Enantioselective Synthesis of Biaryl Atropisomers by Pd-Catalyzed C?H Olefination using Chiral Spiro Phosphoric Acid Ligands

Article abstract of DOI:10.1002/anie.201902126

The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C?H activation. Herein, we reported the synthesis of axially chiral biaryls by Pd-catalyzed atroposelective C?H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.

Full text of DOI:10.1002/anie.201902126

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Accepted Article
Title: Enantioselective Synthesis of Biaryl Atropisomers via Pd-
Catalyzed C–H Olefination using Chiral Spiro Phosphoric Acid
Ligands
Authors: Jun Luo, Tao Zhang, Lei Wang, Gang Liao, Qi-Jun Yao,
Yong-Jie Wu, Bei-Bei Zhan, Yu Lan, Xu-Feng Lin, and Bing-
Feng Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902126
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10.1002/anie.201902126
Angewandte Chemie International Edition
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Enantioselective Synthesis of Biaryl Atropisomers via Pd-
Catalyzed C–H Olefination using Chiral Spiro Phosphoric Acid
Ligands
Jun Luo,[a] Tao Zhang,[b] Lei Wang,[a] Gang Liao,[a] Qi-Jun Yao,[a] Yong-Jie Wu,[a] Bei-Bei Zhan,[a] Yu
Lan,*[b] Xu-Feng Lin,*[a] and Bing-Feng Shi*[a]
Abstract: The discovery of proper ligands to simultaneously
modulate the reactivity and effectively control the stereoselectivity is
a central topic in the field of enantioselective C-H activation. Herein,
we reported the synthesis of axially chiral biaryls via Pd-catalyzed
atroposelective C-H olefination. A novel chiral spiro phosphoric acid,
STRIP, was identified as a superior ligand for this transformation. A
broad range of axially chiral quinoline derivatives were synthesized
Figure 1. Importance of Quinoline-Derived Biaryls and Synthetic Challenge.
in good yields with excellent enantioselectivities (up to 98% ee).
Density functional theory was used to gain
a
theoretical
a) Chiral ligands
understanding of the enantioselectivities in this reaction.
[M]
DG
H
DG
FG
*
chiral ligand
Biaryl atropisomers, especially those containing N-
heteroarenes, are prevalent in bioactive active compounds,
pharmaceuticals, and also play an important role in asymmetric
synthesis.[1] For example, the quinoline-based biaryls has been
identified as a HIV integrase inhibitor with special biological
activity.[2] QUINAP,[3a] one of the most useful chiral P,N-ligands,
has widely applications in asymmetric catalysis (Figure 1a).[3]
The development of efficient methods for the asymmetric
construction of axially chiral biaryls has been a long pursuing
goal in organic synthesis.[4] Recently, transition metal-catalyzed
Murai (2000)
You (2014), Yang (2017)
O
H
OMe
PPh2
N
R'
Fe
Pd(OAc)2
[Rh(coe)2]2
HO
R
MPAA
O
(R),(S)-PPFOMe
b) Transient chiral auxiliary
H
cat. Pd(OAc)2
CHO
H
CHO
R
tBu
CO2H
NH2
N
FG
Pd
O
Tle
O
INT
iPr
directed asymmetric ortho-C-H functionalization to lock
a
Chiral spiro phosphoric acids as ligands
iPr
c) This work:
preformed biaryl axis has emerged as a promising synthetic tool
and several elegant strategies have been developed,[5-13]
including: 1) chiral auxiliary-directed diastereoselective C-H
functionalization, which have been well investigated by Wencel-
Delord and Colobert,[6] and Yang;[10a] 2) chiral CpxRh(III)-
catalyzed atroposelective C-H functionalization, with innovative
contributions by the groups of You;[7a,c,8] 3) catalytic asymmetric
C-H functionalization cooperatively catalyzed by transition
metals and chiral ligands.[7b,9,10b,11] Ideally, the final category of
reactions is more appealing but inherently more challenging for
two main reasons. First, competitive background reaction and
racemization under typically elevated reaction temperatures for
C-H activation might lead to significant erosion of
enantioselectivity. Second, the identification of appropriate chiral
ligands that can simultaneously modulate the reactivity and
effectively control the atroposelectivity is extremely difficult.[5c]
iPr
Pd(OAc)2 (10 mol%)
(R)-STRIP
(20 mol%)
O
O
N
N
P
R
OH
O
iPr
H
R
up to 99% yield
up to 98% ee
ligand acceleration
iPr
(R)-STRIP
rac-
1
iPr
Scheme 1. Synthesis of Axially Chiral Biaryls via Directed, Asymmetric C–H
Functionalization Using Catalytic Chiral Ligands.
Therefore, the discovery of proper ligands has been a central
topic in this field, though with limited success.[7b,9,10b,11] In 2000,
the Murai group reported the enantioselective C-H alkylation of
biaryls catalyzed by [Rh(coe)2]2 and
a chiral ferrocenyl
phosphine ligand [(R),(S)-PPFOMe], albeit only one example
with low enantioselectivity (Scheme 1a, up to 49% ee) was
reported.[9] The major breakthrough was made by You (Scheme
1a). In 2014, they achieved the atroposelective C-H iodination
catalyzed by Pd(OAc)2 and mono-protected amino acid
(MPAA),[7b] a catalytic system first reported by Yu and co-
workers[14] and later was recognized as a privileged catalytic
system for enantioselective C-H activation.[5] This catalytic
system was further applied to phosphine oxide directed
atroposelective C-H functionalization by Yang.[5j,10b] Inspired by
Yu’s innovative work,[15] our group reported the high
enantioselective synthesis of axially chiral biaryls via C-H
functionalization of biaryl aldehydes using catalytic Pd(OAc)2
and tert-leucine (up to >99% ee).[11] In this system, tert-leucine
acted as a catalytic, transient chiral auxiliary rather than a chiral
ligand (Scheme 1b, INT). [15,16] This protocol relies on the use of
[a]
J. Luo, L. Wang, G. Liao, Q.-J. Yao, Y.-J. Wu, B.-B. Zhan, Prof. Dr.
X.-F. Lin, Prof. Dr. B.-F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
E-mail: lxfok@zju.edu.cn; bfshi@zju.edu.cn.
Homepage: http://mypage.zju.edu.cn/en/bfshi/.
Tao Zhang, Prof. Dr. Y. Lan
[b]
School of Chemistry and Chemical Engineering, Chongqing Key
Laboratory of Theoretical and Computational Chemistry,
Chongqing University, Chongqing 400030, China
College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou 450001, People’s Republic of China.
E-mail: lanyu@cqu.edu.cn.
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10.1002/anie.201902126
Angewandte Chemie International Edition
COMMUNICATION
aldehyde as DG, thereby is incompatible with quinoline-derived
atropoisomers. Notably, the synthesis of quinoline-derived
atropoisomers itself is much more challenging than their
naphthalene analogues, because the lower conformational
stability resulted from much less steric hindrance of nitrogen
lone pair and therefore prone to racemization (Figure 1b).[7,17]
Herein, we reported the use of spiro phosphoric acids (SPAs) as
chiral anionic ligands to enable the Pd-catalyzed atroposelective
C-H olefination to prepare axially chiral quinoline-derived biaryls.
A novel chiral spiro phosphoric acid, STRIP, was identified as a
superior ligand in atroposelective C-H activation for the first time.
background reaction. Recently, chiral phosphoric acids (CPAs),
a class of strong Brønsted acids,[19] has been recognized as a
novel type of monodentate chiral ligands in enantioselective C-
H activation to create point chirality.[20,21] In particular, CPA
ligands are compatible with strongly coordinating directing
groups,[20a,c,d,e] though have never been shown to be effective in
the creation of axial chirality.
We then set out to test the effect of CPA ligands (Table 1).
Three kinds of CPAs containing different skeletons, namely
SPAs,[22] BINOL-derived phosphoric acids,[19] and H8-BINOL-
derived phosphoric acids, have been investigated. Generally,
SPAs showed better stereocontrol than the analogous
counterparts (entries 1-6 vs entries 7-12 and 13). We
rationalized that the narrow well-defined channel of SPAs could
provide more rigid chiral pocket than their BINOL-derived
counterparts, thereby leading to better steric interaction with the
Table 1. Optimization of reaction conditions.[a]
substrates.[22]
Gratefully,
(R)-STRIP
L1
gave
high
enantioselectivity at 30% yield (entry 1, 93% ee). The use of
1,4-dioxane as solvent led to better enantocontrol (entry 14,
99%), but with dramatically reduced yield (8%). Thus, we
further tested the influence of oxidants and temperature to
increase the reactivity and maintain the stereoselecitvity. A
significant enhancement on the reactivity was observed, when
T
(oC)
t
Yield
(%)[b]
ee
(%)[c]
Entry
Solvent
Oxidant
CPA
o
[h]
AgOAc was used as oxidant at 70 C (entry 17, 83% isolated
yield, 96% ee). Attempts to increase the enantioselectivity by
lowering reaction temperature with prolonged reaction time, led
to erosion of ee (see Table S1), presumably due to the
racemization under the reaction conditions. Reducing the
loading of L1 to 10 mol% gave slightly lower ee (entry 18, 94%).
Other silver carboxylates led to lower yield or ee (entries 19-20
and Table S2).
1
2
DCE
DCE
BQ
BQ
L1
40
40
40
40
40
40
40
40
40
40
40
40
40
40
60
80
20
20
20
20
20
20
20
20
20
20
20
20
20
20
60
24
30
15
17
18
10
23
23
10
24
24
18
34
16
8
93
43
L2
3
DCE
BQ
L3
-23
40
4
DCE
BQ
L4
5
DCE
BQ
L5
77
6
DCE
BQ
L6
60
7
DCE
BQ
L16
L17
L18
L19
L20
L21
L28
L1
-86
-40
-13
-28
-40
-42
-47
99
8
DCE
BQ
9
DCE
BQ
Table 2. Scope of Pd-catalyzed atroposelective C‒H olefination.[a]
10
11
12
13
14
15
16
DCE
BQ
5
4
DCE
BQ
6
7
3
2
Pd(OAc)2 (10 mol%)
(R)-STRIP
Ar1
Ar1
8
DCE
BQ
(20 mol%)
2 equiv AgOAc
1
N
N
DCE
BQ
R
R
1,4-dioxane, 70 oC, 24 h
H
6'
2'
1,4-dioxane
1,4-dioxane
1,4-dioxane
BQ
2
Ar2
Ar2
BQ
L1
13
93
90
(83)[d]
87
97
3 4
/
(S)-
1
rac-
AgOAc
L1
93
a) Scope of Quinoline-Derived Biaryls
F
17
18[e]
19
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
AgOAc
L1
L1
L1
L1
70
70
70
70
24
24
24
24
96
94
92
98
N
N
Me
CO2nBu
CO2nBu
AgOAc
AdCO2A
g
R
N
R
CO2nBu
R
89
45
i
3j
(S)- : R = Me, 99%, 90% ee
3a
(S)- : R = Pr, 83%, 96% ee
3k
(S)- : R = CF3, 32%, 95% ee
20
Ag2CO3
3b
(S)- : R = Et, 83%, 91% ee
3g
(S)- : R = Et, 77%, 96% ee
3c
(S)- : R = Me, 79%, 82% ee
[a] Reaction conditions: 1a (0.05 mmol), 2a (0.1 mmol), Pd(OAc)2 (10 mol%),
CPA (20 mol%), BQ (1.0 equiv)/AgOAc (2.0 equiv), solvent (0.5 mL) under air.
[b] Determined by 1H NMR using dibromomethane as the internal standard. [c]
The ee value was determined by HPLC. [d] Isolated yield. [e] L1 (10 mol%).
BQ = 1,4-benzoquinone, DCE = 1,2-dichloroethane.
i
3h
(S)- : R = Pr, 74%, 98% ee
t
3d
(S)- : R = Bu, 70%, 97% ee
t
MeO
Me
N
3i
(S)- : R = Bu, 44%, 98% ee
3e
(S)- : R = Cy, 87%, 97% ee
CO2nBu
3f
(S)- : R = CF3, 38%, 93% ee
3l
(S)- 96%, 85% ee
MeO
N
CO2nBu
N
Considering that most Pd-catalyzed C-H activation is
proposed to occur through a carboxylate-assisted concerted
metalation-deprotonation (CMD) mechanism, in which the
presence of carboxylic acid might enhance the reactivity.[18]
Therefore, the use of chiral carboxylate or related anionic
ligands to enable the Pd(II)-catalyzed enantioselective C-H
activation has been realized.[5,14,20] The Yu group pioneeringly
CO2nBu
3m
3n
(S)-
74%, 82% ee
(S)- 66%, 82% ee
b) Scope of Olefins
4f
(S)- : R = p-CF3, 91%, 94% ee
4g
(S)- : R = m-Cl, 99%, 96% ee
4h
(S)- : R = p-Cl, 99%, 94% ee
4i
(S)- : R = p-F, 87%, 93% ee
N
N
R
CO2R
reported
the
Pd(II)-catalyzed
enantioselective
C-H
4j
(S)- : R = m-F, 98%, 95% ee
4k
functionalization using bidentate MPAA ligands,[5,14] which was
later adopted to the biaryl systems by You and Yang.[7b,10b]
Unfortunately, extensive screening of various MPAA ligands only
led to poor enantioselectivity (<3% ee). These results stimulated
us to explore new types of ligands that could significantly
accelerate the reaction to outcompete the quinoline-directed
(S)- : R = p-OAc, 89%, 97% ee
4a
(S)- : R =Me, 75%, 94% ee
4b
(S)- : R = Et, 83%, 95% ee
4c
(S)- : R = TFE, 53%, 85% ee
4d
(S)- : R = Bn, 51%, 95% ee
t
4e
(S)- : R = Bu, 81%, 96% ee
4k
4i
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[a] Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Pd(OAc)2 (0.01 mmol),
CPA (0.02 mmol), AgOAc (0.2 mmol) in 1.4-dioxane (1 mL) at 70 oC for 24 h
under air. Isolated yield.
distance between H1 and H2 atoms is 2.59 Å, which indicates
less steric interaction between quinolone group and isopropyl
group on C5 position. On the other hand, in geometry of
transition state Spinol-ts-R, the distance of H1...H2 and H3…H4
are 2.63 and 2.73 Å, which reveals a significant steric repulsion
between quinoline and two isopropyl groups (C5 and C6
position). As such, the S-configuration phenylacrylate is the
major product. These computational observations suggest that
the enantioselective is determined by the CMD type C-H bond
cleavage step. An 97% of ee value is predicted by theoretical
calculation based on the energy difference between transition
states Spinol-ts-S and Spinol-ts-R, which is in good agreement
with the experimental result, where the S-configuration
phenylacrylate is formed preferentially (ee = 96%, in Table 2).
With the optimal conditions in hand, we set out to explore the
scope of this transformation (Table 2). In general, a range of
quinoline-derived biaryls with different substituents were
amenable to this strategy. The reaction is sensitive to steric
hindrance in the 2’-position and with the increasing bulk from Me
t
to Bu, the enantioselectivities were improved (3c, R = Me, 82%
i
t
ee; 3b, R = Et, 91% ee; 3a, R = Pr, 96% ee; 3d, R = Bu, 97%
ee). Substrates bearing electron-deficient substituents were
generally less reactive than electron-rich ones (3f, 2’-CF3, 38%
yield vs 3a-3e, 2’-alkyl, 70-87% yield; 3k, 3’-CF3, 32% vs 3j, 3’-
Me, 99% yield); while the enantioselectivity were independent on
the electronic effect. The generality of olefins was also
investigated (Table 2b). Various acrylates were compatible with
this reaction, giving the desired products in good yields and
enantioselectivities (4a-4e). This atroposelective olefination was
also suitable for styrenes with various substituents (4f-4k).
Halogens (F, Cl) on the aryl ring proceeded smoothly to afford
the desired products in high yields (87-99%) with high
enantioselectivity (4g-4j, 93-97% ee). The absolute configuration
of products 3n, 4i and 4k was determined as Sa by X-ray
crystallographic analysis and those of the others were assigned
by analogy.[23]
(a)
Small repulsion
iPr
H2
H1
O
O
O
P
N
iPr
O
C1
Pd
H
iPr
C2
C3
iPr
C4
O
O
iPr
Spinol-ts-S
BH1-H2 = 2.59
G= 17.5 Kcal/mol
(Favored)
DC1-C2-C3-C4 = 57.4
ee: 96% (exp.)
ee: 97% (calc.)
(b)
Large repulsion
H3
iPr
H4
H1
H2
O
O
iPr
C1
C2
iPr
N
O
P
Pd
H
O
C3
O
iPr
O
C4
iPr
Spinol-ts-R
G= 20.5 Kcal/mol
A number of experiments were conducted to shed light into
the mechanism. First, on the basis of initial rate kinetics, the KIE
values of 4.93 (without L1) and 5.63 (with L1) was obtained
respectively (eq 1), indicating that the cleavage of C-H bond is
the turnover-limiting step. The dependence of isotope effect on
L1 also suggests a unique ligand effect. This was supported by
a significant ligand acceleration, where initial rate with L1 was
faster than ligandless conditions (Figure S3, krel 4.39). Next, a
linear correlation between the ee value of 3a and L1 was
observed (Figure S4), indicating that a single SPA ligand is
involved in the stereodetermining step.[15]
BH1-H2 = 2.63
BH3-H4 = 2.73
(Disfavored)
DC1-C2-C3-C4 = -57.4
Figure 2. One scenario for C−H cleavage via CMD pathway.
Due to the importance of tetrahydroquinoline derivatives in
numerous bioactive natural products and pharmaceuticals,[17] the
reduction of the resulting axially chiral quinolines was conducted.
We were pleased to find tetrahydroquinoline (S)-5 was obtained
in 98% yield with complete retention of chirality (eq 2).
To better illustrate the origin of enantioselectivity in C-H
olefination, we briefly investigated this new system with the
density functional theory (DFT) method M11-L (see supporting
information for details). Both of acetate and phosphate are
considered as either counterion or base for concerted
metalation-deprotonation (CMD). The computational results
showed that in the presence of chiral phosphate as counterion to
stabilize Pd, acetate plays as base to conduct CMD type C-H
activation. [24,25]
As shown in Figure 2, two possible CMD type transition states
Spinol-ts-S and Spinol-ts-R are located in the C-H bond
cleavage step. The S-configuration product could afford through
transition state Spinol-ts-S with an energy barrier of 17.5
kcal/mol. Alternatively, the R-configuration product would be
formed through transition state Spinol-ts-R with an energy
barrier of 20.5 kcal/mol, the relative free energy of which is 3.0
kcal/mol higher than that of Spinol-ts-S. The geometry
information of transition state Spinol-ts-S shows that the
In summary, we have developed a Pd(II)/STRIP catalytic
system to enable the synthesis of axially chiral quinoline
atropoisomers via enantioselective C-H olefination, which
expanding the existing systems of catalytic atroposelective C-H
functionalizations. Furthermore, SPA is one of the most widely
used chiral ligands in asymmetric synthesis, which means this
strategy might offer a practical and promising opportunity and
fills a major methodology gap.
Acknowledgements
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10.1002/anie.201902126
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COMMUNICATION
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Financial support from the NSFC (21772170, 21572201,
21822303, 21772020), the National Basic Research Program of
China (2015CB856600), the Fundamental Research Funds for
the Central Universities (2018XZZX001-02) and Zhejiang
Provincial NSFC (LR17B020001) is gratefully acknowledged.
We thank Prof. Yong-Gui Zhou from Dalian Institute of Chemical
Physics for providing several substrates.
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Keywords: palladium • C-H olefination • chiral spiro phosphoric
acids • atroposelectivity • quinoline biaryls
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This article is protected by copyright. All rights reserved.

10.1002/anie.201902126
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
iPr
Jun Luo, Tao Zhang, Lei Wang, Gang
Liao, Qi-Jun Yao, Yong-Jie Wu, Bei-Bei
Zhan, Yu Lan,* Xu-Feng Lin,* and Bing-
Feng Shi*
Pd(OAc)2 (10 mol%)
O
(R)-STRIP
(20 mol%)
N
O
iPr
N
H
O
P
R
N
R
O
Pd
iPr
iPr
H
O
up to 99% yield
up to 98% ee
ligand acceleration
O
iPr
1
rac-
Page No. – Page No.
via
Enantioselective Synthesis of Biaryl
Atropisomers via Pd-Catalyzed C–H
The discovery of proper ligands to simultaneously modulate the reactivity and
effectively control the stereoselectivity is central topic in the field of
a
Olefination
using
Chiral
Spiro
enantioselective C-H activation. Herein, we reported the synthesis of axially chiral
biaryls via Pd-catalyzed atroposelective C-H olefination. A novel chiral spiro
phosphoric acid, STRIP, was identified as a superior ligand for this transformation.
A broad range of axially chiral quinoline derivatives were synthesized in good
yields with excellent enantioselectivities (up to 98% ee). Density functional theory
was used to gain a theoretical understanding of the enantioselectivities in this
reaction.
Phosphoric Acid Ligands
This article is protected by copyright. All rights reserved.