DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaphthalene

Article abstract of DOI:10.1016/j.chempr.2020.06.001

Guided by computational design, Tan and colleagues disclose a chiral phosphoric-acid-catalyzed asymmetric functionalization of naphthalenes with nitroso as the activating and directing group. This nucleophilic aromatic substitution reaction allows divergent access to two types of axially chiral arylindole frameworks with wide substrate generality under excellent enantiocontrol and, more importantly, offers a facile approach to the privileged NOBIN (2-amino-2′-hydroxy-1,1′-binaphthyl) structures. DFT calculations illustrate the plausible reaction pathway and provide additional insights into the origins of enantioselectivity.Functionalization of arenes represents the most efficient approach for constructing a core backbone of important aryl compounds. Compared with the well-developed electrophilic aromatic substitution and transition-metal-catalyzed C–H activation, nucleophilic aromatic substitution remains challenging because of the lack of a convenient route for rapid conversion of the σ^H adduct to other stable and versatile intermediates in situ. Guided by computational design, we were able to realize asymmetric nucleophilic aromatic substitution by introducing a nitroso group on naphthalene via chiral phosphoric acid catalysis. This strategy enables efficient construction of atropisomeric indole-naphthalenes and indole-anilines with excellent stereocontrol. Density functional theory (DFT) calculations provide further insights into the origins of enantioselectivity and the reaction mechanisms. The successful application in the synthesis of NOBINs (2-amino-2′-hydroxy-1,1′-binaphthyl) extends the utility of this strategy.Highly efficient conversion of inexpensive and readily available arene materials into high-value-added chiral molecules is of great importance in modern synthetic chemistry given the enormous potential of such structures in functional materials, pharmaceuticals, and other relevant chemical industries. Organocatalytic nucleophilic aromatic substitution enabled by an azo group offers an effective approach to enantioselective functionalization of naphthalene C–H bonds featuring an intramolecular oxidation of an unstabilized σ^H adduct. Premised on density functional theory (DFT) calculations, nitroso has emerged as another promising activating and oxidative group, whose synthetic potential is substantiated in the atroposelective synthesis of several groups of representative biaryl atropisomers processed by a chiral phosphoric acid catalyst. The success of this reaction explicitly exemplifies the ability of computational tools to streamline organic synthesis with intensified robustness in the disclosed strategy.

Full text of DOI:10.1016/j.chempr.2020.06.001

ll
Article
DFT-Guided Phosphoric-Acid-Catalyzed
Atroposelective Arene Functionalization of
Nitrosonaphthalene
Wei-Yi Ding, Peiyuan Yu,
Qian-Jin An, ..., Ying Chen, K.N.
Houk, Bin Tan
houk@chem.ucla.edu (K.N.H.)
tanb@sustech.edu.cn (B.T.)
HIGHLIGHTS
Computation-guided screening of
functional groups for arene
activation
Chemoselective C–H
functionalization of 2-
nitrosonaphthalene at an
unconventional site
One-pot synthesis of optically
active NOBINs by a solo
organocatalytic system
Divergent access to two types of
axially chiral arylindole
frameworks
Guided by computational design, Tan and colleagues disclose a chiral phosphoric-
acid-catalyzed asymmetric functionalization of naphthalenes with nitroso as the
activating and directing group. This nucleophilic aromatic substitution reaction
allows divergent access to two types of axially chiral arylindole frameworks with
wide substrate generality under excellent enantiocontrol and, more importantly,
offers a facile approach to the privileged NOBIN (2-amino-20-hydroxy-1,10-
binaphthyl) structures. DFT calculations illustrate the plausible reaction pathway
and provide additional insights into the origins of enantioselectivity.
Ding et al., Chem 6, 1–14
August 6, 2020 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.06.001

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
DFT-Guided Phosphoric-Acid-Catalyzed
Atroposelective Arene Functionalization
of Nitrosonaphthalene
Wei-Yi Ding,1,4 Peiyuan Yu,1,4 Qian-Jin An,1,4 Katherine L. Bay,2,4 Shao-Hua Xiang,1,3 Shaoyu Li,1,3
1,5,
Ying Chen,1 K.N. Houk,2, and Bin Tan
*
*
SUMMARY
The Bigger Picture
Highly efficient conversion of
inexpensive and readily available
arene materials into high-value-
added chiral molecules is of great
importance in modern synthetic
chemistry given the enormous
potential of such structures in
functional materials,
Functionalization of arenes represents the most efficient approach
for constructing a core backbone of important aryl compounds.
Compared with the well-developed electrophilic aromatic substitu-
tion and transition-metal-catalyzed C–H activation, nucleophilic aro-
matic substitution remains challenging because of the lack of a
convenient route for rapid conversion of the sH adduct to other sta-
ble and versatile intermediates in situ. Guided by computational
design, we were able to realize asymmetric nucleophilic aromatic
substitution by introducing a nitroso group on naphthalene via chi-
ral phosphoric acid catalysis. This strategy enables efficient con-
struction of atropisomeric indole-naphthalenes and indole-anilines
with excellent stereocontrol. Density functional theory (DFT) calcu-
lations provide further insights into the origins of enantioselectivity
and the reaction mechanisms. The successful application in the syn-
thesis of NOBINs (2-amino-20-hydroxy-1,10-binaphthyl) extends the
utility of this strategy.
pharmaceuticals, and other
relevant chemical industries.
Organocatalytic nucleophilic
aromatic substitution enabled by
an azo group offers an effective
approach to enantioselective
functionalization of naphthalene
C–H bonds featuring an
intramolecular oxidation of an
unstabilized sH adduct. Premised
on density functional theory (DFT)
calculations, nitroso has emerged
as another promising activating
and oxidative group, whose
synthetic potential is
INTRODUCTION
Functionalized arene frameworks are involved in many reagents, catalysts, materials,
and pharmaceuticals.1 Electrophilic aromatic substitution reactions (via positively
charged Wheland intermediates), such as the Friedel-Crafts reaction,2–4 are the
classic approach to substituted arenes (Figure 1A). Recent advances in transition-
metal and photoredox catalysis have enriched the synthetic chemists’ toolbox for
the functionalization of different arene scaffolds.5–11 Functionalizations via the nega-
tively charged Meisenheimer sX adduct or sH adduct often bank on the presence of
nitro substituents and nucleofugal halogen (X) or external oxidants (H), which limit
applicability (Figure 1A).12–14 Although it has been established that the formation
of sH adducts precedes the formation of sX adducts,15 we recently employed asym-
metric organocatalysis16–19 and azo groups20 to harness the sH adduct and effi-
ciently enable the functionalization of arenes with bifunctional chiral phosphoric
acid21–23 (CPA) catalysis. The azo substituent constitutes extended conjugation
and electron-withdrawing capability to prime the arene for a regioselective nucleo-
philic attack (Figure 1B). It further serves as an oxidant to promote expeditious intra-
molecular conversion of the sH adduct intermediate to outcompete the formation of
the sX adduct. To further extend this concept and bring about a more universal syn-
thetic tool for arene functionalization, one could, in principle, utilize substrates pos-
sessing substituents with electronic properties similar to those of the azo group.
With the help of electronic structure calculations on a series of naphthalene
substantiated in the
atroposelective synthesis of
several groups of representative
biaryl atropisomers processed by
a chiral phosphoric acid catalyst.
The success of this reaction
explicitly exemplifies the ability of
computational tools to streamline
organic synthesis with intensified
robustness in the disclosed
strategy.
Chem 6, 1–14, August 6, 2020 ª 2020 Elsevier Inc.
1

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
derivatives, we found that a nitroso group exhibits great potential for such a trans-
formation (Figure 1C).
RESULTS AND DISCUSSION
Preliminary Computational Screening
On the basis of these considerations, a series of substituted naphthalenes were de-
signed and subjected to preliminary computational screening in search of optimal
substrate models for catalytic asymmetric nucleophilic aromatic substitution.24–26
We reasoned that the reactivity of arenes toward nucleophilic aromatic substitution
might be closely related to the electron affinity (EA) and lowest unoccupied molec-
ular orbital (LUMO) energies of the substrates. Therefore, we computed these two
simple parameters for a series of substituted naphthalenes. As depicted in Figure 2A,
the EA (computed as the energy difference between the neutral molecule and its
anion with one negative charge) of different 2-substituted naphthalenes was first
computed at the B3LYP-D3BJ/6-311+G(d,p)/B3LYP/6–31G(d) level. Substrates
with nitrogen substituents such as azo (1.72 eV), nitroso (1.50 eV), and nitro (1.41
eV) groups have the highest EA. We next computed the LUMO energy of these sub-
strates, another great indicator of their reactivity toward nucleophilic aromatic sub-
stitution. More importantly, we evaluated the effect of a simple model phosphoric
acid (PA) as well by computing the LUMO of the substrate-PA complexes and
comparing it with their original LUMO. For example, coordination of PA with 2-nitro-
sonaphthalene through hydrogen-bond interaction would lower the LUMO energy
from 0.85 to 0.42 eV (Figure 2B). Hydrogen-bond interactions between the sub-
strates and PA would presumably lower its LUMO energy and consequently allow
for a more facile nucleophilic aromatic substitution to occur. In addition, with CPA
catalysts, the stereochemical outcome could be tuned with judicious choice of cata-
lyst scaffolds. The choice of this simple model PA reduced the large conformational
space of using more complex CPA catalysts and its associated high computational
cost, which allowed us to rapidly screen the effects of different substituents. The
screening results are illustrated in Figure 2C, which shows that the nitroso and azo
groups are the most promising candidates because of their dramatic decreases in
LUMO energy through interactions with PA. The azo group has been verified to
be effective for arene functionalization by our recent work.20 Nitrosoarenes,27–29
which are widely used in aminoxylation and hydroxyamination reactions with
competitive reactive sites on nitrogen and oxygen atoms, proved to be equally
promising. However, as far as we know, the site-selective reaction that occurred
on the aromatic ring was rarely realized. With these doubts in mind, we initiated
the experiment.
Optimizing Reaction Conditions for the Synthesis of Indole-Naphthalene
1Shenzhen Grubbs Institute, Department of
Chemistry, Southern University of Science and
Axially chiral skeletons are recognized as the core structure of numerous competent
Technology, Shenzhen, Guangdong 518055,
China
ligands or catalysts in asymmetric catalysis for a wide spectrum of useful transforma-
tions.30–33 The unique structural features together with the promising chemical and
2Department of Chemistry and Biochemistry,
bioactive properties render the construction of axially chiral scaffolds rewarding yet
University of California, Los Angeles, Los
challenging.34–56 With 2-nitrosonaphthalene (1a) as the promised electrophile,
Angeles, CA 90095, USA
3Academy for Advanced Interdisciplinary Studies,
Southern University of Science and Technology,
Shenzhen, Guangdong 518055, China
indole (2a) was selected as the reaction partner for the asymmetric cross-coupling
reaction because of its availability in building atropisomeric molecules. Initially,
the reaction of 1a (0.105 mmol) and 2a (0.1 mmol) was conducted in CH2Cl2 at
room temperature (RT) for 1 h under the activation of CPA (S)-C1 (5 mol %). Intrigu-
ingly, the expected compound 3a was not detected, and instead, the oxidation
product 4a was obtained in 12% yield with 62% enantiomeric excess (ee). At the
same time, the prevailing nucleophilicity of hydroxylamine yielded compound 5a
containing the axially chiral aniline-indole framework in 18% yield with 65% ee (Table
4These authors contributed equally
5Lead Contact
*Correspondence:
houk@chem.ucla.edu (K.N.H.),
tanb@sustech.edu.cn (B.T.)
https://doi.org/10.1016/j.chempr.2020.06.001
2
Chem 6, 1–14, August 6, 2020

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
A
B
C
Figure 1. Representative Approaches for Arene Functionalization and Our Design Strategy
(A) Electrophilic aromatic substitution and nucleophilic aromatic substitution via Wheland and Meisenheimer intermediates, respectively.
(B) Our strategy with rapid conversion of the unstable sH adduct.
(C) Computational screening for new substrates by electronic structure calculation.
1, entry 1). Despite the convoluted reaction pathway and moderate stereocontrol,
these results substantiated the density functional theory (DFT) calculations and
our hypothesis. For dominant formation of indole-naphthalene 4a, an external
oxidant was applied with excess 1a (2.0 equiv), conceding to the oxidability of the
nitroso moiety. However, this condition failed to provide a satisfactory outcome
(Table 1, entry 2). The aerobic oxidative condition gave similar reaction results (Table
1, entry 3). Delightfully, 81% of 4a was formed with complete inhibition of product 5a
when quinone was applied as the oxidant (Table 1, entry 4). C4 was identified as the
optimal catalyst in terms of yield and enantioselectivity after a series of CPAs were
screened (Table 1, entries 5–12). In addition, an excellent yield (96%) was achieved
without ee erosion when modified quinone O3 was used (Table 1, entry 14).
Although further optimization efforts by examining different solvents were futile, it
was encouraging to reveal that 1 mol % catalyst loading was sufficient to uphold
the high yield and enantioselectivity of this coupling reaction (Table 1, entries
15–18).
Substrate Generality with Respect to Indole-Naphthalene
The generality of the reaction was then examined under the optimized conditions.
First, various 2-nitrosonaphthalenes with different substitutions were tested. As de-
picted in Figure 3A, C6 methoxy-substituted substrate gave the desired product 4b
Chem 6, 1–14, August 6, 2020
3

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
A
B
C
Figure 2. Preliminary Computational Screening of Our Designed Electrophilic Naphthalene Substrates
(A) DFT-computed EA of different substrates.
(B) Illustration of the effect of PA on the LUMO energy of the 2-nitrosonaphthalene substrate.
(C) Computed LUMO energy of the substrates (blue) and of the substrate-PA complexes (red).
in excellent yield with up to 99% ee. The yield declined slightly to 88% (4c) when a
methyl group was installed in place of the methoxy group. Phenyl, benzoyloxy,
amine, and pyrrolyl groups were well tolerated for this reaction to give the corre-
sponding products in excellent yields and enantioselectivities (4d, 4e, and 4h–4j),
whereas moderate yields were obtained for substrates with C6 electron-withdrawing
groups (4f and 4g), which might be ascribed to the poor solubility of the substrates
(1f and 1g) in CH2Cl2. Excellent yields and enantioselectivities were obtained when
the substituents were equipped at the C7 position of 1a (4k–4m). Further substrate
exploration illustrated that all examined indoles with diverse substituents at varied
positions underwent smooth transformations to produce the desired atropisomers
4n–4u in excellent enantiocontrol (Figure 3B). Aside from the tert-butyl group, the
tert-pentyl and 1-adamantyl groups could also effect restricted rotation of the ster-
eogenic axis (4v and 4w), whereas the phenyl, isopropyl, and methyl-substituted cy-
clopropyl moieties posing less steric hindrance were found to be invalid axial-rota-
tion restriction groups; meanwhile, the atropisomerism of the corresponding
products (4x–4z) lost rapidly even at RT in the reaction mixture. To enhance the sta-
bility of the stereogenic axis, a methyl group was introduced at the C4 position of 2-
phenylindole 2n. Even though 72% ee was obtained for the expected 4aa under the
developed conditions, the configurational stability was clearly confirmed. The re-
evaluation of CPAs proved (S)-C20 as the other promising catalyst for this type of
substrate because it furnished atropisomer 4aa in 55% yield with a satisfied enantio-
control (86% ee). It should be mentioned that 5 mol % catalyst loading and 16 h re-
action time were required because of the probably low reactivity of 2aa with C4 sub-
stitution (Table S3). A similar reaction outcome was found for the preparation of 4ab,
whereas C4 was verified to be a better catalyst for assembling indole-naphthalene
4ac in terms of enantioselectivity. Interestingly, a small methyl group at the C2
4
Chem 6, 1–14, August 6, 2020

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
Table 1. Optimization of the Reaction Conditions for Indole-Naphthalene 4a
Entrya
Solvent
CPA
Oxidant
4a
5a
Yield (%)b
12
ee (%)c
62
Yield (%)b
ee (%)c
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
(S)-C1
(S)-C1
(S)-C1
(S)-C1
(S)-C2
(S)-C3
(S)-C4
(S)-C5
(S)-C6
(R)-C7
(R)-C8
(R)-C9
(S)-C4
(S)-C4
(S)-C4
(S)-C4
(S)-C4
(S)-C4
none
excess 1a
O2
18
36
15
trace
–
65
53
60
–
2
21
55
3
12
59
4
O1
81
64
5
O1
75
86
–
6
O1
84
87
–
–
7
O1
87
96
–
–
8
O1
84
96
–
–
9
O1
81
94
–
–
10
11
12
13
14
15
16
17
18d
O1
87
ꢀ96
57
–
–
O1
82
–
–
O1
79
28
–
–
O2
63
94
–
–
O3
96
96
–
–
O3
81
85
–
–
toluene
EtOAc
CH2Cl2
O3
90
95
–
–
O3
93
76
–
–
O3
96
96
–
–
aUnless otherwise stated, all reactions were carried out with 1a (0.105 mol), 2a (0.1 mmol), oxidant (0.11 mmol), and CPA (5 mol %) in 4 mL of solvent at RT for 1 h.
bIsolated yields were provided.
cThe enantiomeric excess (ee) values were determined by chiral HPLC analysis.
dUsing 1 mol % of CPA, 3 h.
position could effectively lock the stereogenic axis with the assistance of C4 methyl
substitution. By contrast, no good results were obtained for the substrates with a
bulky C2 substituent, such as isopropyl or methyl-substituted cyclopropyl, for
both catalysts because of the low activity. The absolute configuration of 4u was
determined by X-ray crystallographic analysis after recrystallization, and those of
other products in Figure 3 were assigned by analogy. Furthermore, the practicality
of this asymmetric cross-coupling reaction was verified by a gram-scale reaction be-
tween 1a and 2a with negligible yield and enantioselectivity variation.
Optimizing Reaction Conditions for the Synthesis of Aniline-Indole
Having secured the enantioselective construction of atropisomeric indole-naphtha-
lene scaffold, we moved on to selectively synthesize axially chiral aniline-indole 5.
Chem 6, 1–14, August 6, 2020
5

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
RT
A
B
a
a
a
b
b
b
6
Chem 6, 1–14, August 6, 2020

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
Figure 3. Substrate Generality for Indole-Naphthalene 4
Reaction conditions: 1 (0.21 mmol), 2 (0.20 mmol), O3 (1.1 equiv), and (S)-C4 (1 mol %) in CH2Cl2 (8 mL) at RT for 1–8 h.
(A) Substrate scope of 2-nitrosonaphthalenes.
(B) Substrate scope of indoles and X-ray structure of compound 4u.
aRapid racemization in the reaction mixture.
b5 mol % catalyst loading for 16 h.
The optimal catalyst (S-C4) and solvent (CH2Cl2) were used for the reaction of 1a and
2a at RT in the absence of an external oxidant. Under this set of conditions, dominant
formation of 5a (48%) was achieved as expected, although formation of 4a (11%) and
recovery of 2a (34%) were also unequivocal (Table 2, entry 1). Subsequently, solvent
screening uncovered that ethyl acetate (EtOAc) was superior for this transformation
in light of the overall reaction outcome (Table 2, entries 2–5). Detailed evaluation of
numerous CPAs suggested that the catalytic activity of C4 was unparalleled (Table 2,
entries 6–13). Further optimizations also disclosed that increased loading of 1a
(2.0 equiv) and lower reaction concentration could improve the isolated yield of
5a to 76% with 99% ee (Table 2, entry 14).
Substrate Generality with Respect to Aniline-Indole
The modified conditions were then applied to a wide range of 2-nitrosonaphthalenes
and indoles. As depicted in Figure 4A, coupling partner 1 bearing a methyl, methoxy,
or phenyl group at the C6 or C7 position was efficacious for this reaction to furnish
desired products with remarkable stereocontrol (5b–5g). However, the introduction
of strong electron-donating methoxy group on 2-nitrosonaphthalene (1b and 1k)
significantly increased the formation of the byproduct (4b and 4k) and gave rise to
the low yield of the corresponding product (5d and 5e). Meanwhile, the poor solubility
of the substrates bearing an electron-withdrawing functionality in EtOAc led to a con-
spicuous decrement in conversion rate and yield (5h–5j). On the contrary, the alter-
ation on the indole ring, including a different substitution pattern (5n–5t), as well as
the axial rotation resistance group (5u–5w), brought about an inconspicuous yield vari-
ation (Figure 4B). Notably, current conditions were also well accommodated by halo-
genated indoles, such as fluoride, chloride, and bromide. Moreover, all investigated
substrates furnished respective aniline-indole atropisomers with up to 99% ee. The ab-
solute configuration of 5k was determined by X-ray crystallographic analysis after
recrystallization, and those of other products in Figure 4 were assigned by analogy.
Reaction Mechanism and Computational Study
On the basis of experimental results and our understanding of organocatalytic asym-
metric construction of atropisomeric structures, a plausible reaction pathway was
proposed (Figure 5A). The reaction is initiated with an enantioselective nucleophilic
attack of indole to 2-nitrosonaphthalene to generate intermediate A through rapid
intramolecular conversion of the unstabilized sH adduct mediated by bifunctional
CPA catalysis. The re-aromatization process thus produces unstable intermediate
B. After an intramolecular cyclization induced by the highly nucleophilic hydroxyl-
amine moiety, the ensuing b-H elimination and C–N bond cleavage form axially chiral
indole-aniline 5a dominantly. Atropisomeric indole-naphthalene structure 4a is
exclusively generated instead in the presence of an external oxidant. We also
computed the transition states (TSs) for the first step (C–C bond forming) of this trans-
formation. The two lowest-energy-transition structures for this CPA-catalyzed asym-
metric nucleophilic attack are shown in Figure 5B. In each of the two TSs, the C–C
bond is being formed, whereas the proton is almost completely transferred from
the CPA to the nitroso oxygen. Simultaneously, the Brønsted basic site of the
CPA coordinates to the N–H of the indole through a hydrogen bond. Overall, the
CPA acts as a bifunctional catalyst to promote this key C–C bond formation. The
Chem 6, 1–14, August 6, 2020
7

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
Table 2. Optimization of the Reaction Conditions for Aniline-Indole 5a
Entrya
CPA
Solvent
Yield (%)
5ac
48
ee (%)b
5a
4ad
11
7
4a
96
96
96
95
88
19
61
81
83
83
ꢀ95
61
65
94
1
(S)-C4
(S)-C4
(S)-C4
(S)-C4
(S)-C4
(S)-C1
(S)-C2
(S)-C3
(S)-C5
(S)-C6
(R)-C7
(R)-C8
(R)-C9
(S)-C4
CH2Cl2
CCl4
98
2
36
98
3
EtOAc
toluene
c-hexane
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
57
6
99
4
45
7
98
5
18
1
95
6
15
16
11
10
6
22
7
27
79
8
33
90
9
51
96
10
11
12
13
14e
43
9
95
51
6
ꢀ99
63
30
16
14
5
24
63
76
99
aUnless otherwise stated, all reactions were carried out with 1a (0.105 mmol), 2a (0.1 mmol), and CPA (5 mol %) in 5 mL of solvent at RT for 24 h under argon
atmosphere.
bThe enantiomeric excess (ee) values were determined by chiral HPLC analysis.
cIsolated yields were provided.
dThe yields were determined by 1H NMR analysis of the crude product.
eUsing 1a (0.4 mmol), 2a (0.2 mmol), and EtOAc (8 mL), 24 h.
lowest-energy TS (TS-major) that ultimately leads to the major atropisomeric product
is 2.2 kcal mol–1 more stable than TS-minor. In TS-major, the C–N bond of the 2-nitro-
sonaphthalene substrate adopts the more stable s-trans conformation (1.4 kcal mol–1
more stable), whereas it is s-cis in TS-minor (the s-trans conformation results in a
poorer fit in the catalyst pocket). In addition, we calculated the distortion energy
and found that the catalyst itself is 0.8 kcal mol–1 more distorted in TS-minor. In
TS-major, one dihedral angle (ꢀ64.1ꢁ) between the anthryl group and the backbone
of the catalyst rotates away from the ideal ꢀ68.0ꢁ geometry,57 whereas the other
dihedral angle is perfectly preserved (ꢀ68.2ꢁ). In contrast, both dihedral angles in
TS-minor rotate away from ideal, causing a slightly higher distortion energy in the
catalyst. These two factors lead to the 2.2 kcal mol–1 difference in energy between
the two TSs, which explains the observed enantioselectivity of this reaction. A dia-
gram of the reaction free energy is shown in Figure 5C. After the formation of the
C–C bond and the subsequent aromatization of the naphthalene ring, II is generated.
In the absence of an external oxidant, an intramolecular cyclization proceeds to form
III (Figure 5C, red pathway), as induced by the highly nucleophilic hydroxylamine
moiety. Subsequent C–N bond cleavage forms Int. 5, which undergoes b-H elimina-
tion to generate Int. 6 (the axially chiral indole-aniline 5a in complex with the CPA). In
8
Chem 6, 1–14, August 6, 2020

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
RT
A
eea
B
Figure 4. Substrate Generality for Aniline-Indole 5
Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), and (S)-C4 (5 mol %) in EtOAc (8 mL) for 24 h under argon atmosphere.
(A) Substrate scope of 2-nitrosonaphthalenes and X-ray structure of compound 5k.
(B) Substrate scope of indoles.
a12 mL of EtOAc was used.
Chem 6, 1–14, August 6, 2020
9

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
A
B
C
Figure 5. Reaction Mechanisms
(A) Proposed mechanism for the CPA-catalyzed asymmetric nitrosonaphthalene functionalization and rearrangement.
(B) DFT-computed stereo-determining transition structures.
(C) Diagram of the computed reaction free energy.
R, tBu; CPA, (S)-C4; BQ, benzoquinone; HQ, hydroquinone.
the presence of an external oxidant, such as benzoquinone, further aromatization of
II generates Int. 4, which could be oxidized to form product 4a (Figure 5C, blue
pathway). More computed mechanistic details can be found in Figures S2 and S3.
Asymmetric Construction of NOBIN Structures
Successful establishment of the highly enantioselective construction of indole-naph-
thalene and indole-aniline analogs inspired us to explore the feasibility of constructing
privileged axially chiral scaffolds. The NOBIN (2-amino-20-hydroxy-1,10-binaphthyl)
structure is present in a multitude of highly prized biaryl atropisomeric catalysts and
ligands for chirality induction in asymmetric catalysis.58,59 However, the catalytic
asymmetric construction approaches are scarce, thus restricting their applica-
tions.60,61 In particular, a facile and universal organocatalytic protocol remains
hitherto inaccessible. As
a result of the unmet challenge in the assembly
of atropisomeric NOBINs, the aforementioned strategy was then extended to 2-naph-
thol nucleophile. Compared with indole, this reaction was assumed to be more chal-
lenging and complicated because of the disparate nucleophilicity and the multiple
10
Chem 6, 1–14, August 6, 2020

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
RT
eea
eea,b
Figure 6. Substrate Generality for NOBINs 7 and the Isolation of Intermediate 8h
Reaction conditions: 1 (0.3 mol), 6 (0.2 mmol), DIAD (0.2 mmol), and (R)-C10 (10 mol %) in CH2Cl2 (4 mL) at ꢀ30ꢁC for 2 days; reaction mixture of the first
step and Raney-Ni (50 mg) in MeOH (4 mL) under H2 atmosphere (1 atm) for 1 h.
aZinc powder and HCO2H were used as the reductant.
bCH2Cl2 (6 mL) for the first step.
reactive sites present. Nonetheless, an array of valuable NOBINs were auspiciously
fashioned with remarkable enantiocontrol through a one-pot, two-step synthesis,
namely asymmetric C–C cross-coupling and reductive N–O bond cleavage. Notably,
CPA (R)-C10 with a cyclohexyl-fused spirobiindane backbone62 was found to be the
best catalyst, and the addition of diisopropyl azodicarboxylate (DIAD) as an oxidant
could significantly boost the yield (Tables S1 and S2). The generality and limitation
of this reaction are depicted in Figure 6. First, the model reaction with C7 methoxy-
substituted 2-naphthol afforded the desired 7a in 59% yield with 87% ee in CH2Cl2
at ꢀ30ꢁC for 2 days. Subsequent evaluation demonstrated that the substitution on
the C7 position of 2-naphthol strongly influenced the reaction results (7b–7d). Pleas-
ingly, the yield was improved to 72% when a methyl group was introduced (7d). We
next examined the substitution effect on 2-nitrosonaphthalene with 6d as the coupling
partner, and the results further proved the positive impact of C7 methyl substitution
on 2-naphthol (7e–7k). In addition, the installation of a methyl group on the C7 posi-
tion of 2-nitrosonaphthalene could contribute to the enantiocontrol of atroposelective
Chem 6, 1–14, August 6, 2020
11

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
cross-coupling reactions (7h and 7l–7p). Delightfully, the isolation of enantioenriched
2-hydroxy-20-nitroso-binaphthyl 8h clearly indicated a reaction pathway similar to that
presented in Figure 5A and the oxidation effect of DIAD. Comparison of the chiral
high-performance liquid chromatography (HPLC) spectrum of synthesized 7b with
that of commercially available (S)-NOBIN determined the absolute configuration of
7b to be (S). Those of other products 7 and 8h were assigned analogously.
An efficient organocatalytic arene functionalization strategy with 2-nitrosonaphtha-
lene as the electrophile was efficiently developed, guided by DFT calculations. The
nitroso group could serve as a directing electron-withdrawing group and an oxidant
for rapid conversion of the unstabilized sH adduct. The atroposelective nucleophilic
aromatic substitution reactions were realized under mild reaction conditions enabled
by CPA catalysis, generating two types of highly enantioenriched atropisomers
(indole-naphthalenes and indole-anilines) encompassing a wide substrate scope.
Employing a CPA with a cyclohexyl-fused spirobiindane backbone, we further
demonstrated the practicality of this strategy by applying a one-pot, two-step syn-
thesis of privileged axially chiral NOBIN and its derivatives. Compared with the pre-
viously disclosed azo group,20,60 a nitroso group effectively negates the necessity of
an appending electron-withdrawing ester functionality. Accordingly, the atom econ-
omy of the current approach was significantly improved. Meanwhile, the high reac-
tivity of the 2-nitrosonaphthalene authorized a solo organocatalytic system that aptly
realized the asymmetric construction of NOBINs, thus signifying another graceful de-
parture from a more reactive and complex catalytic species required to facilitate anal-
ogous transformation of azo-embedded arene substrates. DFT calculations provide
additional insights into the origins of enantiocontrol.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
Resource Availability
Lead Contact
Further information and requests for resources should be directed to and will be ful-
filled by the Lead Contact, Bin Tan (tanb@sustech.edu.cn).
Materials Availability
This study did not generate new unique reagents.
Data and Code Availability
The X-ray crystallographic coordinates for the structures of 4u and 5k reported in this
article have been deposited at the Cambridge Crystallographic Data Centre (CCDC)
under accession numbers CCDC: 1893414 and CCDC: 1893419. These data can be
obtained free of charge from CCDC via http://www.ccdc.cam.ac.uk/data_request/
cif. Experimental procedures and characterization of new compounds are available
in the Supplemental Information.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.06.001.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural Science Foundation
of China (21772081, 21825105, 21702092, and 21901105), the Shenzhen Nobel
12
Chem 6, 1–14, August 6, 2020

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
Prize Scientists Laboratory Project (C17213101), Shenzhen Special Funds
(JCYJ20180305123508258), and the US National Science Foundation (CHE-
1764328) and Saul Winstein Chair in Organic Chemistry funds to K.N.H. Computa-
tional work was supported by the Center for Computational Science and Engineer-
ing at SUSTech and by the UCLA Institute of Digital Research and Education.
AUTHOR CONTRIBUTIONS
B.T. and K.N.H. conceived and directed the project; W.-Y.D. and Q.-J.A. designed
and performed experiments; P.Y. and K.L.B. conducted the DFT calculations and
provided mechanism analysis; S.-H.X., S.L., and Y.C. helped with the collection of
some new compounds and data analysis; B.T., K.N.H., S.-H.X., and P.Y. wrote the
paper with input from all other authors; and all authors discussed the results and
commented on the manuscript. W.-Y.D., P.Y., Q.-J.A., and K.L.B. contributed
equally to this work.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: February 6, 2020
Revised: April 20, 2020
Accepted: May 29, 2020
Published: June 23, 2020
REFERENCES
1. Mortier, J. (2015). Arene Chemistry: Reaction
Mechanism and Methods for Aromatic
Compounds (John Wiley & Sons).
10. Wang, P., Verma, P., Xia, G., Shi, J., Qiao, J.X.,
Tao, S., Cheng, P.T.W., Poss, M.A., Farmer,
M.E., Yeung, K.S., and Yu, J.-.Q. (2017). Ligand-
accelerated non-directed C–H
20. Qi, L.W., Mao, J.H., Zhang, J., and Tan, B.
(2018). Organocatalytic asymmetric arylation of
indoles enabled by azo groups. Nat. Chem. 10,
58–64.
2. Friedel, C., and Crafts, J.-M. (1877). Sur une
nouvelle me´ thode ge´ ne´ rale de synthe` se
d’hydrocarbures, d’ace´ tones, etc. C. R. Chim.
84, 1392–1395.
functionalization of arenes. Nature 551,
489–493.
21. Akiyama, T. (2007). Stronger Brønsted acids.
Chem. Rev. 107, 5744–5758.
11. Romero, N.A., Margrey, K.A., Tay, N.E., and
Nicewicz, D.A. (2015). Site-selective arene C-H
amination via photoredox catalysis. Science
349, 1326–1330.
22. Terada, M. (2008). Binaphthol-derived
phosphoric acid as a versatile catalyst for
enantioselective carbon-carbon bond forming
reactions. Chem. Commun. 2008, 4097–4112.
3. Sartori, G., and Maggi, R. (2017). Advance in
Friedel-Crafts Acylation Reactions: Catalytic
and Green Processes (CRC Press).
12. Ma˛kosza, M. (2010). Nucleophilic substitution
of hydrogen in electron-deficient arenes, a
general process of great practical value. Chem.
Soc. Rev. 39, 2855–2868.
4. Bandini, M., and Umani-Ronchi, A. (2009).
Catalytic Asymmetric Friedel-Crafts Alkylations
(John Wiley & Sons).
23. Parmar, D., Sugiono, E., Raja, S., and Rueping,
M. (2014). Complete field guide to asymmetric
BINOL-phosphate derived Brønsted acid and
metal catalysis: history and classification by
mode of activation; Brønsted acidity, hydrogen
bonding, ion pairing, and metal phosphates.
Chem. Rev. 114, 9047–9153.
13. Ma˛kosza, M. (2014). Reactions of nucleophiles
with nitroarenes: multifacial and versatile
electrophiles. Chemistry 20, 5536–5545.
5. Daugulis, O., Do, H.Q., and Shabashov, D.
(2009). Palladium- and copper-catalyzed
arylation of carbon-hydrogen bonds. Acc.
Chem. Res. 42, 1074–1086.
14. Wilson, A.S.S., Hill, M.S., Mahon, M.F., Dinoi,
C., and Maron, L. (2017). Organocalcium-
mediated nucleophilic alkylation of benzene.
Science 358, 1168–1171.
24. Bella, M., Kobbelgaard, S., and Jørgensen, K.A.
(2005). Organocatalytic regio- and asymmetric
C-selective SNAr reactions-stereoselective
synthesis of optically active spiro-pyrrolidone-
3,30-oxoindoles. J. Am. Chem. Soc. 127, 3670–
3671.
6. Colby, D.A., Bergman, R.G., and Ellman, J.A.
(2010). Rhodium-catalyzed C–C bond
formation via heteroatom-directed C–H bond
activation. Chem. Rev. 110, 624–655.
15. Ma˛kosza, M., and Winiarski, J. (1987). Vicarious
nucleophilic substitution of hydrogen. Acc.
Chem. Res. 20, 282–289.
7. Lyons, T.W., and Sanford, M.S. (2010).
Palladium-catalyzed ligand-directed C-H
functionalization reactions. Chem. Rev. 110,
1147–1169.
25. Shirakawa, S., Koga, K., Tokuda, T., Yamamoto,
K., and Maruoka, K. (2014). Catalytic
asymmetric synthesis of 3,3’-diaryloxindoles as
triarylmethanes with a chiral all-carbon
quaternary center: phase-transfer-catalyzed
SNAr reaction. Angew. Chem. Int. Ed. 53, 6220–
6223.
16. Houk, K.N., and List, B. (2004). Asymmetric
organocatalysis. Acc. Chem. Res. 37, 487.
8. Wencel-Delord, J., Droge, T., Liu, F., and
¨
17. List, B. (2007). Introduction: organocatalysis.
Glorius, F. (2011). Towards mild metal-
catalyzed C-H bond activation. Chem. Soc.
Rev. 40, 4740–4761.
Chem. Rev. 107, 5413–5415.
18. MacMillan, D.W.C. (2008). The advent and
development of organocatalysis. Nature 455,
304–308.
9. Engle, K.M., Mei, T.S., Wasa, M., and Yu, J.Q.
(2012). Weak coordination as a powerful means
for developing broadly useful C-H
functionalization reactions. Acc. Chem. Res. 45,
788–802.
26. Armstrong, R.J., and Smith, M.D. (2014).
Catalytic enantioselective synthesis of
atropisomeric biaryls: a cation-directed
nucleophilic aromatic substitution reaction.
Angew. Chem. Int. Ed. 53, 12822–12826.
19. B. List, ed. (2010). Asymmetric Organocatalysis
(Springer). https://doi.org/10.1007/978-3-642-
02815-1.
Chem 6, 1–14, August 6, 2020
13

Please cite this article in press as: Ding et al., DFT-Guided Phosphoric-Acid-Catalyzed Atroposelective Arene Functionalization of Nitrosonaph-
thalene, Chem (2020), https://doi.org/10.1016/j.chempr.2020.06.001
ll
Article
27. Zhong, G.-F. (2003). A facile and rapid route to 41. Wang, J.Z., Zhou, J., Xu, C., Sun, H., Kurti, L.,
52. Liao, G., Chen, H.M., Xia, Y.N., Li, B., Yao, Q.J.,
and Shi, B.F. (2019). Synthesis of chiral
aldehyde catalysts by Pd-catalyzed
¨
highly enantiopure 1,2-diols by novel catalytic
asymmetric a-aminoxylation of aldehydes.
Angew. Chem. Int. Ed. 42, 4247–4250.
and Xu, Q.L. (2016). Symmetry in cascade
chirality-transfer processes: a catalytic
atroposelective direct arylation approach to
BINOL derivatives. J. Am. Chem. Soc. 138,
5202–5205.
atroposelective C–H naphthylation. Angew.
Chem. Int. Ed. 58, 11464–11468.
28. Brown, S.P., Brochu, M.P., Sinz, C.J., and
MacMillan, D.W.C. (2003). The direct and
enantioselective organocatalytic a-oxidation of
aldehydes. J. Am. Chem. Soc. 125, 10808–
10809.
53. Jiang, F., Chen, K.W., Wu, P., Zhang, Y.C., Jiao,
Y., and Shi, F. (2019). A strategy for synthesizing
axially chiral naphthyl-indoles: catalytic
asymmetric addition reactions of racemic
substrates. Angew. Chem. Int. Ed. 58, 15104–
15110.
42. Quinonero, O., Jean, M., Vanthuyne, N.,
Roussel, C., Bonne, D., Constantieux, T.,
Bressy, C., Bugaut, X., and Rodriguez, J. (2016).
Combining organocatalysis with central-to-
axial chirality conversion: atroposelective
Hantzsch-type synthesis of 4-arylpyridines.
Angew. Chem. Int. Ed. 55, 1401–1405.
29. Lu, M., Zhu, D., Lu, Y., Zeng, X., Tan, B., Xu, Z.,
and Zhong, G. (2009). Chiral Brønsted acid-
catalyzed enantioselective a-hydroxylation of
b-dicarbonyl compounds. J. Am. Chem. Soc.
131, 4562–4563.
54. Deng, R., Xi, J., Li, Q., and Gu, Z. (2019).
Enantioselective carbon-carbon bond
cleavage for biaryl atropisomers synthesis.
Chem 5, 1834–1846.
43. Raut, V.S., Jean, M., Vanthuyne, N., Roussel, C.,
Constantieux, T., Bressy, C., Bugaut, X., Bonne,
D., and Rodriguez, J. (2017). Enantioselective
syntheses of furan atropisomers by an oxidative
central-to-axial chirality conversion strategy.
J. Am. Chem. Soc. 139, 2140–2143.
30. Noyori, R., and Takaya, H. (1990). BINAP: an
efficient chiral element for asymmetric
catalysis. Acc. Chem. Res. 23, 345–350.
55. Shen, D., Xu, Y., and Shi, S.L. (2019). A bulky
chiral N-heterocyclic carbene palladium
catalyst enables highly enantioselective Suzuki-
Miyaura cross-coupling reactions for the
synthesis of biaryl atropisomers. J. Am. Chem.
Soc. 141, 14938–14945.
31. Chen, Y., Yekta, S., and Yudin, A.K. (2003).
Modified BINOL ligands in asymmetric
catalysis. Chem. Rev. 103, 3155–3212.
44. Zhang, H.H., Wang, C.S., Li, C., Mei, G.J., Li, Y.,
and Shi, F. (2017). Design and enantioselective
construction of axially chiral naphthyl-indole
skeletons. Angew. Chem. Int. Ed. 56, 116–121.
32. Brunel, J.M. (2005). BINOL: a versatile chiral
reagent. Chem. Rev. 105, 857–897.
56. Witzig, R.M., Faseke, V.C., Haussinger, D., and
¨
¨
45. Jolliffe, J.D., Armstrong, R.J., and Smith, M.D.
(2017). Catalytic enantioselective synthesis of
atropisomeric biaryls by a cation-directed O-
alkylation. Nat. Chem. 9, 558–562.
Sparr, C. (2019). Atroposelective synthesis of
tetra-ortho-substituted biaryls by catalyst-
controlled non-canonical polyketide
cyclizations. Nat. Catal. 2, 925–930.
33. Berthod, M., Mignani, G., Woodward, G., and
Lemaire, M. (2005). Modified BINAP: the how
and the why. Chem. Rev. 105, 1801–1836.
34. Kozlowski, M.C., Morgan, B.J., and Linton, E.C.
(2009). Total synthesis of chiral biaryl natural
products by asymmetric biaryl coupling. Chem.
Soc. Rev. 38, 3193–3207.
46. Zhao, K., Duan, L., Xu, S., Jiang, J., Fu, Y., and
Gu, Z. (2018). Enhanced reactivity by torsional
strain of cyclic diaryliodonium in Cu-catalyzed
enantioselective ring-opening reaction. Chem
4, 599–612.
57. Wang, Y.-B., Yu, P., Zhou, Z.P., Zhang, J., Wang,
J., Luo, S.H., Gu, Q.S., Houk, K.N., and Tan, B.
(2019). Rational design, enantioselective
synthesis and catalytic applications
of axially chiral EBINOLs. Nat. Catal. 2,
504–513.
35. Gustafson, J.L., Lim, D., and Miller, S.J. (2010).
Dynamic kinetic resolution of biaryl
atropisomers via peptide-catalyzed
asymmetric bromination. Science 328, 1251–
1255.
47. Hornillos, V., Carmona, J.A., Ros, A., Iglesias-
Siguenza, J., Lo´ pez-Serrano, J., Ferna´ndez, R.,
¨
ꢀ
ꢀ
ꢀ
58. Kocovsky´, P., Vyskocil, S., and Smrcina, M.
(2003). Non-symmetrically substituted
1,10-binaphthyls in enantioselective catalysis.
Chem. Rev. 103, 3213–3246.
and Lassaletta, J.M. (2018). Dynamic kinetic
resolution of heterobiaryl ketones by zinc-
catalyzed asymmetric hydrosilylation. Angew.
Chem. Int. Ed. 57, 3777–3781.
36. Mori, K., Ichikawa, Y., Kobayashi, M., Shibata,
Y., Yamanaka, M., and Akiyama, T. (2013).
Enantioselective synthesis of multisubstituted
biaryl skeleton by chiral phosphoric acid
48. Jia, S., Chen, Z., Zhang, N., Tan, Y., Liu, Y.,
Deng, J., and Yan, H. (2018). Organocatalytic
enantioselective construction of axially chiral
sulfone-containing styrenes. J. Am. Chem. Soc.
140, 7056–7060.
59. Ding, K., Li, X., Ji, B., Guo, H., and Kitamura, M.
(2005). Ten years of research on NOBIN
chemistry. Curr. Org. Syn. 2, 499–545.
catalyzed desymmetrization/kinetic resolution
sequence. J. Am. Chem. Soc. 135, 3964–3970.
37. Barrett, K.T., Metrano, A.J., Rablen, P.R., and
Miller, S.J. (2014). Spontaneous transfer of
chirality in an atropisomerically enriched two-
axis system. Nature 509, 71–75.
60. Qi, L.-W., Li, S., Xiang, S.H., Wang, J., and Tan,
B. (2019). Asymmetric construction
of atropisomeric biaryls via a redox
neutral cross-coupling strategy. Nat. Catal. 2,
314–323.
49. Zheng, S.C., Wang, Q., and Zhu, J. (2019).
Catalytic atropenantioselective
heteroannulation between isocyanoacetates
and alkynyl ketones: synthesis of
enantioenriched axially chiral 3-arylpyrroles.
Angew. Chem. Int. Ed. 58, 1494–1498.
38. Kumarasamy, E., Raghunathan, R., Sibi, M.P.,
and Sivaguru, J. (2015). Nonbiaryl and
heterobiaryl atropisomers: molecular
templates with promise for atropselective
chemical transformations. Chem. Rev. 115,
11239–11300.
ꢀ
61. Smrcina, M., Vyskocil, S., Maca, B., Polasek, M.,
Claxton, T.A., Abbott, A.P., and Kocovsky, P.
(1994). Selective cross-coupling of 2-naphthol
and 2-naphthylamine derivatives. A facile
synthesis of 2,2’,3-trisubstituted and 2,2’,3,3’-
tetrasubstituted 1,1’-binaphthyls. J. Org.
Chem. 59, 2156–2163.
50. He, Y.P., Wu, H., Wang, Q., and Zhu, J. (2020).
Palladium-catalyzed enantioselective Cacchi
reaction: asymmetric synthesis of axially chiral
2,3-disubstituted indoles. Angew. Chem. Int.
Ed. 59, 2105–2109.
39. Wencel-Delord, J., Panossian, A., Leroux, F.R.,
and Colobert, F. (2015). Recent advances and
new concepts for the synthesis of axially
stereoenriched biaryls. Chem. Soc. Rev. 44,
3418–3430.
51. Luo, J., Zhang, T., Wang, L., Liao, G., Yao, Q.J.,
Wu, Y.J., Zhan, B.B., Lan, Y., Lin, X.F., and Shi,
B.F. (2019). Enantioselective synthesis of biaryl
atropisomers by Pd-catalyzed C–H olefination
using chiral spiro phosphoric acid ligands.
Angew. Chem. Int. Ed. 58, 6708–6712.
62. Zheng, Z., Cao, Y., Chong, Q., Han, Z., Ding, J.,
Luo, C., Wang, Z., Zhu, D., Zhou, Q.L., and
Ding, K. (2018). Chiral cyclohexyl-fused
spirobiindanes: practical synthesis, ligand
development, and asymmetric catalysis. J. Am.
Chem. Soc. 140, 10374–10381.
40. Wang, Y.B., and Tan, B. (2018). Construction of
axially chiral compounds via asymmetric
organocatalysis. Acc. Chem. Res. 51, 534–547.
14
Chem 6, 1–14, August 6, 2020