Catalytic Atroposelective Synthesis of N-Aryl Quinoid Compounds

Article abstract of DOI:10.1021/jacs.9b12994

Diarylamines and related scaffolds are among the most common chemotypes in modern drug discovery. While they can potentially possess two chiral axes, there are no studies on their enantioselective synthesis, as these axes typically possess lower stereochemical stabilities. Herein, we report a chiral phosphoric acid catalyzed atroposelective electrophilic halogenation of N-aryl quinoids, a class of compounds that are analogous to diarylamines. This chemistry yields a large range of stereochemically stable N-aryl quinoids in excellent yields and atroposelectivity. This work represents the first example of the atroposelective synthesis of a diarylamine-like scaffold and will serve as a gateway to fundamental and applied studies on the scarcely studied chirality of these ubiquitous chiral scaffolds.

Full text of DOI:10.1021/jacs.9b12994

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Communication
Catalytic Atroposelective Synthesis of N-Aryl Quinoid Compounds
Sagar Dilip Vaidya, Sean T. Toenjes, Nobuyuki Yamamoto, Sean M Maddox, and Jeffrey L. Gustafson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12994 • Publication Date (Web): 16 Jan 2020
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Catalytic Atroposelective Synthesis of N-Aryl Quinoid Compounds
Sagar D. Vaidya, Sean T. Toenjes, Nobuyuki Yamamoto, Sean M. Maddox and Jeffrey L. Gustafson*
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Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, California
92182-1030, United States
Supporting Information Placeholder
Scheme 1. Atropisomerism in Diarylamines and related
ABSTRACT: Diarylamines and related scaffolds are among the
most common chemotypes in modern drug discovery. While they
can potentially possess two chiral axes, there are no studies on their
enantioselective synthesis as these axes typically possess lower
stereochemical stabilities. Herein we report a chiral phosphoric
acid catalyzed atroposelective electrophilic halogenation of N-aryl
quinoids, a class of compounds that are analogous to diarylamines.
This chemistry yields a large range of stereochemically stable N-
aryl quinoids in excellent yields and atroposelectivity. This work
represents the first example of the atroposelective synthesis of a
diarylamine-like scaffold and will serve as a gateway to
fundamental and applied studies on the scarcely studied chirality of
these ubiquitous chiral scaffolds.
scaffolds
A. Atropisomeric rapidly interconverting diarylamines and N-aryl quinoids in drug discovery
Br
N
O
O
N
N
O
O
N
N
O
F
Cl
O
N
CN
NH
N
N
N
O
O
O
H
H
H
N
OH
OBn
Cl
Bosutinib
B. Previous examples of atropisomerically stable diarylamines
Cl
O
VEGFR inhibitor
Binimetinib
i) Kawabata et al.
ii) Clayden et al.
MeHN
O2N
O
N
O
N
NaHMDS
H
N
N
Unactivated
Smiles
O2N
NH
rearrangement
Atropisomerism, or axial chirality, is ubiquitous throughout
modern drug discovery1–4 and natural products chemistry.5,6 While
most chemists recognize atropisomeric axes pertaining to biaryls,7
benzamides,8 and anilides,9 axial chirality in diarylamines and
related scaffolds such as N-aryl quinoids are largely overlooked.
Nonetheless, these structural motifs are among the most common
potentially atropisomeric chemotypes in medicinal chemistry, with
the FDA-approved drugs binimetinib and bosutinib representing
examples of diarylamines that exist as rapidly interconverting
atropisomers, and a VEGFR inhibitor from Wyeth representing a
G rot = 25.45 kcal/mol
G rot = 28.20 kcal/mol
C. This work. Enantioselective synthesis of N-aryl quinoids.
OH
O
O
R3
R3
P
O
H
N
O
H
N
Ar
O
Ar
R2
R2
CPA
NXS
R1
R1
X
O
O
First example of atroposelective
synthesis of N-aryl quinoids
Class 3 atropisomer
G rot  29 kcal/mol in ethanol
(R)-CPA, Ar = 1-naphthyl
As instances of stereochemically stable diarylamines and related
scaffolds have been scarce, there are no published examples of their
enantioselective synthesis. Herein we describe studies that have led
to the first catalytic atroposelective synthesis of a diarylamine-like
scaffold, finding N-aryl quinoids that possess a 5-membered
intramolecular N-H-O hydrogen bond to exist as stereochemically
10–12
potentially atropisomeric N-aryl quinoid (Scheme 1A).
Indeed, a cursory search in the PDB will reveal thousands of co-
crystal structures of diarylamine and related scaffolds bound to
proteins in an atroposelective manner. With the rapid advancement
of synthetic methodologies to form C(sp2)-N bonds,13,14 the
ubiquitous nature of diarylamines and related scaffolds in drug
discovery will likely continue to grow. These structural motifs are
also interesting from a stereochemical perspective as they possess
two contiguous atropisomeric axes which leads to a complex
conformational profile as well as a potential gearing mechanism
that can lead to lower than expected barriers to racemization.15,16
Kawabata17,18 has resolved the atropisomers of a series of
diarylamines that possessed an intramolecular N-H-N hydrogen
bond that preorganized one of the axes into a planar conformation
(Scheme 1B), simplifying diarylamines to a single axis system and
resulting in compounds that possessed barriers to racemization of
up to ~28 kcal/mol, existing as class 2 atropisomers according to
LaPlante’s19 atropisomer stability classification system (t1/2 to
racemization on the day to month timescale at 37 oC ). Kawabata’s
system proved sensitive to the strength of the intramolecular
hydrogen bond, and the stereochemical stabilities quickly
decreased upon removal of electron withdrawing groups. More
recently, Clayden15 resolved the atropisomers for diarylamines
without an internal H-bond, finding them to only have
stereochemical stabilities on the hour time scale at room
temperature.
stable class
3 atropisomers with barriers to racemization
approaching and exceeding 30 kcal/mol (t1/2 (37° C) > 4.5 years) in
both protic and aprotic solvents, a classification that is considered
sufficiently stereochemically stable for drug development.
Scheme 2. N-Aryl quinoids as a diarylamine surrogate with
one chiral axis.
R1
O
R1
O
H
N
R1
H
N
H
N
R1
R
t-Bu
R2
R
t-Bu
O
R2
O
endo 7.88 kcal/mol
exo 0 kcal/mol
Intramolecular hydrogen bonding for structural rigidity and high
diastereoselectivity
Dual axes system
1e
X-ray crystal structures of both atropisomeric conformations of N-aryl quinoid
exo conformation
locked in
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Inspired by Kawabata’s work, as well as a series of N-aryl
Unfortunately, the synthesis of substrates with halogen
substitution at the ortho position of the arene using literature
methodologies failed due to
Table 1. Condition Optimizationa
1
2
3
4
5
6
7
8
quinoid-based kinase inhibitors (also in Scheme 1A),20 we
synthesized N-aryl naphthoquinoide 1a which exists as a
stereochemically unstable class 1 atropisomer. Computational
studies and X-ray crystallographic analysis (Scheme 2) suggested
that the quinoid-nitrogen axis exists in a planar ‘exo’ conformation
due to a strong intramolecular N-H-O hydrogen bond, simplifying
the 2-axis system into a single axis system in a manner analogous
to that of Kawabata. We hypothesized that functionalization of the
quinoid C-H could lead to stable atropisomerism. Indeed, Tan and
others have pioneered atroposelective synthesis via the addition of
aryl nucleophiles into quinones,21–25 and we have studied other
nucleophiles in the context of the atroposelective synthesis.16,26
Unfortunately, 1a proved unreactive under these conditions.
Ph
O
H
O
H
N
Ph
N
Ph
3
Cat , NBS or NBP
Toluene+Hexane
exo : endo
100:0
Ph
1a
t-Bu
Br
2a exo
O
S
O
,
b
c
Entry
1
Catalyst Br Source Concentration Time Temp. (°C)
2a%
2a
Yield (
)
e.r. (
)
9
3a 5%
3b 5%
3c 5%
NBS
NBS
NBS
0.025M
0.025M
0.025M
0.025M
0.025M
0.025M
0.025M
0.025M
0.025M
0.025M
0.025M
0.0055M
6 h
6 h
24
24
24
24
24
24
24
24
24
24
24
24
94
45:55
51:49
56:44
77:23
80:20
82:18
74:26
75:25
50:50
91:9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
94
94
95
94
94
95
95
94
94
94
95
3
6 h
As the amino naphthoquinone moiety could be considered
‘enamine-like’ we next evaluated electrophilic functionalization of
1a, observing facile electrophilic halogenation using achiral Lewis
basic catalysts and N-halosuccinimides.27,28 Excitingly, these
halogenated products proved quite stereochemically stable (vida
infra), confirming that this system may be amenable to atropisomer
selective catalysis in which a stereochemical labile axis is rigidified
via a ‘net C-H functionalization’, as exemplified in work by Miller
and colleagues.7,8,19,29–32
4
3d
5%
6 h
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBP
NBP
5
3e 5%
3f 5%
3g 5%
3h 5%
3i 5%
3j 5%
3j 10%
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
6
7
8
9
10
11
12
92:8
The evaluation of chiral Lewis basic catalysts yielded little to no
enantioselectivity (See SI). Inspired by the seminal work of
Akiyama33–38 on the atroposelective bromination of biaryl systems,
we next evaluated several chiral phosphoric acids (CPA) with N-
Bromosuccinimide (NBS) for the bromination of 1a (Table 1,
entries 1-4). While many of these catalysts yielded poor selectivity,
the venerable CPA (R)-TRIPS 3d effected this reaction to near
quantitative conversions with promising enantioselectivity (77:23
e.r.). We next evaluated the less acidic octahydro-BINOL (H8-
BINOL) scaffold, finding H8-BINOL (R)-TRIPS (3e, Table 1,
entry 5) resulted in a slight increase in enantioselectivity (80:20
e.r.). This result encouraged us to try other H8-BINOL based
catalysts (Table 1, entries 6-9). While modifying the 3,3’ positions
largely led to minor changes in selectivity, we found that CPA 3j,
which possesses 1-naphthyl substitution at the 3,3’ position, to be
an effective catalyst yielding brominated product 2a in 94% yield
and an e.r. of 91:9 (Table 1, entry 10). We next evaluated other
reaction parameters such as temperature, solvent, reaction
concentration, catalyst loading and bromination reagent (Table 1,
entries 11-13), arriving to conditions that yielded 2a in greater than
96:4 e.r. We finally evaluated 3k, the BINOL based analog of our
optimal catalyst, observing a slight loss in enantioselectivity (entry
14).
3j
95:5
10%
13
14
3j 10%
NBP
NBP
0.0055M
0.0055M
12 h
6 h
Ar
24
24
95
91
96:4d
3k 10%
90:10d
Ar
Ar
O
O
O
O
O
O
P
O
O
P
OH
P
O
OH
OH
Ar
Ar
Ar
3a
3b
3c
3d
3k
) (S)-Ar = 9-antracenyl
) (R)-Ar = 9-phenanthrenyl
) (R)-Ar = 3,5-(CF3)2-C6H3
) (R)-Ar = 2,4,6-(i-Pr)3-C6H2
) (R)-Ar = 1-naphthyl
3h
3i
3j
) (R)-Ar = 2,4,6-(Me)3-C6H2
) (R)-Ar = 9-phenanthrene
) (R)-Ar = 1-naphthyl
3e
) (R)-Ar = 2,4,6-(i-Pr)3-C6H2
3f
) (R)-Ar = o-tolyl
3g
) (R)-Ar = phenyl
a
1a
Reaction conditions: Starting material
(0.055 mmol), Catalyst (10%), Toluene:Hexane
(1:1) 10 mL then bromine source (0.06 mmol) at 24 °C for 12 h. bisolated yield. cDetermined
by HPLC analysis on a chiral stationary phase. d 2 fold 4Å MS. NBP = N-Bromophthalimide
an unexpected cyclization (see SI). Replacing the aryl substitution
at both positions with methyl groups resulted in a large drop in e.r
to 60:40 (2u, 91%), suggesting the ortho- aryl group partakes in an
interaction with the catalyst that is crucial for enantiomer
discrimination. We next evaluated different quinone fragments,
finding an anthraquinone based substrate to give excellent yields
and selectivities (2v, 95% yield with 96:4 e.r). A substituted
benzoquinone-based substrate also reacted cleanly to give 2w in
90% yield and 98:2 e.r.
With optimal conditions in hand we next sought to define
reaction scope. The chemistry proved to be tolerant of diverse aryl
substitutions of the 2,4-positions of the aniline. Electron rich aryl
substitutions yielding e.r.s above 95:5 (Scheme 3, 2b-2e, 2i, 2j, 2n,
2o) and electron poor aryl substitutions yielding e.r.s around 90:10
(2f-2h, 2k). Notably, aryls groups with ortho fluorine substitutions
(2l, 2m) yielded selectivities greater than 95:5 e.r. We were able
to obtain a crystal structure of 2l, confirming the stereochemical
induction of this reaction to be the (S)-atropisomer in the exo
conformation.
We next evaluated anilines that did not possess a t-Bu group at
the 6-position, observing that replacing the tert-butyl by isopropyl
as in 2x and trifluoromethyl as in 2y resulted in good yield but
drastic decreases in e.r. to 63:37 and 56:44 respectively, likely due
to a low barrier to racemization (measured to be~24 kcal/mol) for
these substrates leading to racemization during the course of the
reaction. Finally, we observed that this chemistry was amenable to
chlorination in the presence of a Lewis basic catalyst and NCS (2z,
91% yield with 87:13 e.r.) and iodination using NIS (2aa, 93%
yield 80:20 e.r.), albeit with somewhat attenuated selectivities.
This chemistry also proved tolerant of fused ring systems
including naphthyl (2p, 91% yield with 95:5 e.r.), benzofuran
(2q, 89% yield with 85:15 e.r.) and benzothiophene (2r in 93%
yield with 95:5 e.r.). We next evaluated substrates that possess
2-aryl-4-chloro substitution, obtaining 2s and 2t in excellent
yield and enantioselectivity. We find these results significant,
as the ability to transform aryl chlorides into diverse
functionalities in a manner orthogonal to bromides23 will allow
for significant synthetic utility to obtain diverse analogs.
Racemization studies were also carried out to investigate the
stereochemical stability of representative products. Product 2a was
o
found to have a barrier to rotation of 30.31 kcal/mol at 100 C in
toluene, which would be considered a stable class 3 atropisomer.
o
Notably, when the barrier was measured in ethanol at 80 C the
barrier was only slightly lower (29.1 kcal/mol). Furthermore, the
stereochemical stability was minimally affected under strongly
acidic conditions (28.92 kcal/mol in a 4:1 mixture of EtOH and
0.5M HCl), and was largely unchanged from toluene under
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Scheme 3. Substrate Scope
OH
O
O
3
4
5
6
R3
R1
R3
R1
R3
P
O
O
X
O
H
H
N
H
N
O
R2
O
R2
N
R2
3j
(10 mol %), NXS (1.1 equiv)
Toluene+Hexane, 4 Å MS, 12 h
24 ºC
R1
X
O
3j
O
1(a-aa)
exo 2(a-aa)
endo 2(a-aa)'
7
8
R
R
2
e.r.
%
R
9
2b
2c
2d
2e
2f
Me
i-Pr
t-Bu
OMe
F
96:4
97:3
97:3
97:3
94
95
94
89
2
e.r.
%
R
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
O
O
O
O
O
O
2i
2j
Me
OMe
F
95:5 91
92:8 87
91:9 88
H
N
H
N
H
N
R
R
2k
89:11 84
93:7 87
t-Bu
t-Bu
t-Bu
Br
Br
Br
2g
2h
Cl
89:11 83
CF3
2
e.r.
%
2b
2a
, (2 mmol scale, e.r. = 96:4, 95%)
, G = 30.31 kcal/mol @ 100 °C in toluene
and G = 29.11 kcal/mol @ 80 °C in ethanol
2l
95:5 85
F
O
O
H
O
H
H
N
N
N
F
t-Bu
t-Bu
t-Bu
Br
Br
Br
2l
O
O
O
2
e.r.
%
2
2
e.r.
%
e.r.
%
2o
95:5 95
2m
2n
96:4 90
94:6 93
MeO
S
X
O
O
O
O
O
O
O
H
H
H
N
H
N
N
Cl
N
Cl
X
t-Bu
t-Bu
t-Bu
t-Bu
Br
Br
Br
Br
2
e.r.
%
R
O
2
2
e.r.
%
e.r.
%
2
e.r.
%
2q
85:15 89
O
2t
2p
95:5 86
95:5 91
2s
97:3 92
2r
S
95:5
93
t-Bu
MeO
MeO
O
O
H
N
t-Bu
O
O
O
Br
H
N
H
N
H
N
t-Bu
OMe
OMe
2
e.r.
%
i-Pr
t-Bu
t-Bu
Br
2u
Br
60:40 91
Br
2
e.r.
%
O
O
O
G=30.21 kcal/mol @ 100 °C in toluene
2
e.r.
%
2
e.r.
%
2x
64:36 91
2w
98:2 90
2v
96:4 95
G = 24.21 kcal/mol @ 24 °C in toluene
MeO
O
O
H
O
O
O
O
Me
H
H
N
N
N
OMe
N
t-Bu
CF3
t-Bu
t-Bu
Cl
Br
I
Br
2a
2z
2b
e.r.
87:13 91
G = 29.78 kcal/mol @ 100 °C in toluene
%
e.r.
%
2
e.r.
%
O
O
2
e.r.
%
0
2aa
80:20 93
2y
56:44 87
2ab
--
G = 24.04 kcal/mol @ 24 °C in toluene
G = 30.48 kcal/mol @ 100 °C in toluene
a
1a
e
Reaction conditions: Starting material
(0.054 mmol), Cat.3 (2.5%), Me3PS (2.5%) Toluene:Hexane (1:1) 10 mL and 2 fold 4 Å MS then NCS (0.06 mmol) 24 °C for 12 h .
3j
(0.054 mmol), Cat. (10%) Toluene:Hexane (1:1) 10 mL and 2 fold 4 Å MS then NIS (0.06 mmol) 24 °C for 24 h .
b
1a
Starting material
buffered aqueous conditions (30.56 kcal/mol at pH 7.5 in 1 M tris
buffer). We also measured the barriers for products 2b, 2u, 2z
which possess varying substituent sizes about the chiral axis,
finding the barrier to rotation tracked well with what is expected
with other atropisomeric systems.39 These observed trends are also
in line with what Kawabata observed.
to embed this scaffold into catalysts to give never before explored
chiral environments.
We next studied the ability to modify these products to evaluate
their synthetic utility (Scheme 4). We first found that the anilide
functionality in 2b could be tosylated to give sulfonamide 4 in 63%
yield with no observed racemization. Compound 4, which now
lacks the internal H-bond, proved to exist as a class-2 atropiosmer
with a barrier to rotation of 27.8 kcal/mol, in line with other
literature precedence concerning anilide atropisomers. We also
found that the bromide could be modified via Suzuki cross-
coupling at room temperature using Organ’s PEPPSI-i-Pr catalyst
to afford 5 in 53% yield, also with complete retention of e.r. 95:5.
As aryl substitution is significantly smaller than bromide
Taken together, this data is significant as it suggests that these
compounds would be stereochemically stable under biological
environments; thus, this work could be a gateway towards the
development of atropisomerically stable analogs for the myriad
diarylamines in medicinal chemistry. Moreover, these scaffolds
would be stable under routine reaction conditions, thus it is possible
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substitution39, 5 also existed as a class-2 atropisomer. While 4 and
group away from the catalyst, which would result in this axis being
organized into the (Sa) conformation. Notably, the (Sa)
conformation would also have the potential for the ortho aryl group
to participate in pi-stacking with the catalyst naphthyl group,
whereas the enantiomeric conformation would not. Finally, the
acidic proton from CPA can activate the electrophilic halogenation
reagent via H-bonding which will also allow for direction of
bromination towards the naphthoquinone site. Upon electrophilic
bromination, the axis will be rigidified selectively into the (Sa)
configuration. In support of the importance of the H-bond, a N-
methylated substrate analog (1ab) proved unreactive under our
optimal conditions (scheme 3).
1
2
3
4
5
6
7
8
5 are less stable, they still possess t (1/2) of racemization at 37 oC on
the multi-month timescale. It should be noted that this scaffold
proved recalcitrant to reduction to the hydroquinone (see SI).
Scheme 4. Derivatization of Enantioenriched Products
O
O
O
O
O
S
H
N
N
TsCl, DMAP
DCM, 25 °C
48 h
t-Bu
t-Bu
Br
Br
9
O
4
(
) e.r. = 95:5, 63%
2b
(
) e.r.= 96:4
G = 27.8 kcal/mol @ 100°C in toluene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Proposed transition state with substrate, catalyst
and N-bromophthalimide

O
H
stacking
steric crowding
(HO)2B
OMe
N
Pd-peppsi-i-pr, K3PO4, Dioxane:H2O (3:1)
t-Bu
25 °C, 12 h
O
O
O
P
O
) e.r. = 95:5, 53%
G = 27.65 kcal/mol @ 100 °C in toluene
P
5
(
O
O
H
H
H-Bond
ns
Br
O
O
We next sought out to better understand the unexpected stereo-
chemical stability that was observed. In the X-ray crystal structure
of 2l, the naphthoquinone-N axis is locked into a planar exo
orientation due to the aforementioned intramolecular hydrogen
bonding.
Br
interactio
N
N
interactio
O
O
ns
H-Bond
A) Proposed transition state towards
B) Proposed transition state towards
observed (S)-atropisomer
not observed (R)-atropisomer
We have described the first catalytic atropisomer selective
synthesis of a diarylamine-like scaffold. This chemistry proceeds
via phosphoric acid catalyzed halogenation of N-aryl quinoids and
yields products in upwards of 95:5 e.r. and 90% yield. Surprisingly,
we found these products existed as stereochemically stable class-3
atropisomers in protic and aprotic conditions due to a strong
intramolecular H-bond that locks one of the axes into a planar
conformation. As diarylamines and related scaffolds are among the
most ubiquitous scaffolds in drug discovery, the chemistry,
concepts and principles put forward can extend far beyond this
work and be of use for the design and enantioselective synthesis of
diarylamine surrogates with applications in drug discovery and
asymmetric synthesis.
Scheme 5. Mechanism of Racemization
2a
(exo, Ra)
2a
(endo, Ra)
t-Bu
H
Br
t-Bu
O
H
N
N
Ph
O
Ph
X
Ph
O
Ph
Br
2.87 kcal/mol
O
0 kcal/mol
No
"geari
ng"
Racemization
G = 30.3 kcal/mol
allo
wed
2a
2a
(endo, Sa)
(exo, Sa)
Ph
H
N
Ph
Br
O
H
N
Ph
O
Ph
X
t-Bu
t-Bu
Br
O
ASSOCIATED CONTENT
Supporting Information
O
0 kcal/mol
2.87 kcal/mol
We further explored this by computationally evaluating the
relative energy values of other conformations (Scheme 5). Both
exo, (Ra) and exo, (Sa) conformations (0 kcal/mol) were
significantly lower in energy than their respective endo
conformations that possessed no intramolecular hydrogen bonding
(+2.87 kcal/mol). Previously reported 2 axes systems are able to
undergo concerted “gearing” to racemize, allowing for a lower
energy pathway to racemization (barrier to rotations of 25-27
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, and
characterization data for all new compounds including 1H- and 13C-
NMR spectra, Single-crystal X-ray diffraction, and HPLC traces
(PDF).
AUTHOR INFORMATION
Corresponding Author
kcal/mol with similar sized substituents).
The strong
intramolecular hydrogen bonding likely precludes the gearing
mechanism for racemization, requiring a more rigid pathway to
racemization that is more analogous to biaryl and benzamide
systems. Indeed, computational studies predicted barrier to
rotations that agreed with our experimentally determined values
when freezing the naphthoquinone-N axis; when the system was
allowed to rotate both axes, predicted barriers to rotations were
significantly lower than the experimental values (See SI).
*E-mail: jgustafson@mail.sdsu.edu.
ORCID
Sagar D. Vaidya: 0000-0003-2283-7795
Sean T. Toenjes: 0000-0001-8782-3023
Jeffrey L. Gustafson: 0000-0001-7054-7595
Notes
The authors declare no competing financial interest.
Based on our data thus far, we propose the mechanism for
stereochemical induction depicted in Scheme 6. We postulate the
CPA 3j engages in hydrogen bonding with the substrates O-H-N
network with the substrate locked in the exo conformation. This H-
bonding interaction would be expected to increase the energy level
of the HOMO of the enamine-like amino naphthoquinone. The N-
aryl axis would then be expected to rotate as to orientate the t-Bu
ACKNOWLEDGMENT
We thank Dr. Greg Elliott for assistance with HRMS and Dillan
Stengel for assistance with NMR. This work was funded by
NIGMS (R35GM124637).
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Journal of the American Chemical Society
H.; Wang, J.-Q.; Xiao, J.; Tan, B. Organocatalytic
Atroposelective Construction of Axially Chiral Arylquinones.
Nat. Commun. 2019, 10, 1–10.
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Page 6 of 6
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R1
R2
O
O
H
R3
N
Chiral
Catalyst
S
O
O
H
H
Halogen Source
NXS/NXP
N
Cl
Rapidly Interconverting
t-Bu
Br
86%, e.r = 95:5
8
9
OH
O
O
P
F
O
F
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O
O
H
N
t-Bu
Br
85%, e.r = 95:5
Strong intramolecular hydrogen bonding for high level of stereochemical stability
X = Br/Cl/I, up to 98:2 e.r. G =  29 Kcal/mol in protic solvent
6
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