in good yields and enantioselectivities.
Interestingly, olefination of 1-naphthylamine-derived rac-2m
occurred at both 2- and 8-positions, affording the mono- and
diolefination products (2ma, 61%, 93% ee; 2maa, 34%, 86% ee).
Notably, rac-2n bearing sterically more demanding tert-butyl
substituent at the 6-position was configurationally stable and
cannot quickly racemize under 50 °C, just enabling a kinetic
resolution reaction. The reaction of rac-2n with methyl acrylate
for 96 h, affording 2na in 37% yield with 94% ee and the starting
martial 2n, was recovered in 51% yield with 61% ee (s-factor =
52). Moreover, a variety of substituents on nitrogen, including
substituted benzyl (3ba−3fa), alkyl (3ga), acetate (3ha),
isopentenyl (3ia), cyclopropylmethyl (3ja), and aryl (3ka),
were well tolerated, giving the products in excellent enantiocon-
trol (3ba−3ka, 96% to >99% ee). The absolute configuration of
olefination products 1ja and 2maa was determined by X-ray
diffraction analysis, and those of the others were assigned by
analogy.
The scope of the other coupling partner, olefins, was then
evaluated (Table 3). A wide range of electronically biased
olefins, such as acrylates (4b−4e), acrylaldehyde (4f), α,β-
unsaturated ketone (4g), acrylamide (4h), and styrenes (4i and
4j), all worked well to give the desired products with good
results (Table 3, 1ab−1aj, 60−99% yield and 96 → 99% ee).
Notably, when using rac-1b as a mode substrate, unactivated
simple aliphatic olefins (4k, 1-hexene and 4l, 1-nonene) also
reacted smoothly, affording the formal C−H allylation products
in moderate yield and high ee (1bk, 41%, 91% ee; 1bl, 42%, 92%
ee). To further demonstrate the utility of this protocol, we
further examined the atroposelective C−H olefination with
olefins derived from the core structures of natural products (l-
menthol, 4m; tyrosine, 4n; estrone, 4o), chiral skeleton
(BINOL, 4p), and drug molecule (4q). All of the desired
olefinated products were obtained in good yield with high
diastereomeric excess (79−92% yield and 95 → 99% de),
irrespective of the existing chiral centers and complexity.
Based on the experimental kinetic isotope effects (Scheme
S1) and previous mechanistic studies of Pd-catalyzed asym-
metric C−H bond functionalizations,22,23 we next explored the
reaction mechanism with density functional theory (DFT)
calculations, using experimental amide substrate rac-1a and
methyl acrylate (2a) as the model compounds.24 The DFT-
E
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 2. DFT-computed free energy profile of the most favorable pathway for the Pd/L-pGlu-catalyzed atroposelective C−H alkenylation.
computed free energy changes of the most favorable pathway for
the Pd(II)/L-pGlu-catalyzed atroposelective C−H alkenylation
are shown in Figure 2. The pyridine substrate can form a
hydrogen-bonding complex with TFE solvent, and this complex
would coordinate to palladium to create an off-cycle resting state
6.25 The catalytically active palladium acetate monomer
complexes with L-pGlu to form intermediate 7.26 Subsequent
substrate coordination generates intermediate 8, and 8 under-
goes the enantioselective concerted-metalation deprotonation
(CMD) step via TS9 to form the arylpalladium species 10. From
10, the alkene coordination and subsequent insertion via TS13
generates the alkylpalladium intermediate 14.27 14 then
undergoes a facile intramolecular pyridine-assisted β-hydride
transfer through TS16, leading to the reduced palladium(0)
complex 17 with product coordination.28 17 would be oxidized
to regenerate the palladium(II) active catalyst and liberate the
product. Based on the DFT-computed free energy profile, the
rate-determining step is the CMD step via TS9, with an overall
barrier of 22.7 kcal/mol, which is consistent with the
experimental result (KIE = 2.3). We also confirmed that the
racemization of the axial chirality of the organopalladium species
is not feasible after the C−H bond activation step (Figure S10).
To reveal the origins of enantioselectivity, Figure 3a shows the
optimized structures and relative energies of the two competing
stereoselectivity-determining CMD transition states. TS9 is 1.7
kcal/mol more favorable than TS18, which corroborated the
observed enantioselectivitiy (Table 1, entry 2, TFE as solvent).
The comparison between the experimental substrate rac-1a and
the truncated model indicated that the iPr substituent is not
responsible for the enantioselectivity (Figure 3a vs b). Further
analysis revealed that the distortion of amino acid leads to the
chiral induction in the C−H bond activation. The DFT-
computed transition state TS21 for the Pd/L-pGlu-OH-
catalyzed C−H bond activation of benzene suggested that this
process intrinsically prefers to occur in the fourth quadrant
(Figure 3c) due to the chirality of amino acid. The geometries of
the benzene and pyridine fragments match well with the axial
chirality of the favored transition state TS9 when the amide
tether links the two fragments in substrate rac-1a. In contrast,
chirality mismatch exists in the disfavored transition state TS18.
Thus, significant distortion of the amino acid ligand is required
to force the C−H bond activation occurring in the fourth
quadrant. The pyramidalization angle of the amino acid nitrogen
in TS18 is only 11.0°, suggesting that the amino acid nitrogen is
much more planar as compared to that in TS9 or TS21 (28.7°,
26.3°, respectively). The 2.0 kcal/mol energy difference of the
Pd(L-pGlu-OH) fragment in TS9 and TS18 further supported
the hypothesis that the amino acid ligand distortion is
responsible for the enantioselectivity in the C−H bond
activation step. This chiral induction rationale provides a useful
mechanistic model for future designs of Pd/L-pGlu-OH-
catalyzed asymmetric C−H bond activation.
In order to investigate the relationship of the conformational
stability of these axially chiral anilides with the electronic effect,
we measured the N−Ar rotational barriers (ΔG‡) of a series of
chiral anilides with similar steric circumstances. We found that
substituents on the aryl ring with high Hammett constant values
(σ) lower the barriers (Figure 4a). This is consistent with a
bigger Hammett constant (more electron-withdrawing sub-
stituents) making the conjugation of the lone pair on the
nitrogen atom with carbonyl more difficult, causing the N atom
to tend to pyramidalize. Since Hammett constants are not
suitable to represent the electronic property of the pyridyl ring,
we considered that the 13C NMR chemical shift of carbonyl
F
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 3. Origins of enantioselectivity in Pd/L-pGlu-OH-catalyzed asymmetric C−H olefination. (a) Enantioselectivity-determining C−H activation
transition states with experimental substrate rac-1a. (b) Enantioselectivity-determining C−H activation transition states with truncated model rac-1a.
(c) Mechanistic model of chiral induction.
(δCO) would be a useful parameter to describe the electronic
property of picolinamide DG (vide infra). A negative correlation
between δCO and the rotational barriers was also observed
(Figure 4b). Those results are consistent with the idea that
pyramidalization of the nitrogen atom significantly affects the
N−Ar bond rotation.29 Therefore, the atropostability of chiral
anilides is governed by both steric and electronic effects.30
Finally, to demonstrate the potential applications of the chiral
anilides in asymmetric catalysis, we investigated the applications
in several catalytic asymmetric reactions. Inspired by the recent
success of chiral olefin ligands in asymmetric catalysis,31 we
reasoned that the resulting products might act as a novel type of
olefin-pyridine ligand with an unusual N−C axial chirality.
When using the olefination product L8 (1ga) as a chiral ligand in
rhodium-catalyzed conjugate addition of phenylboronic acid to
cyclohexanone, promising enantioselectivity was afforded
(Scheme 1a, 53% yield, 30% ee).32 In contrast, the analogous
axially chiral styrene ligand L922b could not introduce any
enantioselectivity to this reaction, and no product was observed
when using axially chiral biaryl ligand L10.20f The preliminary
results demonstrated that the anilide atropisomers were superior
to the analogous styrene and biaryl atropisomers in controlling
the enantioselectivity of the conjugate addition and encouraged
us to further investigate other chiral anilides. We decided to test
styrene-derived chiral anilides that synthesized by enantiose-
lective C−H olefination with styrenes, due to it being much
easier to tune the electronic effect of the olefin part. A significant
improvement in enantiocontrol was obtained when using the
new styrene-derived chiral olefin-pyridine ligands (L11−L13).
Gratifyingly, the use of p-methoxy-substituted ligand L13 gave
18 in 69% yield with 87% ee.
The enantioselective addition of allylic silanes to carbonyl
compounds to produce chiral homoallylic alcohols represents an
important transformation in asymmetric synthesis.33 We then
investigated the use of the resulting chiral anilides as a new type
of chiral Lewis base to catalyze the asymmetric allylation of
aldehyde. To our delight, chiral product 19 was obtained in 47%
yield with 88% ee when using 1ah as a chiral catalyst (Scheme
1b). There results demonstrate that these anilide atropisomers
hold great potential as a new type of chiral ligand/catalyst in
asymmetric catalysis.
CONCLUSION
■
In summary, we have reported a novel strategy for the synthesis
of chiral anilides via Pd(II)-catalyzed atroposelective C−H
olefination. A broad range of axially chiral anilides were prepared
in good yields (up to 99% yield) and excellent enantioselece-
tivities (up to >99% ee) using commercially available L-pGlu-
OH as an inexpensive and catalytic chiral ligand. This protocol is
also compatible with various alkenes bearing core structures of
G
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 4. Relationship of the conformational stability of chiral anilides with the electronic effect. (a) Negative correlation between Hammett
substituent constants (σ) of the aryl ring with rotational barriers (ΔG‡). (b) Negative correlation between 13C chemical shifts of carbonyl (δCO) with
a
b
half-lives and rotational barriers (ΔG‡). Measured at 80 °C in isopropyl alcohol. Measured at 110 °C in isopropyl alcohol. See the Supporting
Information for details.
natural products, chiral skeleton, and drug molecule. Exper-
imental studies revealed that the atropostability of those anilide
atropisomers toward racemization relies on the electronic effects
of both the picolinamide and aromatic ring. Computational
studies were conducted to elucidate the reaction mechanism and
the chiral induction model of the atroposelective C−H
olefination. Moreover, the chiral anilide atropisomers hold
great promise as chiral ligands/catalysts in asymmetric synthesis.
We anticipate that this study will boost the use of an asymmetric
C−H functionalization strategy to construct other types of chiral
H
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09400
Scheme 1. Applications of Axially Chiral Anilides. (a) Olefin-
Pyridine Type Ligand with N−C Axial Chirality in Rh-
Catalyzed Asymmetric Conjugate Addition. (b) Application
o f Chiral Anilides as Chiral Lewis Base Catalyst in the
Asymmetric Allylation of Aldehydes
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NSFC (21925109, 21772170 for B.-
F.S.) and (21702182, 21873081 for X.H.), Outstanding Young
Talents of Zhejiang Province High-level Personnel of Special
Support (ZJWR0108 for B.-F. S.), the Fundamental Research
Funds for the Central Universities (2018XZZX001-02 for B.-F.
S.) and (2019QNA3009 for X. H.), and Zhejiang Provincial
NSFC (LR17B020001 for B.-F. S.) is gratefully acknowledged.
We are also grateful for Prof. Ji-Yong Liu (Zhejiang University)
for help with X-ray analysis and Prof. Chuan-De Wu (Zhejiang
University) for helpful discussions. This work is dedicated to the
70th anniversary of the Shanghai Institute of Organic Chemistry,
CAS.
REFERENCES
■
(1) Topics in Stereochemistry. Vol. 1: Atropisomerism; Oki, M., Ed.;
Wiley Interscience: New York, 1983.
(2) For selected reviews, see: (a) Bringmann, G.; Price Mortimer, A.
J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Atroposelective
Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed.
2005, 44, 5384. (b) Baudoin, O. The Asymmetric Suzuki Coupling
Route to Axially Chiral Biaryls. Eur. J. Org. Chem. 2005, 2005, 4223.
(c) Tanaka, K. Transition-metal-catalyzed enantioselective [2 + 2+2]
cycloadditions for the synthesis of axially chiral biaryls. Chem. - Asian J.
2009, 4, 508. (d) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.;
Colobert, F. Recent advances and new concepts for the synthesis of
axially stereoenriched biaryls. Chem. Soc. Rev. 2015, 44, 3418. (e) Link,
A.; Sparr, C. Stereoselective arene formation. Chem. Soc. Rev. 2018, 47,
3804. (f) Liao, G.; Zhou, T.; Yao, Q.-J.; Shi, B.-F. Recent advance in the
synthesis of axially chiral biaryls via transition metal-catalysed
asymmetric C−H functionalization. Chem. Commun. 2019, 55, 8514.
(g) Wang, Y.-B.; Tan, B. Construction of axially chiral compounds via
asymmetric organocatalysis. Acc. Chem. Res. 2018, 51, 534.
(3) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. Atroposelective
thermal reactions of axially twisted amides and imides. J. Am. Chem. Soc.
1994, 116, 3131.
skeletons. Further synthetic applications of the axially chiral
anilides in the synthesis of bioactive molecules and asymmetric
reactions are underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09400.
■
sı
Experimental procedures, spectral data for all new
compounds (PDF)
X-ray crystal structure for 1ja (CCDC 1975637) (CIF)
X-ray crystal structure for 2maa (CCDC 19675642)
(CIF)
(4) (a) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivaguru, J.
Nonbiaryl and heterobiaryl atropisomers: molecular templates with
promise for atropselective chemical transformations. Chem. Rev. 2015,
115, 11239. (b) Takahashi, I.; Suzuki, Y.; Kitagawa, O. Asymmetric
synthesis of atropisomeric compounds with an N−C chiral axis. Org.
Prep. Proced. Int. 2014, 46, 1.
(5) (a) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. The
challenge of atropisomerism in drug discovery. Angew. Chem., Int. Ed.
2009, 48, 6398. (b) LaPlante, S. R.; Fader, L. D.; Fandrick, K. R.;
Fandrick, D. R.; Hucke, O.; Kemper, R.; Miller, S. P.; Edwards, P. J.
Assessing atropisomer axial chirality in drug discovery and develop-
ment. J. Med. Chem. 2011, 54, 7005. (c) Toenjes, S. T.; Gustafson, J. L.
Atropisomerism in medicinal chemistry: challenges and opportunities.
Future Med. Chem. 2018, 10, 409.
(6) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.;
Jørgensen, K. A. Non-biaryl atropisomers in organocatalysis. Chem. -
Eur. J. 2006, 12, 6039.
(7) Paul, B.; Butterfoss, G. L.; Boswell, M. G.; Renfrew, P. D.; Yeung,
F. G.; Shah, N. H.; Wolf, C.; Bonneau, R.; Kirshenbaum, K. Peptoid
atropisomers. J. Am. Chem. Soc. 2011, 133, 10910−10919.
(8) Cyclic chiral anilides with carbonyl trapped in a rigid ring only
have one rotation around N−Ar, which are comparable with biaryls;
AUTHOR INFORMATION
Corresponding Authors
Bing-Feng Shi − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China; orcid.org/0000-0003-0375-
955X; Email: bfshi@zju.edu.cn
■
Xin Hong − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China; Email: hxchem@zju.edu.cn
Authors
Qi-Jun Yao − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Pei-Pei Xie − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Yong-Jie Wu − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Ya-Lan Feng − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Ming-Ya Teng − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
I
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
see: (a) Fan, X.; Zhang, X.; Li, C.; Gu, Z. Enantioselective
atropisomeric anilides synthesis via Cu-catalyzed intramolecular
adjacent C−N coupling. ACS Catal. 2019, 9, 2286. (b) Diener, M.
E.; Metrano, A. J.; Kusano, S.; Miller, S. J. Enantioselective synthesis of
3-arylquinazolin-4(3H)-ones via peptide-catalyzed atroposelective
bromination. J. Am. Chem. Soc. 2015, 137, 12369. (c) Rae, J.; Frey, J.;
Jerhaoui, S.; Choppin, S.; Wencel-Delord, J.; Colobert, F. Synthesis of
Axially Chiral C−N Scaffolds via Asymmetric Coupling with
Enantiopure Sulfinyl Iodanes. ACS Catal. 2018, 8, 2805.
(9) Kitagawa, O.; Kohriyama, M.; Taguchi, T. Catalytic asymmetric
synthesis of optically active atropisomeric anilides through enantiose-
lective N-allylation with chiral Pd-tol-BINAP catalyst. J. Org. Chem.
2002, 67, 8682.
(10) Terauchi, J.; Curran, D. P. N-Allylation of anilides with chiral
palladium catalysts: the first catalytic asymmetric synthesis of axially
chiral anilides. Tetrahedron: Asymmetry 2003, 14, 587.
(11) Liu, Y.; Feng, X.; Du, H. Asymmetric synthesis of axially chiral
anilides by Pd-catalyzed allylic substitutions with P/olefin ligands. Org.
Biomol. Chem. 2015, 13, 125.
(12) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.; Takahashi,
M.; Dobashi, Y.; Taguchi, T. Highly enantioselective synthesis of
atropisomeric anilide derivatives through catalytic asymmetric N-
arylation: conformational analysis and application to asymmetric
enolate chemistry. J. Am. Chem. Soc. 2006, 128, 12923.
(13) Shirakawa, S.; Liu, K.; Maruoka, K. Catalytic asymmetric
synthesis of axially chiral o-iodoanilides by phase-transfer catalyzed
alkylations. J. Am. Chem. Soc. 2012, 134, 916.
(14) Li, S.-L.; Yang, C.; Wu, Q.; Zheng, H.-L.; Li, X.; Cheng, J.-P.
Atroposelective catalytic asymmetric allylic alkylation reaction for
axially chiral anilides with achiral Morita-Baylis-Hillman carbonates. J.
Am. Chem. Soc. 2018, 140, 12836.
Antonchick, A. P.; Waldmann, H. General enantioselective C-H
activation with efficiently tunable cyclopentadienyl ligands. Angew.
́
Chem., Int. Ed. 2017, 56, 2429. (e) Jang, Y.-S.; Wozniak, L.; Pedroni, J.;
Cramer, N. Access to P-and axially chiral biaryl phosphine oxides by
enantioselective CpxIrIII-catalyzed C-H arylations. Angew. Chem., Int.
Ed. 2018, 57, 12901. (f) Tian, M.; Bai, D.; Zheng, G.; Chang, J.; Li, X.
Rh(III)-catalyzed asymmetric synthesis of axially chiral biindolyls by
merging C−H activation and nucleophilic cyclization. J. Am. Chem. Soc.
2019, 141, 9527. (g) Wang, Q.; Cai, Z.-J.; Liu, C.-X.; Gu, Q.; You, S.-L.
Rhodium-Catalyzed Atroposelective C−H Arylation: Efficient Syn-
thesis of Axially Chiral Heterobiaryls. J. Am. Chem. Soc. 2019, 141, 9504.
(20) (a) Yao, Q.-J.; Zhang, S.; Zhan, B.-B.; Shi, B.-F. Atroposelective
synthesis of axially chiral biaryls by palladium-catalyzed asymmetric C−
H olefination enabled by a transient chiral auxiliary. Angew. Chem., Int.
Ed. 2017, 56, 6617. (b) Liao, G.; Yao, Q.-J.; Zhang, Z.-Z.; Wu, Y.-J.;
Huang, D.-Y.; Shi, B.-F. Scalable, stereocontrolled formal syntheses of
(+)-isoschizandrin and (+)-steganone: development and applications
of palladium(II)-catalyzed atroposelective C−H alkynylation. Angew.
Chem., Int. Ed. 2018, 57, 3661. (c) Fan, J.; Yao, Q.-J.; Liu, Y.-H.; Liao,
G.; Zhang, S.; Shi, B.-F. Asymmetric Total Synthesis of TAN-1085
Facilitated by Pd-Catalyzed Atroposelective C-H Olefination. Org. Lett.
2019, 21, 3352. (d) Liao, G.; Li, B.; Chen, H.-M.; Yao, Q.-J.; Xia, Y.-N.;
Luo, J.; Shi, B.-F. Pd-Catalyzed Atroposelective C-H Allylation via β-O
Elimination: Diverse Synthesis of Axially Chiral Biaryls. Angew. Chem.,
Int. Ed. 2018, 57, 17151. (e) Zhang, S.; Yao, Q.-J.; Liao, G.; Li, X.; Li,
H.; Chen, H.-M.; Hong, X.; Shi, B.-F. Enantioselective Synthesis of
Atropisomers Featuring Pentatomic Heteroaromatics by Pd-Catalyzed
C−H Alkynylation. ACS Catal. 2019, 9, 1956. (f) Luo, J.; Zhang, T.;
Wang, L.; Liao, G.; Yao, Q.-J.; Wu, Y.-J.; Zhan, B.-B.; Lan, Y.; Shi, B.-F.;
Lin, X.-F. Enantioselective Synthesis of Biaryl Atropisomers via Pd-
Catalyzed C−H Olefination using Chiral Spiro Phosphoric Acid
Ligands. Angew. Chem., Int. Ed. 2019, 58, 6708. (g) Liao, G.; Chen, H.-
M.; Xia, Y.-N.; Li, B.; Yao, Q.-J.; Shi, B.-F. Synthesis of chiral aldehyde
catalysts via Pd-catalyzed atroposelective C−H naphthylation. Angew.
Chem., Int. Ed. 2019, 58, 11464. (h) Zhan, B.-B.; Wang, L.; Luo, J.; Lin,
X.-F.; Shi, B.-F. Synthesis of Axially Chiral Biaryl-2-amines by PdII-
Catalyzed Free-Amine-Directed Atroposelective C−H Olefination.
Angew. Chem., Int. Ed. 2020, 59, 3568.
(15) Lu, S.; Ng, S. V. H.; Lovato, K.; Ong, J.-Y.; Poh, S. B.; Ng, X. Q.;
Kurti; Zhao, Y. Practical access to axially chiral sulfonamides and biaryl
̈
amino phenols via organocatalytic atroposelective N-alkylation. Nat.
Commun. 2019, 10, 3061.
(16) Brandes, S.; Bella, M.; Kjaersgaard, A.; Jørgensen, K. A. Chirally
aminated 2-naphthols-organocatalytic synthesis of non-biaryl atro-
pisomers by asymmetric Friedel−Crafts amination. Angew. Chem., Int.
Ed. 2006, 45, 1147.
(21) (a) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Pd(II)-
catalyzed enantioselective activation of C(sp2)-H and C(sp3)-H bonds
using monoprotected amino acids as chiral ligands. Angew. Chem., Int.
Ed. 2008, 47, 4882. (b) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-
H.; Yu, J.-Q. Pd(II)-catalyzed enantioselective C-H olefination of
diphenylacetic acids. J. Am. Chem. Soc. 2010, 132, 460. (c) Gao, D.-W.;
Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. Enantioselective synthesis of
planar chiral ferrocenes via palladium-catalyzed direct coupling with
arylboronic acids. J. Am. Chem. Soc. 2013, 135, 86. (d) Engle, K. M.; Yu,
J.-Q. Developing ligands for palladium(II)-catalyzed C-H functional-
ization: intimate dialogue between ligand and substrate. J. Org. Chem.
2013, 78, 8927. (e) Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S.; Yu, J.-Q.
From Pd(OAc)2 to Chiral Catalysts: The Discovery and Development
of Bifunctional Mono-N-Protected Amino Acid Ligands for Diverse C-
H Functionalization Reactions. Acc. Chem. Res. 2020, 53, 833.
(22) (a) Han, H.; Zhang, T.; Yang, S.-D.; Lan, Y.; Xia, J.-B. Palladium-
catalyzed enantioselective C−H aminocarbonylation: synthesis of
chiral isoquinolinones. Org. Lett. 2019, 21, 1749. (b) Jin, L.; Yao, Q.-
J.; Xie, P.-P.; Li, Y.; Zhan, B.-B.; Han, Y.-Q.; Hong, X.; Shi, B.-F.
Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric
C−H Functionalization Strategy. Chem. 2020, 6, 497.
(23) (a) Cheng, G.-J.; Yang, Y.-F.; Liu, P.; Chen, P.; Sun, T.-Y.; Li, G.;
Zhang, X.; Houk, K. N.; Yu, J.-Q.; Wu, Y.-D. Role of N-acyl amino acid
ligands in Pd(II)-catalyzed remote C−H activation of tethered arenes.
J. Am. Chem. Soc. 2014, 136, 894. (b) Cheng, G.-J.; Chen, P.; Sun, T.-Y.;
Zhang, X.; Yu, J.-Q.; Wu, Y.-D. A combined IM-MS/DFT study on
[Pd(MPAA)]-catalyzed enantioselective C−H activation: relay of
chirality through a rigid framework. Chem. - Eur. J. 2015, 21, 11180.
(c) Musaev, D. G.; Kaledin, A. L.; Shi, B.-F.; Yu, J.-Q. Key Mechanistic
Features of Enantioselective C-H Bond Activation Reactions Catalyzed
(17) Tanaka, K.; Takeishi, K.; Noguchi, K. Enantioselective synthesis
of axially chiral anilides through Rhodium-catalyzed [2 + 2+2]
cycloaddition of 1,6-diynes with trimethylsilylynamides. J. Am. Chem.
Soc. 2006, 128, 4586.
(18) (a) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q.
Transition metal-catalyzed C−H activation reactions: diastereoselec-
tivity and enantioselectivity. Chem. Soc. Rev. 2009, 38, 3242. (b) Zheng,
C.; You, S.-L. Recent development of direct asymmetric functionaliza-
tion of inert C−H bonds. RSC Adv. 2014, 4, 6173. (c) Newton, C. G.;
Wang, S.-G.; Oliveira, C. C.; Cramer, N. Catalytic enantioselective
transformations involving C−H bond cleavage by transition-metal
complexes. Chem. Rev. 2017, 117, 8908. (d) Saint-Denis, T. G.; Zhu, R.-
Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Enantioselective C(sp3)−H bond
activation by chiral transition metal catalysts. Science 2018, 359,
eaao4798. (e) Zhang, Q.; Shi, B.-F. From Reactivity and Regiose-
lectivity to Stereoselectivity: An Odyssey of Designing PIP Amine and
Related Directing Groups for C-H Activation. Chin. J. Chem. 2019, 37,
647. (f) Loup, J.; Dhawa, U.; Pesciaioli, F.; Wencel-Delord, J.;
Ackermann, L. Enantioselective C−H Activation with Earth-Abundant
3d Transition Metals. Angew. Chem., Int. Ed. 2019, 58, 12803.
(19) For selected examples, see: (a) Gustafson, J. L.; Lim, D.; Miller, S.
J. Dynamic kinetic resolution of biaryl atropisomers via peptide-
catalyzed asymmetric bromination. Science 2010, 328, 1251. (b) Zheng,
J.; You, S.-L. Construction of axial chirality by rhodium-catalyzed
asymmetric dehydrogenative Heck coupling of biaryl compounds with
alkenes. Angew. Chem., Int. Ed. 2014, 53, 13244. (c) Hazra, C. K.;
Dherbassy, Q.; Wencel-Delord, J.; Colobert, F. Synthesis of axially
chiral biaryls through sulfoxide-directed asymmetric mild C−H
activation and dynamic kinetic resolution. Angew. Chem., Int. Ed.
2014, 53, 13871. (d) Jia, Z.-J.; Merten, C.; Gontla, R.; Daniliuc, C. G.;
J
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
by [(Chiral Mono-N-Protected Amino Acid)-Pd(II)] Complexes. J.
Am. Chem. Soc. 2012, 134, 1690.
(24) Computations were performed with the Gaussian 09 software
package. Computational details are included in the Supporting
Information.
(25) We carefully explored the possibile complexation of solvent with
substrate and L-pGlu and possible hydrogen bondings between the
TFE solvent and every intermediate and transition state in the catalytic
cycle; details are included in the Supporting Information (Figures S1−
S5).
(26) Zhong, X.-M.; Cheng, G.-J.; Chen, P.; Zhang, X.; Wu, Y.-D.
Mechanistic Study on Pd/Mono-N-protected Amino Acid Catalyzed
Vinyl-Vinyl Coupling Reactions: Reactivity and E/Z Selectivity. Org.
Lett. 2016, 18, 5240.
(27) Various forms of the coordinating amino acids and their olefin
insertion transition states were considered; details are included in the
Supporting Information (Figure S7).
(28) The alternative β-hydride elimination involving palladium-
hydride species and carboxylate-assisted β-hydride transfer were
considered; details are included in the Supporting Information (Figures
S8 and S9).
(29) (a) Suzumura, N.; Kageyama, M.; Kamimura, D.; Inagaki, T.;
Dobashi, Y.; Hasegawa, H.; Fukaya, H.; Kitagawa, O. Studies on
rotational barriers of N−C axially chiral compounds: increase in the
rotational barrier by aromatization. Tetrahedron Lett. 2012, 53, 4332.
(b) Mandel, J.; Pan, X.-H.; Hay, E. B.; Geib, S. J.; Wilcox, C. S.; Curran,
D. P. Rotational isomers of N-methyl-N-arylacetamides and their
derived enolates: implications for asymmetric Hartwig oxindole
cyclizations. J. Org. Chem. 2013, 78, 4083.
(30) (a) Santiago, C. B.; Guo, J.-Y.; Sigman, M. S. Predictive and
mechanistic multivariate linear regression models for reaction develop-
ment. Chem. Sci. 2018, 9, 2398. (b) Sigman, M. S.; Harper, K. C.; Bess,
E. N.; Milo, A. The Development of Multidimensional Analysis Tools
for Asymmetric Catalysis and Beyond. Acc. Chem. Res. 2016, 49, 1292.
(31) (a) Feng, X.; Du, H. Synthesis of Chiral Olefin Ligands and their
Application in Asymmetric Catalysis. Asian J. Org. Chem. 2012, 1, 204.
(b) Dong, H.-Q.; Xu, M.-H.; Feng, C.-G.; Sun, X.-W.; Lin, G.-Q. Recent
Applications of Chiral N-tert-Butanesulfinyl Imines, Chiral Diene
Ligands and Chiral Sulfur−Olefin Ligands in Asymmetric Synthesis.
Org. Chem. Front. 2015, 2, 73.
̈
(32) Hahn, B. T.; Tewes, F.; Frohlich, R.; Glorius, F. Olefin−
Oxazolines (OlefOx): Highly Modular, Easily Tunable Ligands for
Asymmetric Catalysis. Angew. Chem., Int. Ed. 2010, 49, 1143.
(33) For reviews, see: (a) Denmark, S. E.; Fu, J. Catalytic
Enatioselective Addition of Allylic Organometallic Reagents to
Aldehydes and Ketones. Chem. Rev. 2003, 103, 2763. (b) Yus, M.;
́
́
Gonzalez-Gomez, J.-C.; Foubelo, F. Catalytic Enantioselective
Allylation of Carbonyl compounds and Imines. Chem. Rev. 2011, 111,
7774.
K
https://dx.doi.org/10.1021/jacs.0c09400
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX