Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric C–H Functionalization Strategy

Article abstract of DOI:10.1016/j.chempr.2019.12.011

Axially chiral styrenes, which exhibit a chiral axis between a substituted alkene and an aromatic ring, have been largely overlooked. The hurdle is the lower barriers to rotation compared with that of their biaryl counterparts, rendering their asymmetric synthesis more difficult. We report herein the highly atroposelective synthesis via a C?H functionalization strategy of axially chiral styrenes with an open-chained alkene. Various axially chiral styrenes were produced by Pd(II)-catalyzed C?H alkenylation and alkynylation in good yields (up to 99%) and enantioselectivities (up to 99% ee) by using L-pyroglutamic acid as an inexpensive chiral ligand. The potent application of the styrene atropisomers is demonstrated by a Co(III)-catalyzed enantioselective C?H amidation of ferrocene with axially chiral styrene-type acid as chiral ligand. Experimental and computational studies were conducted to elucidate the reaction mechanism. The chiral induction model of the enantioselectivity-determining C?H bond activation step was also provided based on DFT calculations. Atropisomerism, which stems from the hindered rotation around a chiral axis, is widely present in natural products, pharmaceuticals, and chiral catalysts or ligands. In contrast to the well-investigated biaryl atropisomers, the asymmetric synthesis of axially chiral styrenes bearing a chiral axis between an alkene and an aromatic ring remains a significant challenge. Here, we report a highly atroposelective synthesis of styrene atropisomers with open-chained alkene by asymmetric C?H functionalization by using available L-pyroglutamic acid as a chiral ligand. This strategy enables rapid access to a broad range of enantio-enriched axially chiral styrenes under mild conditions in an atom- and step-economical manner. The resulting axially chiral styrenes are important precursors for further elaborations, including the transformation into axially chiral styrene-type acids, which were demonstrated to be efficient chiral ligands in Co(III)-catalyzed enantioselective C?H amidation reactions. An asymmetric C–H functionalization strategy with L-pGlu-OH as chiral ligand has been developed for the atroposelective synthesis of styrene atropisomers with open-chained alkene. The strategy allows quick access to a wide range of enantio-enriched axially chiral styrenes in high yields and enantioselectivities. The axially chiral styrene-derived chiral acids have been demonstrated to be an efficient type of chiral ligands in Co(III)-catalyzed enantioselective C?H amidation reactions.

Full text of DOI:10.1016/j.chempr.2019.12.011

Article
Atroposelective Synthesis of Axially Chiral
Styrenes via an Asymmetric C–H
Functionalization Strategy
Liang Jin, Qi-Jun Yao, Pei-Pei
Xie, ..., Ye-Qiang Han, Xin Hong,
Bing-Feng Shi
hxchem@zju.edu.cn (X.H.)
bfshi@zju.edu.cn (B.-F.S.)
HIGHLIGHTS
Highly atroposelective synthesis
of axially chiral styrenes
L-pyroglutamic acid as an
inexpensive and catalytic chiral
ligand
Chiral styrene-type acid as ligand
in Co-catalyzed enantioselective
C–H amidation
A ligand deceleration effect (LDE)
in this reaction
An asymmetric C–H functionalization strategy with L-pGlu-OH as chiral ligand has
been developed for the atroposelective synthesis of styrene atropisomers with
open-chained alkene. The strategy allows quick access to a wide range of enantio-
enriched axially chiral styrenes in high yields and enantioselectivities. The axially
chiral styrene-derived chiral acids have been demonstrated to be an efficient type
of chiral ligands in Co(III)-catalyzed enantioselective CÀH amidation reactions.
Jin et al., Chem 6, 1–15
February 13, 2020 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.12.011

Please cite this article in press as: Jin et al., Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric C–H Functionalization Strategy,
Chem (2019), https://doi.org/10.1016/j.chempr.2019.12.011
Article
Atroposelective Synthesis of Axially
Chiral Styrenes via an Asymmetric C–H
Functionalization Strategy
Liang Jin,1,2 Qi-Jun Yao,1,2 Pei-Pei Xie,1,2 Ya Li,1 Bei-Bei Zhan,1 Ye-Qiang Han,1 Xin Hong,1,
*
and Bing-Feng Shi1,3,
*
SUMMARY
The Bigger Picture
Atropisomerism, which stems
from the hindered rotation around
a chiral axis, is widely present in
natural products,
Axially chiral styrenes, which exhibit a chiral axis between a substituted alkene
and an aromatic ring, have been largely overlooked. The hurdle is the lower bar-
riers to rotation compared with that of their biaryl counterparts, rendering their
asymmetric synthesis more difficult. We report herein the highly atroposelec-
tive synthesis via a CꢀH functionalization strategy of axially chiral styrenes
with an open-chained alkene. Various axially chiral styrenes were produced by
Pd(II)-catalyzed CꢀH alkenylation and alkynylation in good yields (up to 99%)
and enantioselectivities (up to 99% ee) by using L-pyroglutamic acid as an inex-
pensive chiral ligand. The potent application of the styrene atropisomers is
demonstrated by a Co(III)-catalyzed enantioselective CꢀH amidation of ferro-
cene with axially chiral styrene-type acid as chiral ligand. Experimental and
computational studies were conducted to elucidate the reaction mechanism.
The chiral induction model of the enantioselectivity-determining CꢀH bond acti-
vation step was also provided based on DFT calculations.
pharmaceuticals, and chiral
catalysts or ligands. In contrast to
the well-investigated biaryl
atropisomers, the asymmetric
synthesis of axially chiral styrenes
bearing a chiral axis between an
alkene and an aromatic ring
remains a significant challenge.
Here, we report a highly
atroposelective synthesis of
styrene atropisomers with open-
chained alkene by asymmetric
C‒H functionalization by using
available L-pyroglutamic acid as a
chiral ligand. This strategy
INTRODUCTION
Axially chiral compounds are ubiquitous in natural products and pharmaceuticals1,2
and have been widely used as versatile chiral ligands or catalysts in asymmetric syn-
thesis.3–8 In distinct contrast to the well-investigated axially chiral biaryls,9–14 axially
chiral styrenes, which exhibit a chiral axis between a substituted alkene and an aro-
matic ring have been largely overlooked,15 despite the fact that this type of axial
chirality was realized and intensively studied by Adams and co-workers in the
1940s.16 The main hurdle is basically due to the flexible structure, which results in
relatively lower barriers to rotation in comparison with their biaryl counterparts,
rendering their asymmetric synthesis drastically more difficult (Scheme 1A).15,16
On the other hand, axially chiral styrenes have flourished gradually, as chiral olefins
can not only be employed as synthons for total synthesis17 but also can be applied to
asymmetric synthesis as chiral catalysts or ligands.18–20 Consequently, considerable
efforts have been devoted to the development of efficient strategies for the asym-
metric synthesis of the axially chiral styrene skeletons. In the early efforts, point-to-
axial chirality transfer strategy has been reported by Baker,21 Hattori and Miyano,22
and Suzuki,17 employing stoichiometric chiral molecules with point chirality.
Recently, more appealing catalytic asymmetric synthesis were achieved by the
groups of Gu23,24 and Smith.25 However, the scope of chiral styrenes were limited
to arylcyclohexenes with the alkene skeleton trapped within a rigid ring to mimic
the rigidity of biaryls and ensure the conformational stability. The situation becomes
significantly more difficult when the targeted chiral styrene contains a chiral axis
enables rapid access to a broad
range of enantio-enriched axially
chiral styrenes under mild
conditions in an atom- and step-
economical manner. The resulting
axially chiral styrenes are
important precursors for further
elaborations, including the
transformation into axially chiral
styrene-type acids, which were
demonstrated to be efficient
chiral ligands in Co(III)-catalyzed
enantioselective CꢀH amidation
reactions.
Chem 6, 1–15, February 13, 2020 ª 2019 Elsevier Inc.
1

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A
Challenges of Synthesis of Axially Chiral Styrenes with an Acyclic Alkenes
X
more flexible
X
Y
Y
conformationally less stable
axially chiral biaryls
axially chiral styrenes
well investigated
less explored
B
Previous Strategy: Asymmetric Organocatalytic Addition
Tan's Approach
CHO
Ar
N
Nu
Ar
OTIPS
CHO
R
N
H
·
Nu
H
R
R
Nu-H
Nu =
EWG
R
EWG
54-95% ee
Yan's Approach
H
RSO2
Ar
Ar
H
SO2R
OH
quinine-derived
thiourea
Ar
·
O
L-proline
RSO2Na
OH
E/Z > 99:1, 91-99% ee
C
Our Strategy: Asymmetric C-H Functionalization
O
O
DG
DG
DG
N
FG
Pd(II)/L*
Pd
H
FG
H
H
N
O
configurationally labile
L* = L-pGlu-OH
DG = 2-pyridyl
FG = alkenyl, alkynyl
up to 99% yield
up to 99% ee
rotation around axis
under reaction conditions
Scheme 1. Challenges and Strategies for Construction of Axially Chiral Styrenes with an Acyclic
Alkene
(A) Challenges of synthesis of axially chiral styrenes with an acyclic alkene.
(B) Previous strategy: asymmetric organocatalytic addition by the groups of Tan and Yan.
(C) Our strategy: asymmetric CꢀH functionalization.
between an open-chained alkene and an aromatic ring. Thus far, only a single strat-
egy involving asymmetric organocatalytic addition has been reported by the Tan26
and Yan27,28 groups to access these axially chiral styrenes with an acyclic alkene
(Scheme 1B). We speculated that an asymmetric CꢀH activation strategy involving
the enantiospecific introduction of a bulky substituent at the ortho-position of the
configurationally labile achiral compounds to lock the preformed axis would be an
appealing approach.14,29–33 The success of this strategy would offer a straightfor-
ward way to access these synthetically challenging atropisomers in an atom- and
step-economical manner (Scheme 1C).
1Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
2These authors contributed equally
3Lead Contact
*Correspondence: hxchem@zju.edu.cn (X.H.),
bfshi@zju.edu.cn (B.-F.S.)
Although asymmetric CꢀH functionalization has emerged as a powerful synthetic
tool for the rapid generation of axially chiral biaryl skeletons,11,14,34–48 the
https://doi.org/10.1016/j.chempr.2019.12.011
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construction of axially chiral styrenes bearing an open-chained alkene with more
flexibility via catalytic asymmetric CꢀH functionalization remains elusive. At least
two main difficulties needed to be addressed: first, the reaction has to be conducted
under mild conditions in order to preserve enantiomeric purity of the resulting prod-
ucts because of the relatively lower conformational stability. Second, the judicious
choice of a proper ligand and directing group (DG), which could cooperatively act
to modulate the reactivity and effectively induce the enantioselectivity, is extremely
challenging. Continuing with our long-standing efforts in construction of axial
chirality via enantioselective CꢀH activation,43–48 we decided to tackle this synthetic
challenge. Herein, we describe the highly atroposelective synthesis of axially chiral
styrenes with open-chained alkene by Pd(II)-catalyzed atroposelective CꢀH alkeny-
lation and alkynylation by using readily available L-pyroglutamic acid as a chiral
ligand.
RESULTS AND DISCUSSION
Our initial investigations started with examining the reaction of styrene 1a bearing a
pyridyl DG with butyl acrylate (2a). In this system, interconversion between the cor-
responding atropoisomers of 1a could occur easily while the resulting alkenylation
product 3aa is reasonably stable under elevated temperature typically employed
in CꢀH activation reactions. Since the pioneering work by Yu and co-workers in
2008,49 N-monoprotected a-amino acids (MPAAs) have been recognized as privi-
leged chiral ligands for Pd(II)-catalyzed asymmetric CꢀH functionalization.49–53
Therefore, a variety of chiral carboxylic acids were tested first. To our delight, the
desired alkenylation product 3aa was obtained in 65% yield with 43% ee, when using
L-pGlu-OH as ligand and AgOAc as oxidant in DCE (Table 1, entry 1).54 After a sur-
vey of various solvents, we found that MeCN and MeOH could give promising results
(entries 1–6). Encouraged by these results, a careful screening of a range of mixed
solvents revealed that MeCN:tBuOH (1:1, 0.05M) was the optimal solvent combina-
tion (entry 7, 93%, 89% ee). Further investigations of reaction temperature indicated
that the well-designed model substrate is a good platform to test our hypothesis, as
the alkenylation reaction could proceed at 50ꢁC and both the reactivity and enantio-
control were maintained (entry 8, 96%, 89% ee). Next, we evaluated the effect of sil-
ver salts, and Ag3PO4 was found to be the best oxidant (entry 13). The ee value could
be improved to 95% without affecting the yield by further tuning the reaction con-
centration (entry 14). The use of Boc-L-pGlu-OH as ligand led to significantly low
ee (entry 15, 21% ee). L-pGlu-OH was found to be the best ligand after a thorough
evaluation of various chiral ligands, including spiro phosphoric acid, BINOL-derived
phosphoric acid, BINOL, and other MPAAs (See Table S2 for details).
With the optimal reaction conditions in hand, we set out to explore the generality of
the atroposelective CꢀH alkenylation (Scheme 2). Considering the low rotation bar-
riers of axially chiral styrenes, 2,6-disubstitution is required to inhibit the rotation and
epimerization. We first examined the steric effect in the ortho-position of the aro-
matic ring. Alkyl groups (1b, methyl; 1c, ethyl; 1a, isopropyl) and chloro (1d), were
well-tolerated, giving high enantiocontrol (3aa–3da, 91%–96% ee). These experi-
mental results are consistent with our computations that the alkenylation product
bearing relatively larger substituent (R1) leads to over 30 kcal/mol enantiomerization
barrier (Figure S11). Substituents in the alkene terminus were also investigated. The
replacement of dimethyl with diethyl or dipropyl in the alkene terminus is well-toler-
ated, giving the desired products in excellent yield and enantioselectivity (3ea, 99%,
92% ee; 3fa, 95%, 93% ee). Cyclohexyl and cyclopentyl in the alkene terminus also
gave high yield and good enantioselectivity (3ga, 99%, 91% ee; 3ha, 87%, 95%
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Table 1. Optimization of CꢀH Alkenylation
Entry
1
[Ag]
Solvent
T (oC)
60
60
60
60
60
60
60
50
40
30
50
50
50
50
50
Yield (%)a
65
ee (%)b
43
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2SO4
Ag3PO4
Ag3PO4
DCE
2
MeCN
90
79
3
1,4-dioxane
56
40
4
Toluene
85
25
5
MeOH
60
69
6
HFIP
85
ꢀ21
89
7
MeCN-tBuOH (1:1)
MeCN-tBuOH (1:1)
MeCN-tBuOH (1:1)
MeCN-tBuOH (1:1)
MeCN-tBuOH (4:1)
MeCN-tBuOH (4:1)
MeCN-tBuOH (4:1)
MeCN-tBuOH (4:1, 4 mL)
MeCN-tBuOH (4:1, 4 mL)
93
8
96
89
9
95
88
10
11
12
13
14
15d
44
84
93
90
94
93
93
94
92 (85)c
78
95
21
See also Table S1.e
aDetermined by 1H NMR with CH2Br2 as the internal standard.
bThe ee value was determined by chiral HPLC.
cIsolated yield.
dBoc-L-pGlu-OH.
e1a (0.1 mmol), 2a (2.0 equiv), Pd(OAc)2 (10 mol %), [Ag] (2.0 equiv), L-pGlu-OH (20 mol %) in solvent (2 mL) at TꢁC for 36 h under air.
ee). However, small cyclic substituents, such as cyclobutyl and cyclopropyl resulted
in significant loss of reactivity and enantioselectivity (3ia, 42%, 4% ee; 3ja, trace). The
loss of reactivity could be explained by angle strain, which prevents the agostic inter-
action of palladium with the ortho-CꢀH bond in the aryl ring. Various substituents on
the pyridyl ring were then tested, and we found that both electron-donating (1k, Me;
1l, OMe), halogen atoms (1m, 1p, Cl; 1o, F), trifluoromethyl (1n), and fluorinated aryl
(1q and 1r) were all compatible with this reaction, affording the alkenylation prod-
ucts in high enantioselectivities (88%–95% ee). Naphthyl and 1,2-dihydroace-
naphthyl type of substrates also showed good reactivity (3sa, 83%, 91% ee; 3ta,
79%, 91% ee). When a quinoline group was used as DG, the alkenylation product
3ua was obtained in excellent enantioselectivity (96% ee), albeit with moderate yield
(47%).
The generality of olefins was also investigated (Scheme 2B). Various acrylates were
compatible with this reaction, giving the desired products in moderate to good yield
and good enantioselectivities (3aa–3af). Besides, acrolein, vinyl ketone, acrylamide,
alkenylphosphate, and 4-methoxystyrene, were all suitable partners and the corre-
sponding axially chiral styrenes were afforded in good yields and enantioselectivities
(3ag–3ak). The absolute configuration of products 3af was determined as Ra by X-ray
4
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R3
Pd(OAc)2 (10 mol %)
L-pGlu-OH (20 mol %)
R3
R2
R2
2.0 equiv Ag3PO4
R3
R1
N
R3
R1
N
H
R
+
R
MeCN/tBuOH (4:1, 0.025 M)
50 oC, 36 h, air
2
1
3
a) Scope of Styrenes
R3
( )n
3aa, R1 = iPr, R3 = Me, 85%, 95% ee
3ba, R1 = R3 = Me, 47%, 92% ee
3ca, R1 = Et, R3 = Me, 57%, 91% ee
3da, R1 = Cl, R3 = Me, 43%, 96% ee
3ea, R1 = Me, R3 = Et, 99%, 92% ee
N
N
R3
R1
BuO2C
iPr
BuO2C
3fa, R1 = Me, R3
=
nPr, 95%, 93% ee
3ga, n = 3, 99%, 90% ee
3ha, n = 2, 87%, 95% ee
3ia, n = 1, 42%, 4% ee
3ja, n = 0, trace, --% ee
R2
R2
N
3na, R2 = CF3, 84%, 94% eec
iPr
BuO2C
3oa, R2 = F, 95%, 95% ee
3pa, R2 = Cl, 67%, 92% ee
N
3qa, R2 = 3,4,5-F3C6H2, 99%, 95% ee
iPr
BuO2C
3ra, R2 = 3,5-(CF3)2C6H3, 86%, 94% ee
3ka, R2 = Me, 72%, 88% eeb
3la, R2 = OMe, 79%, 88% ee
3ma, R2 = Cl, 99%, 93% ee
N
N
N
BuO2C
iPr
BuO2C
BuO2C
3sa, 83%, 91% ee
3ta, 79%, 91% ee
b) Scope of Olefins
3ab, R = Me, 57%, 88% ee
3ua, 47%, 96% ee
3ac, R = Et, 60%, 92% ee
3ad, R = tBu, 74%, 89% ee
3ae, R = TFE, 47%, 92% ee
3af , R = Bn, 73%, 83% ee
N
iPr
RO2C
3af
3ag, R = CHO, 20%, 89% ee
N
3ah, R = COEt, 57%, 94% ee
3ai, R = CON(Me)2, 92%, 89% ee
3aj, R = P(O)(OEt)2, 36%, 90% ee
3ak, R = 4-MeOC6H4, 46%, 88% ee
iPr
R
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Scheme 2. Scope of Pd(II)-catalyzed Atroposelective C–H Alkenylation
a1 (0.1 mmol), 2 (2.0 equiv), Pd(OAc)2 (10 mol %), Ag3PO4 (2.0 equiv), and L-pGlu-OH (20 mol %) in MeCN:tBuOH (4:1, 0.025 M) at 50ꢁC for 36 h under air.
bAg2SO4 (2.0 equiv).
cAgOAc (2.0 equiv).
crystallographic analysis (see also Figure S1), and those of the others were assigned
analogously.
These results prompted us to further investigate whether the strategy could be
applied to other CꢀH functionalization reactions. We explored the asymmetric
CꢀH alkynylation of 1a with TIPS-protected alkynyl bromide 4 and found that the re-
action proceeded efficiently under slightly modified conditions using L-pGlu-OH as
chiral ligand (see Table S2 for detailed optimizations). The desired alkylation prod-
uct 5a was finally obtained in 86% yield with 99% ee in the presence of 10 mol %
Pd(OAc)2, 20 mol % L-pGlu-OH, and 2.0 equiv of Ag3PO4 in MeOH:DMSO (1:1,
0.025 M) at 60ꢁC for 24 h.
The scope of the CꢀH alkynylation was then examined with 4 as the coupling partner
(Scheme 3). Generally, the atroposelective CꢀH alkynylation (5a–5i, 97%–99% ee)
gave better enantiocontrol than the analogous CꢀH alkenylation (3aa–3ea, 3ga–
3ha, 3na–3oa, 88%–96% ee).
Pd(OAc)2 (10 mol %)
R2
L-pGlu-OH (20 mol %)
2.0 equiv Ag2CO3
TIPS
R2
N
H
N
+
TIPS
R1
R1
MeOH/DMSO (1:1, 0.025 M)
60 oC, 24 h, air
Br
4
1
5
N
N
N
TIPS
TIPS
TIPS
iPr
Et
Me
5a, 86%, 99% ee
5b, 72%, 98% ee
5c, 74%, 97% ee
N
TIPS
N
N
TIPS
TIPS
iPr
5d, 54%, 97% ee
5e, 58%, 98% ee
5f, 66%, 98% ee
OMe
Cl
N
TIPS
N
N
TIPS
TIPS
Cl
iPr
iPr
5g, 77%, 97% ee
5h,86%, 99% ee
5i, 28%, 98% ee
Scheme 3. Scope of Pd(II)-catalyzed Atroposelective C–H Alkynylation
a1 (0.10 mmol), 4 (2.0 equiv), Pd(OAc)2 (10 mol %), Ag2CO3 (2.0 equiv), L-pGlu-OH (20 mol %) in
MeOH:DMSO (1:1, 0.025 M) at 60ꢁC for 24 h under air.
6
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A
Scale-up preparation of 3aa and further elaboration
O
N
1a
(3 mmol)
i) OsO4, NaIO4
THF/H2O, 40 o
C
N
1.2 equiv m-CPBA
HO2C
ii) NaClO2, NaH2PO4
2-methylbut-2-ene
tBuOH/H2O
standard
conditions
iPr
iPr
BuO2C
DCM, rt, 12 h
3aa
78%, 94% ee
(886 mg)
9, 88%, 93% ee
6, 76%, 93% ee
O
N
5.0 equiv m-CPBA
O
iPr
CO2Bu
DCM, rt, 24 h
7, 47%, 95% ee
B
Scale-up preparation of 5a and further elaboration
MeO2C
Pd(PPh3)2Cl2
CuI, DIPEA
N
1a (3 mmol)
iPr
ArI, 60 oC
standard
conditions
11, 47%, 99% ee
N
TBAF
THF
H
5a
iPr
85%, 99% ee
(1.1 g)
N
N
CuSO4•5H2O
sodium ascorbate
iPr
10, 94%, 98% ee
N
tBuOH, 50 oC, 24 h
N
Bn
12, 35%, 99% ee
C
Application in Co(III)-catalyzed enantioselective C-H amination of ferrocene
Cp*Co(CO)I2 (5 mol %)
CCA (20 mol %)
AgOTf (20 mol %)
S
S
N
N
O
O
H
N
N
H
O
Ph
CHCl3:t-AmylOH (1:1, 0.1 M)
Ph
Fe
Fe
N2 , 0 oC , 12 h
O
17, 0.1 mmol
18, 1.5 equiv
19
R
O
BzHN
OH
N
CO2H
CO2H
CO2H
CO2H
HO2C
OH
16
9a, R = H, 89%, 70.5:29.5 er
9b, R = OMe, 96%, 72.6:27.4 er
(75%, 78.8:21.2 er)a
13
14
15
89%, 51.2:48.8 er
95%, 72.5:27.5 erb
95%, 50:50 er
93%, 50:50 er
9c, R = Me, 93%, 71.2:28.8 er
MPAA-type CCA
point chirality
styrene-type CCA
axial chirality
binaphthyl CCA
axial chirality
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Scheme 4. Scale-Up Preparation, Derivatization and Application
Please see the Supplemental Information for detailed experimental conditions (see also Scheme S3).
(A) Scale-up preparation of 3aa and further elaborations.
(B) Scale-up preparation of 5a and further elaborations.
(C) Application of chiral styrene atropisomers in Co(III)-catalyzed asymmetric C–H amination.aꢀ20ꢁC.bThe result was reported in Liu et al.55
It should be noted that both of the CꢀH alkenylation and alkynylation reactions
could be conducted on gram scale without the erosion of reactivity and enantiose-
lectivity (Scheme 4A, 3aa, 886 mg, 78%, 94% ee; Scheme 4B, 5a, 1.1 g, 85%, 99%
ee). Further derivatization of the resulting products was also conducted to showcase
the synthetic potential. 3aa could be oxidized to N-oxide pyridine derivative 6 with
1.2 equiv of m-CPBA in 76% yield with 93% ee. When the amount of m-CPBA was
increased to 5.0 equiv, the epoxidation of the alkene at the chiral axis occurred
smoothly, giving epoxide 7 in moderate yield and excellent enantioselectivity
(47%, 95% ee). Notably, the axial chirality was completely transferred to the point
chirality.
Moreover, the selective oxidative cleavage of the less hindered alkene with OsO4/
NaIO4, followed by oxidation of the resulting aldehyde with NaClO2, gave the axially
chiral styrene-type carboxylic acid 9 in high yield and complete retention of chirality
(88% yield for two steps, 93% ee). The absolute configuration of product 9 was also
determined as Ra by X-ray crystallographic analysis (see also Figure S2). The alkyny-
lation product 5a could be desilylated to give the corresponding terminal alkyne 10
without the erosion of ee (94%, 98% ee). Subsequent Sonogashira coupling and cop-
per-catalyzed alkyne-azide cycloadditon gave 11 and 12 in moderate yield and no
erosion of enantioselectivity, respectively.
To demonstrate potential applications of these styrene atropisomers in asymmetric
synthesis, we embarked to use the resulting axially chiral styrene-type acids 9 as chi-
ral carboxylic acid (CCA) ligands in Co(III)-catalyzed enantioselective CꢀH amidation
of ferrocenes (Scheme 4C).55 In our previous study, the best result of enantioselec-
tive CꢀH amidation of thioamide 17 was achieved using D-N-benzoyl-p-hydroxy-
phenylglycine (Bz-Hpg-OH, 16), a mono-protected a-amino acid (MPAA) with a
point chirality, as chiral ligand (72.5:27.5 er).55 We first attempted the use of 9a as
a chiral ligand and a comparable enantiocontrol was obtained (70.5:29.5 er). A pre-
liminary screening of axially chiral acids (9a–9c) with different substituents on pyri-
dine revealed that that axially chiral styrene-type acid 9b with 4-methoxy substituted
on pyridine gave better stereocontrol than that using Bz-Hpg-OH (9b, 78.8:21.2 er
versus 16, 72.5:27.5 er).55 For comparison, axially chiral carboxylic acids possessing
a binaphthyl or biaryl backbone either gave no enantiocontrol (13 and 14, racemic)
or very low enantioselectivity (15, 51.2:48.8 er). These results showcase that the
styrene atropisomers might be superior or complementary to axially chiral biaryl
skeletons in certain asymmetric reactions.
A number of experiments were conducted to gain some preliminary insight into
the mechanism. First, a linear correlation between the ee value of 3aa and L-
pGlu-OH was observed (Figure S3), indicating that a single L-pGlu-OH is involved
in the stereo-determining step. Second, the kinetic isotope effect (KIE) was deter-
mined by comparing the initial reaction rate with H-1a to that with D-1a, the KIE
values of 1.30 (without L-pGlu-OH) and 1.20 (with L-pGlu-OH) were obtained,
respectively (Figure 1A; see Figures S2 and S3 for details), indicating that CꢀH
bond cleavage process might not be involved in a rate-determining step. Initial
rate studies revealed a ligand deceleration effect (LDE) in this reaction (Figure 1B;
8
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.12.011
A
standard conditions
N
N
iPr
iPr
H/D
without L-pGlu-OH: kH/kD = 1.30
with L-pGlu-OH: kH/kD = 1.20
BuO2C
H-1a/D-1a
R-3aa
B
standard conditions
N
H
N
iPr
iPr
BuO2C
with or without L-pGlu-OH
1a
R-3aa
Figure 1. Mechanism Experiments
(A) KIE studies by comparing the initial rate with H-1a to that with D-1a (see Figures S4–S5 for
details).
(B) Ligand effect on the reaction rate of atroposelective C–H alkenylation of 1a (see also Figure S6).
see Figure S14 for computational details). This is in sharp contrast to Pd-catalyzed
atroposelective CꢀH alkenyaltion of biaryls using chiral spiro phosphoric acid li-
gands, in which the high enantioselectivity originated from a dramatic ligand ac-
celeration effect.47 LDE-induced highly enantioselective asymmetric synthesis is
significantly more challenging than the accelerated scenario.56 We rationalized
that the high ee resulted from the suppression of background reaction by a highly
favorable ligand exchange of L-pGlu-OH with Pd(OAc)2 to form a chiral Pd(L-pGlu-
O)(OAc)-type catalyst. This could also explain the need of excess of chiral ligand
(2:1 ratio of ligand:palladium) to ensure that no uncomplexed palladium acetate
is present.
We next explored the reaction mechanism and origins of enantioselectivity with
density functional theory (DFT) calculations, using experimental styrene 1a and
Chem 6, 1–15, February 13, 2020
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.12.011
G(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(acetonitrile)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ
O
HN
O
O
Py
O
Pd
O
N
Pd
H
MeO2
C
N
i-Pr
i-Pr
O
16.3
TS27
O
H
13.0
O
O
O
O
N
H
O
TS22
Pd
O
N
N
Pd
MeO2
O
H
O
C
O
H
O
7.4
H
i-Pr
HN
MeO2
C
4.7
20
1a
26
O
O
2
4.4
TS30
Py
2.2
Pd
0.0
Cat.
21
MeO2
C
2 HOAc
i-Pr
O
-4.6
-5.5
N
O
N
1/3[Pd(OAc)2]3
+
N
23
O
O
-7.5
Pd
25
N
-7.6
O
O
O
Py
O
Pd
N
H
Pd
28
i-Pr
H
MeO2
O
C
N
24
N
O
O
CO2
H
i-Pr
OH
N
H
Pd
i-Pr
NH
Pd
O
O
i-Pr
MeO2
C
L-pGlu
-12.4
29
O
i-Pr
H
N
O
O
N
-14.5
Pd
O
NH
O
N
H
O
TS32
-16.5
H
i-Pr
-16.7
33
N
O
Pd
31
O
O
N
H
O
O
MeO2
C
O
i-Pr
N
H
O
N
H
H
Pd
N
O
MeO2
C
Pd
MeO2
C
H
i-Pr
i-Pr
H
ligand exchange
isomerization
migratory insertion
C–H activation
pyridine-assisted E-hydride transfer
Figure 2. DFT-Computed Free-Energy Profile of the Most Favorable Pathway for the Pd/L-pGlu-Catalyzed Atroposelective C‒H Alkenylation
See Figures S7–S9 for details.
methyl acrylate as the model compounds.57 The DFT-computed free energy
changes of the most favorable pathway for the Pd(II)/L-pGlu-catalyzed atroposelec-
tive CꢀH alkenylation are shown in Figure 2 (see the Supplemental Information for
details). The Pd(OAc)2 trimer first deprotonates the amino acid L-pGLu, generating
the intermediate 20. Subsequent complexation with styrene 1a leads to the
intermediate 21, which undergoes the concerted metalation-deprotonation via
TS22 to produce the aryl-palladium species 23. 23 isomerizes to the more stable
25 to allow the alkene insertion via TS27.58 This alkene insertion generates
the alkyl-palladium species 28. 28 isomerizes to the more stable 29 with pyridine
coordination, followed by the pyridine-assisted b-hydride transfer,59–61 through
TS30. Subsequent proton transfer from pyridinium to carboxylate via TS32
produces the product-coordinated complex 33. This pyridine-assisted b-hydride
transfer process is significantly more favorable than the alternative b-hydride elim-
ination involving palladium-hydride species and carboxylate-assisted b-hydride
transfer (Figures S8 and S9). Based on the computed free energy profile, the on-cy-
cle resting state is the aryl-palladium species 24. The rate-determining step is the
alkene insertion via TS27, which requires an overall barrier of 23.9 kcal/mol
comparing with the resting state 24. The facile CꢀH bond activation is consistent
with the KIE experimental results.
To reveal the origins of enantioselectivity, DFT calculations of the enantioiso-
meric product-formation pathways were conducted (Figure 3). The formation of
the major enantiomer (black pathway) involves a reversible CꢀH bond activation
via TS22 and the subsequent rate-determining alkene insertion via TS27. The
10
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Please cite this article in press as: Jin et al., Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric C–H Functionalization Strategy,
Chem (2019), https://doi.org/10.1016/j.chempr.2019.12.011
DG(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(acetonitrile)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ
O
O
O
N
O
Pd
H
HN
HN
N
O
i-Pr
O
O
O
O
Py
Py
Pd
O
Pd
O
20.8
N
MeO2C
MeO2
C
Pd
H
i-Pr
TS35
i-Pr
N
i-Pr
16.4
16.3
O
TS37
TS27
13.0
TS22
Py
Py
MeO2
C
MeO2
O
C
MeO2
C
MeO2
O
C
2
2
Pd
i-Pr
Pd
6.0
i-Pr
N
O
O
34
O
NH
O
O
2.2
Pd
NH
O
N
38
28
i-Pr
21
O
N
O
O
N
N
Pd
MeO2C
i-Pr
N
N
O
N
O
O
i-Pr
O
N
-7.5
Pd
MeO2
C
Pd
H
i-Pr
-7.6
O
-8.5
N
3-major
-9.1
H
28
i-Pr
i-Pr
24
36
38
O
O
3-minor
Formation of Minor Enantiomer
Formation of Major Enantiomer
Figure 3. DFT-Computed Free-Energy Changes of the Enantioisomeric Pathways in the Pd/L-pGlu-Catalyzed Atroposelective C‒H Alkenylation
Free energies are compared to separate [Pd(OAc)2]3 and ligands (see also Figure S13).
competing formation of the minor enantiomer (red pathway) is inhibited by the
CꢀH bond activation step via TS35.62 Comparing the determining steps (TS27
versus TS35), the formation of the major enantiomer is 4.5 kcal/mol more favor-
able than that of the minor enantiomer, which corroborated the excellent enan-
tioselectivities in experimental observations. The dramatic energy difference be-
tween the CꢀH bond activation transition states (TS22 versus TS35) is the key
reason that differentiates the enantioisomeric pathways. We also confirmed
that the racemization of axial chirality is not feasible after the CꢀH bond activa-
tion step (Figure S10). The alkenyl tether is not related to the enantioselectivity
control (Figures 4A and 4B); replacing the alkenyl tether (TS22 versus TS35) with
a simple methylene unit (TS39 versus TS40) also leads to excellent chiral discrim-
ination in the CꢀH bond activation step. The analysis of the chiral induction of
CꢀH bond activation step is included in Figure 4C. The model transition state
TS41 for the CꢀH bond activation of benzene suggested that the chiral amino
acid intrinsically prefers to have the CꢀH bond activation occurring in the third
quadrant. This chiral induction nicely matches the axial chirality of the CꢀH
bond activation via TS22 for the major product-formation pathway. TS22 does
not require significant distortion of amino acid ligand. The sp3-hybridized nitro-
gen of amino acid in TS22 has a similar pyramidalization geometry as compared
to that in TS41, as reflected in the highlighted pyramidalization63 at nitrogen. In
contrast, the disfavored CꢀH bond activation transition state TS35 has a chiral
mismatch between the amino acid ligand and the axial chirality of styrene. This
forces the significant distortion of the amino acid ligand in TS35. The pyramidal-
ization angle of the amino acid nitrogen is only 4.7ꢁ. We further computed the
energy difference of the Pd(L-pGlu) fragment in the competing transition states.
The 5.6 kcal/mol energy difference corroborated the rationale that the amino
acid ligand distortion controls the enantioselectivity in the CꢀH bond activation
step.
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.12.011
A
B
O
O
O
O
O
O
O
O
N
N
N
N
H
H
H
H
Pd
H
Pd
H
Pd
H
Pd
H
N
N
N
N
i-Pr
i-Pr
O
O
O
O
TS22
TS35
= 7.8 kcal/mol
TS39
= 0.0 kcal/mol
TS40
G
= 0.0 kcal/mol
G
G
G
= 7.3 kcal/mol
C
cN = 25.6o
cN = 37.7o
cN = 4.7o
O
O
O
O
O
O
N
Pd
N
N
Pd
N
N
Pd
N
G
G
= 0.0 kcal/mol
G
= 5.6 kcal/mol
O
H
O
H
O
H
TS22
TS35
TS41
= 0.0 kcal/mol
G
= 7.8 kcal/mol
i-Pr
i-Pr
Figure 4. Computational Details
(A) Origins of enantioselectivity in the Pd/L-pGlu-catalyzed atroposelective C–H alkenylation.
(B) Tether effect on the enantioselectivity.
(C) Chiral induction through ligand distortion. For computational details, see the Supplemental Information.
Conclusions
In summary, we have developed a Pd(II)/L-pGlu-OH catalytic system to enable the
synthesis of axially chiral styrenes with an open-chained alkene via atroposelective
CꢀH alkenylation and alkynylation, which significantly expands the synthetic toolkit
for the accessing this family of atropoisomers. Experimental and computational
studies were conducted to elucidate the reaction mechanism of atroposelective
CꢀH alkenylation, which involves sequential CꢀH bond activation, alkene insertion,
and pyridine-assisted b-hydride transfer. The chiral induction model of the enantio-
selectivity-determining CꢀH bond activation step was also provided based on DFT
calculations. We expect that the newly developed asymmetric CꢀH functionalization
strategy would streamline access to chiral styrenes. The use of commercially avail-
able L-pGlu-OH as a uniquely effective chiral ligand might also offer great opportu-
nities in enantioselective CꢀH activation.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
12
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Chem (2019), https://doi.org/10.1016/j.chempr.2019.12.011
See Schemes S1–S3; Figures S1–S267 for synthesis and characterization of all new
compounds.
DATA AND CODE AVAILABILITY
The crystallography data have been deposited at the Cambridge Crystallographic
Data Center (CCDC) under accession number CCDC: 1907624 (3af), 1907625 (9)
and can be obtained free of charge from www.ccdc.cam.ac.uk/getstructures.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.12.011.
ACKNOWLEDGMENTS
Financial support from the NSFC (21772170 and 21572201 for B.-F.S.) and
(21702182 and 21873081 for X.H.), Outstanding Young Talents of Zhejiang Province
High-level Personnel of Special Support (ZJWR0108 for B.-F.S.), the Fundamental
Research Funds for the Central Universities (2018XZZX001-02 for B.-F.S. and
2019QNA3009 for X.H.), and Zhejiang Provincial NSFC (LR17B020001 for B.-F.S.)
is gratefully acknowledged.
AUTHOR CONTRIBUTIONS
B.-F.S., L.J., and Q.-J.Y. conceived and designed the study. B.-F.S., X.H., L.J., and
P.-P.X. co-wrote the paper. X.H. and P.-P.X. provided the density functional theory
(DFT) calculations. L.J., Q.-J.Y., Y.L., B.-B.Z., and Y.-Q.H. performed the experi-
ments and analyzed the data.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: July 23, 2019
Revised: November 5, 2019
Accepted: December 10, 2019
Published: January 9, 2020
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Please cite this article in press as: Jin et al., Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric C–H Functionalization Strategy,
Chem (2019), https://doi.org/10.1016/j.chempr.2019.12.011
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