Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C?H Olefination Enabled by an Amino Amide Transient Directing Group

Article abstract of DOI:10.1002/anie.201915949

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd

Full text of DOI:10.1002/anie.201915949

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Accepted Article
Title: Synthesis of Axially Chiral Styrenes via Pd-Catalyzed Asymmetric
C-H Olefination Enabled by an Amino Amide Transient Directing
Group
Authors: Hong Song, Ya Li, Qi-Jun Yao, Liang Jin, Lei Liu, Yan-Hua
Liu, and Bing-Feng Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915949
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10.1002/anie.201915949
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Axially Chiral Styrenes via Pd-Catalyzed Asymmetric
C-H Olefination Enabled by an Amino Amide Transient Directing
Group
Hong Song, Ya Li, Qi-Jun Yao, Liang Jin, Lei Liu, Yan-Hua Liu and Bing-Feng Shi*
Abstract: The atroposelective synthesis of axially chiral styrenes
remains a formidable challenge, due to their relatively lower rotational
barriers compared to the biaryl atropoisomers. Herein, we describe
the construction of axially chiral styrenes by Pd(II)-catalyzed
atroposelective C–H olefination, using a bulky amino amide as
transient chiral auxiliary. Various axially chiral styrenes were
produced with good yields and high enantioselectivities (up to 95%
yield and 99% ee). The resulting axially chiral styrenes derivatized
chiral carboxylic acids showed superior enantiocontrol over the biaryl
counterparts in Co(III)-catalyzed enantioselective C(sp3)-H amidation
of thioamide. Mechanistic studies suggest that C-H cleavage is the
enantioselectivity-determining step.
(TCA) enabled C-H functionalization strategy,[11] we recently
reported the highly atroposelective construction of biaryl
atropoisomers using tert-leucine (Tle) as TCA.[12] As part of our
ongoing efforts in asymmetric C−H functionalization,[12,13] we had
great interests in constructing axially chiral styrenes via TCA
strategy. We assumed that the enantiocontrolled introduction of a
large substituent at the ortho-position of properly designed 2-
arylacrylaledhydes to lock the preformed axis through TCA
enabled C-H activation would be an attractive synthetic approach.
Although this strategy sounds promising, the adoption of
atroposelective C-H functionalization to styrene atropoisomers is
not straightforward, due to the following daunting challenges: (1)
unlike organocatalytic synthesis that generally conducted at room
temperature or below, C-H activation usually occurs at relatively
high temperature, which might lead to poor enantiocontrol and
significantly loss of chirality due to the low atropo-stability of
styrene atropoisomers. (2) acrylaldehydes contain multiple
reactive sites and are prone to undergo several undesired
reactions, such as oxidation, Michael addition, and/or
isomerization. We now describe our efforts that overcome those
challenges and prepare axially chiral styrenes with an open-
chained alkene through a Pd-catalyzed atroposelective C−H
olefination using a bulky amino amide as transient auxiliary
(Scheme 1b).
Axially chiral styrenes, a class of atropoisomers arising from the
sterically hindered rotation along a single bond between a
substituted alkene and an aromatic ring, was first studied by
Adams and co-workers in the 1940s.[1] This novel type of
atropoisomers have been overlooked for a long time and received
attentions only recently. These atropoisomers have been used as
versatile synthons in total synthesis[2] and as chiral ligands in
asymmetric catalysis.[3] Consequently, the development of novel
strategies for the atroposelective synthesis of these skeletons has
been a central topic in organic synthesis. However, in sharp
contrast to the well-established approaches for the asymmetric
synthesis of axially chiral biaryls,[4] methods to the
enantioselective synthesis of axially chiral styrenes remains rare
(Scheme 1a).[5] Early studies focused on the use of stoichiometric
chiral compounds with point chirality via point-to-axial chirality
transfer strategy.[2,6] Catalytic asymmetric synthesis is more
attractive but also more challenging. Gu[7] and Smith[8] reported
the highly enantioselective construction of axially chiral
arylcyclohexenes, a kind of styrene atropoisomers with the alkene
unit trapped within a rigid hexacycle to maintain a comparable
stability with that of biaryls. Due to the flexible structure and
relatively lower conformational stability, the asymmetric synthesis
of chiral styrene with an acyclic alkene is more challenging. To
date, the only strategy for its efficient synthesis is asymmetric
organocatalytic addition developed by the Tan and Yan groups
recently.[9] The mild reaction conditions generally used in
organocatalytic synthesis (at or below room temperature) ensure
the high enantiocontrol in the transition state and the maintenance
of the chirality of the resulting styrene atropoisomers.
Scheme 1. Challenges of synthesis of axially chiral styrenes, previous
approaches and our strategy.
Recently, asymmetric C-H functionalization has emerged as a
powerful synthetic approach for the rapid access of axially chiral
biaryls.[4f,h,10] Inspired by the pioneering work by Yu on the
construction of central chirality through transient chiral auxiliary
To verify the feasibility of our assumption, we initiated our
investigations by investigating the reaction of rac-1a and butyl
acrylate (2a). The desired product 3aa was obtained in 91% yield
and 95% ee when using 10 mol% Pd(OAc)2, 1.0 equivalent of BQ,
1.0 equivalent of Co(OAc)2·4H2O, 0.5 equivalent of (BnO)2PO2H and
[*]
H. Song, Y. Li, Q.-J. Yao, L. Jin, L. Liu, Y.-H. Liu, Prof. Dr. B.-F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
0.3 equivalent of TCA-1 in HOAc/DMSO at 40o
C for 48 hours under
O2 atmosphere (Table 1, entry 1, standard conditions). Control
experiments showed that no olefination product was observed in the
absence of the palladium catalyst (entry 2). The use of tert-leucine
E-mail: bfshi@zju.edu.cn.
Homepage: http://mypage.zju.edu.cn/en/bfshi/.
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10.1002/anie.201915949
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(TCA-8) instead of TCA-1 led to reduced yield and enantioselectivity
(entry 3, 39%, 80% ee). In 2018, Yu and co-workers developed a
bulky amino amide transient auxiliary to control the stereochemistry
of the C(sp3)-H activation.[11b] Inspired by this pionnering work, a
number of α-amino acids derived amides were screened (Tables S3
and S7) and we were delighted to find that tert-leucine-derived amino
amide TCA-1 was the optimal one. Control experiments on the effect
of other additives were tested (entries 4-12). The choices of oxidants
and solvents were crucial for this reaction. The removal of BQ resulted
in significantly reduced yield (entry 4). Only trace product was
observed in the absence of DMSO (entry 6), which might act as ligand
to stabilize the palladium catalyst. (BnO)2PO2H was also an important
additive to better tune the acidity of the reaction system.
Co(OAc)2·4H2O was found to promote the reaction (entry 8), probably
acting as a co-oxidant. The reaction proceeded more effectively under
O2 atmosphere (entry 9).
donating groups on the phenyl ring also gave good to excellent
enantioselectivity (3ha, p-Me; 3ia, o-OMe; 3ja, R = p-NMe2).
acrylaldehydes with alkyl substituents were compatible with the
protocol, albeit with relatively lower yield, and sterically bulky
substituents gave higher enantioselectivity as expected (3ka, tBu,
33%, 99% ee; 3la, Me, 10%, 92% ee). (3ka, up to 99% ee). The
absolute configuration of product 3ac was determined by the X-
ray analysis and those of the other products were assigned by
analogy.[15]
Table 2. Scope of acrylaldehydes.[a]
Table 1. Optimization of reaction conditions.[a]
Deviation from standard
Entry
Yield(%)[b]
ee(%)[c]
conditions
none
1
2
3
4
5
6
7
8
9
91
0
95
-
no Pd(OAc)2
tert-leucine instead of TCA-1
no BQ
39
80
90
85
82
87
82
89
58
add BQ (30 mol%)
no DMSO
51
trace
89
no (BnO)2PO2H
no Co(OAc)2·4H2O
air instead of O2
HOAc:MeOH:DMSO (7:3:1)
instead of HOAc:DMSO (10:1)
64
85
[a] rac-1 (0.1 mmol), 2a (4.0 equiv), Pd(OAc)2 (0.1 equiv), TCA-1 (0.3 equiv),
BQ (1 equiv), Co(OAc)2·4H2O (1 equiv), (BnO)2PO2H (0.5 equiv) in
HOAc/DMSO (10:1, v/v,1.1 mL) under O2 for 48 h, isolated yield. [b] 96 h.
10
41
92
[a] Standard conditions: rac-1a (0.1 mmol), 2a (4.0 equiv), Pd(OAc)2 (0.1 equiv),
TCA-1 (0.3 equiv), BQ (1 equiv), Co(OAc)2·4H2O (1 equiv), (BnO)2PO2H (0.5
equiv) in HOAc/DMSO (10:1, v/v,1.1 mL) under O2 for 48 h. [b] Determined by
1H NMR spectroscopy using tetrachloroethane as the internal standard. [c] The
ee value was determined by HPLC. DMSO = dimethyl sulfoxide, TCA=transient
chiral auxiliary
Table 3. Scope of Olefins.[a]
With the optimal reaction conditions in hand, we explored the
generality of the atroposelective C-H olefination. The scope of
acrylaldehydes was first examined (Table 2). Generally, sterically
bulkyl substituents positioned ortho to the chiral axis were
necessary to ensure enantioselectivity (3da, R = iPr, 96% ee; 3ea,
R = Me, 73% ee). Cinnamaldehyde 1g bearing ortho-butoxyl
group led to 3ga with no axial chirality. To explain these results,
density functional theory (DFT) calculations were performed to
investigate the atropostability of several representative products.
There appeared a noteworthy trend that the cinnamaldehyde
derivatives bearing relatively larger substituent have significantly
higher rotational barriers compared with the smaller substituent
(3da, R = iPr, ∆G‡ = 31.4 kcal/mol; 3ea, R = Me, ∆G‡ = 29.6
kcal/mol; 3ga, R = nBuO, ∆G‡ = 22.4 kcal/mol).[14] This effect is an
interesting addition to the general consensus that the steric
bulkiness of the ortho-substituents of styrenes compounds is the
leading factor that controls the rotational barrier. These results
also proved that the formation of 3ga as racemate is due to the
lack of atropostability under the reaction conditions or even at
temperature (t1/2= 6.1 minutes at 40 oC; t1/2 = 37.5 minutes at 25
oC, see SI for details). Cinnamaldehyde derivatives with electron-
[a] rac-1d (0.1 mmol), 2 (4.0 equiv), Pd(OAc)2 (0.1 equiv), TCA-1 (0.3 equiv),BQ
(1 equiv), Co(OAc)2·4H2O (1 equiv), (BnO)2PO2H (0.5 equiv) in HOAc/DMSO
(10:1, v/v,1.1 mL) under O2 for 48 h, isolated yield. [b] 2 (2.0 equiv).
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Next, cinnamaldehyde derivative (rac-1d) bearing relatively
larger substituent (iPr) was used to test the generality of olefins
(Table 3). To our delight, various olefins, such acrylates,
alkenylphosphate, phenylsulphate, and styrenes, were
compatible with our optimal conditions and the corresponding
axially chiral products
were obtained in excellent
atroposelectivities (94-99% ee). Moreover, aliphatic olefin 2h was
also compatible, giving 3dh with high enantioselectivity, albeit
with lower isolated yield (28%, 98% ee). Moreover, natural
product-derived acrylates were also efficient coupling partners
(3dl-3do), which might found potential application in
pharmaceuticals. Styrenes with electron-withdrawing substituents,
such as fluoro and chloro, could also give good yields and
excellent atroposelectivities (3dj and 3dk).
To demonstrate the practicality of our strategy, gram-scale
synthesis and transformations have been conducted (Scheme 2).
First, the reaction of rac-1d and 2b on a 5 mmol scale was
performed, and the desired product 3db was isolated with
retentive enantioselectivity (84%, 98% ee, 1.46 g). Subsequently,
a series of transformations of axially chiral styrene 3db were
demonstrated. 3db could be oxidized to carboxylic acid 4 and
selectively reduced to form alcohol 5 under mild conditions
without the loss of enantioselectivity. Ester hydrolysis also gave
carboxylic acid 6 without significant change of atroposelectivity.
Scheme 3. Application as chiral ligand in Co(III)-catalyzed enantioselective
C(sp3)-H amidation of thioamide.
To shed light on the reaction mechanism, stoichiometric
reaction of the pre-formed imine 10 and Pd(OAc)2 was performed
in AcOD-d1 at 40 oC and palladacycle intermediate 11 was
isolated after chromatography.[11b] The structure of 11 was
confirmed by single-crystal X-ray diffraction, which has the same
stereochemistry as 3ba.[15] The reaction of 1b and 2a using
intermediate 11 as catalyst led to 3ba in good yield and slightly
reduced enantioselectivity (Scheme 4). Furthermore, a KIE value
of 2.3 was observed (see SI for details). These results suggested
that C-H cleavage is both the enantioselectivity- and rate-
determining step. The reaction of rac-1d in AcOD-d1 with
omission of butyl acrylate for 24 h led to 25% deuteration of the
recovered starting material, indicating the C-H activation step is
reversible.
Scheme 2. Gram-scale synthesis and transformation of 3db.
To demonstrate the significance of the axially chiral
atropoisomers, the use as chiral ligands in asymmetric synthesis
was shown Scheme 3. Recently, the Matsunaga group reported
the enantioselective C(sp3)–H amidation of thioamides catalysed
by a Co(III)/chiral carboxylic acid (CCA) hybrid system.[16] They
have elegantly demonstrated that both bulky α-amino acid
bearing a central chirality[16a] and 2-aryl ferrocene carboxylic acids
with planar chirality[16b] are suitable chiral ligands for this reaction.
the target product 9 was obtained in good yield and moderate
enantioselectivity (73%, 82:18 er). To expanding the scope of
CCA-enabled enantioselective C-H activation reactions,[13d,17,18]
we aimed to further develop proper CCAs with axial chirality.
Although axially chiral biaryl-type CCAs (L1-L4) gave poor
enantiocontrol (48:52 to 29:71 er), the newly developed axially
chiral styrene-type CCA 4dl gave better enantioselectivity (82:18
er), indicating that the novel styrene atropisomers might open up
a new door in asymmetric synthesis.
Scheme 4. Mechanistic studies.
In summary, we have developed an efficient and practical
method to construct a new class of axially chiral styrenes by Pd-
catalyzed atroposelective C-H olefination. This method employs
a bulky amino amide as transient chiral auxiliary. We hope that
strategy would provide new chance to construct axially chiral
styrene skeletons, which might be a class of promising axially
chiral ligands/catalysts in asymmetric synthesis.
Acknowledgements
Financial support from the NSFC (21772170, 21925109,
21822303, 21772020), Outstanding Young Talents of Zhejiang
Province High-level Personnel of Special Support (ZJWR0108),
the Fundamental Research Funds for the Central Universities
(2018XZZX001-02)
and
Zhejiang
Provincial
NSFC
(LR17B020001) is gratefully acknowledged.
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10.1002/anie.201915949
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Keywords: C-H olefination • palladium • transient directing
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Centre.
group • axially chiral styrenes
· atroposelectivity •
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Hong Song, Ya Li ,Qi-Jun Yao, Liang Jin,
Lei Liu, Yan-Hua Liu and Bing-Feng Shi*
Page No. – Page No.
Synthesis of Axially Chiral Styrenes via
Pd-Catalyzed
Olefination Enabled by an Amino Amide
Transient Directing Group
Asymmetric
C-H
The atroposelective synthesis of axially chiral styrenes remains a formidable
challenge, due to their relatively lower rotational barriers compared to the biaryl
atropoisomers. Herein, we describe the construction of axially chiral styrenes by
Pd(II)-catalyzed atroposelective C–H olefination, using a bulky amino amide as
transient chiral auxiliary. Various axially chiral styrenes were produced with good
yields and high enantioselectivities (up to 95% yield and 99% ee). The resulting
axially chiral styrenes derivatized chiral carboxylic acids showed superior
enantiocontrol over the biaryl counterparts in Co(III)-catalyzed enantioselective
C(sp3)-H amidation of ferrocenes. Mechanistic studies suggest that C-H cleavage is
the enantioselectivity-determining step.
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