Pd-Catalyzed Atroposelective C?H Allylation through β-O Elimination: Diverse Synthesis of Axially Chiral Biaryls

Article abstract of DOI:10.1002/anie.201811256

Biaryl atropisomers are of great importance in natural products, pharmaceuticals, and asymmteric synthesis. The efficient synthesis of these chiral scaffolds with full enantiocontrol and high diversity remains challenging. Reported herein is a Pd-catalyzed atroposelective C?H allylation with tert-leucine as an efficient catalytic chiral transient auxiliary. A wide range of enantioenriched biaryl aldehydes were prepared in synthetically useful yields with excellent enantioselectivity (up to >99 % ee) through β-O elimination. The reaction could be carried out on a gram scale without erosion of the ee value. A variety of axially chiral carboxylic acids could be obtained with high enantiopurity. The resulting axially chiral biaryl aldehydes and carboxylic acids might be used in asymmetric synthesis as chiral ligands and/or organocatalysts.

Full text of DOI:10.1002/anie.201811256

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Accepted Article
Title: Pd-Catalyzed Atroposelective C−H Allylation via β-O Elimination:
Diverse Synthesis of Axially Chiral Biaryls
Authors: Gang Liao, Bing Li, Hao-Ming Chen, Qi-Jun Yao, Yu-Nong
Xia, Jun Luo, and Bing-Feng Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811256
Angew. Chem. 10.1002/ange.201811256
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10.1002/anie.201811256
COMMUNICATION
Pd-Catalyzed Atroposelective C−H Allylation via β-O Elimination:
Diverse Synthesis of Axially Chiral Biaryls
[a]
[a]
[c]
[a]
[a]
[a]
Gang Liao, Bing Li, Hao-Ming Chen, Qi-Jun Yao, Yu-Nong Xia, Jun Luo , and Bing-Feng
Shi*[a,b]
Abstract: Biaryl atropisomers are of significant importance in natural
products, pharmaceuticals and asymmteric synthesis. The efficient
synthesis of these chiral scaffords with full enantiocontrol and high
diversity remains challenging. Reported herein is a Pd-catalyzed
atroposelective C‒H allylation with tert-leucine as an efficient,
catalytic chiral transient auxiliary. A wide range of enantioenriched
biaryl aldehydes were prepared in synthetically useful yields with
excellent enantioselectivities (up to >99% ee) via β-O elimination. The
reaction could be carried out in gram scale without the erosion of ee
value. A variety of axially chiral carboxylic acids could be obtained in
high enantiopurity. The resulting axially chiral biaryl aldehydes and
carboxylic acids might be used in asymmetric synthesis as chiral
ligands and/or organocatalysts.
demonstrated the catalytic asymmetric activation of glycine esters
using a novel chiral aldehyde catalyst modified from chiral
BINOL.[8b] Zhao and co-workers recently designed a novel N-
quaternized biaryl axially chiral pyridoxal catalyst for biomimetic
asymmetric Mannich reaction.[9] In this regard, the discovery and
identification of novel types of axially chiral aldehydes and/or
carboxylic acids as ligands/catalysts might strongly depend on the
developing of new synthetic methodologies.
a) Atropisomerism in Natural Products
OMe
OGlu
Cl
O
O
O
O
O
MeO
HO
OH
O
Cl
OH
O
H
O
H
N
O
MeO
MeO
N
N
N
N
H
NHMe
Me
O
H
H
H
H
MeO
MeO
NH
H
O
H
O
O
O
2
HO C
NH
2
MeO
Me
OMe
OMe
OH
OH
Axially chiral biaryls are common structural motifs in a broad
range of synthetically challenging and medicinally important
agents, such as natural products and pharmaceuticals (Scheme
1
2
OH
(
-)-steganone
(+)-isoschizandrin
Vancomycin
b) Atropisomerism in Ligands
Br
R
CHO
a).[1] Moreover, axially chiral biaryl compounds, such as 1,1’-bi-
-naphthols (BINOLs) and their derivatives (eg. chiral phosphoric
H
N
OH
OH
OH
CO
CO
2
H
H
OH
OH
O
R
2
O
acids, phosphoramidites, etc) have also been widely used as
privileged ligands in asymmetric synthesis (Scheme 1 b).[2,3] In
I
N
R
R
OH
BINOL
Axially Chiral
Dicarboxylic Acid
BINOL-derived Axially
Chiral Aldehyde
N-Quaternized Biaryl Axially
2
004, Akiyama[4] and Terada[5] pioneeringly reported the use of
Chiral Pyridoxal
C
2
-Symmetric Biaryls
2
Non-C -Symmetric Biaryls
BINOL-derived phosphoric acids as a new family of chiral
Brønsted acid catalysts. Since then, chiral Brønsted acid catalysts
has received considerable attentions for asymmetric synthesis.
Numerous variations, mostly derived from BINOLs have been
developed. Surprisingly, the corresponding axially chiral
carboxylic acids, an important class of moderate Brønsted acids,
has rarely been employed, probably due to the lack of efficient
strategies to access these ligands with high enantiopurity and
structural diversity. A breakthrough in this field was made by
Maruoka and coworkers, who developed a series of axially chiral
dicarboxylic acids possessing a binaphthyl backbone.[6] These
2
c) This work: Pd-catalyzed atroposelective C-H allylation to access diverse non-C -symmetric axiallychiral
aldehydesand carboxylic acids
cat. Pd(OAc)
L-tert-leucine
2
FG = allyl, alkyl
CHO
H
CHO
FG
CO
2
H
allyl sources
FG
R
O
O
OR'
O
Non-
C
-Symmetric
Non-C
Chiral Carboxylic Acids
2
-Symmetric Axially
rac-1
2
Axially Chiral Adehydes
allyl sources
Scheme 1. The importance of axially chiral biaryls and our synthetic
strategy.
Therefore, substantial efforts have been devoted to the
synthesis of these axially chiral biaryl backbones.[10] Among these
elegant methods, the atroposelective C‒H functionalization
provides an efficient and straightforward strategy to access these
axially chiral structures.[11] Seminal works by Murai,[12] Milller,[13]
You,[14] Wencel-Delord and Colobert,[15] Antonchick and
Waldmann,[ and Cramer,[17] have proved the power of this
strategy. Despite of these advances, the construction of these
important scaffolds with full stereocontrol remains particularly
challenging, likely as a result of the difficulty in finding proper
ligands for enantioselective synthesis.
axially chiral dicarboxylic acids have been widely used in a series
of enantioselective reactions.[6]
More recently, there has been a growing interest in developing
new asymmetric reactions using axially chiral aldehydes as
ligands.[7-9] In 2014, Guo and coworkers reported the first
enantioselective α-alkylation of 2-aminomalonates with 3-
indolylmethanols using axially chiral aldehyde.[8a] They also
16]
[a]
G. Liao, B. Li, Q.-J. Yao, Y.-N. Xia, J. Luo, Prof. Dr. B.-F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
In 2016, a pioneering work of Pd-catalyzed enantioselective
3
E-mail: bfshi@zju.edu.cn.
C(sp )–H arylation to create a point chirality using a chiral amino
Homepage: http://mypage.zju.edu.cn/en/bfshi/.
Prof. Dr. B.-F. Shi
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071 (China)
acid as a transient directing group was demonstrated by Yu and
coworkers.[ More recently, the same group has further achieved
[
b]
c]
18]
3
the Pd(II)-catalyzed enantioselective fluorination of C(sp )−H
bond via a Pd(II)/Pd(IV).[19] Inspired by these advances, coupled
[
H.-M. Chen
School of Chemical & Environmental Engineering, Wuyi University,
Jiangmen 529020 (China)
with the goal of synthesizing new types of non-C
2
-symmetric
axially chiral ligands as asymmetric catalysts and our long-
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Angewandte Chemie International Edition
10.1002/anie.201811256
COMMUNICATION
standing interests in enantioselective C‒H functionalization,[ we
sought to develop a general and efficient strategy to prepare
these axially chiral biaryl motifs with high levels of enantiocontrol
and high diversity. Asymmetric allylic alkylation (AAA) reaction
with Morita–Baylis–Hillman (MBH) carbonates or acetates has
been demonstrated to be an effective method to create a new
stereogenic center. In addition, the resulting allylic moiety is also
a versatile handle for further transformations.[21] As all reported
asymmetric allylation reactions are limited to the preparation of
centrally chiral compounds, there is still no report on the creation
of axial chirality by the introduction of allylic surrogates into the
20]
Table 1. Scope for Pd-catalyzed C‒H allylation with MBH/DKR of biaryls[a]
Ar
1
Ar
1
6
Pd(OAc)
L-tert-leucine (20 mol%)
.0 equiv. BQ
HFIP:HOAc = 4:1
2
(10 mol%)
2
CHO
H
R
CHO
R
+
OAc
R
6'
2'
1
Ar
2
Ar2
3
o
60 C, 48 h
rac-1a
2
R
F
CHO
CHO
CHO
CO
2
Et
CO
2
Et
CO
2
Et
3b, 58%, >99% ee
3c
3f, R = OMe, 65%, 99% ee
b] 3g, R = Me, 70%, 98% ee
3h, R = F, 66%, >99% ee
, R = Me, 45%, 99% ee
biaryl atropisomers. Here we report
a
highly atropo-
[
3d, R = 1-Naph, 67%, 99% ee
e, R = SPh, 33%, 99% ee
enantioselective route to these biaryl compounds by Pd-catalyzed
C‒H allylation with different allylic reagents via β-O elimination.
This strategy provides an efficient access to a wide range of
enantioenriched biaryls (up to >99% ee). The realization of this
3
3i, R = Cl, 63%, >99% ee
3j, R= CF
3
, 71%, >99% ee
F
F
Me
CHO
CHO
2
strategy also establishes a platform for rapid access of non-C -
CHO
symmetric axially chiral aldehydes and carboxylic acids, offering
an opportunity for developing new types of axially biaryl chiral
ligands/catalysts for asymmetric reactions.
2
CO Et
CO
2
Et
CO Et
2
R
3k, 58%, 96% ee
3l, 62%, 98% ee
3
m, R = Me, 74%, >99% ee
(
CCDC 1877116)
3n, R = Ph, 67%, 99% ee[c]
3o, R = F, 63%, 99% ee[c]
We initiated our research by conducting the reaction of biaryl
o
rac-1a with 2a at 60 C in the presence of 10 mol% Pd(OAc)
2
(
Table S1). After screening several solvents, we were delighted
CHO
o
CHO
to find that the reaction proceeded smoothly at 60 C in HFIP and
gave the allylation product 3a in 16% yield with excellent
enantioselectivity using L-tert-leucine as a transient chial auxilary,
CHO
2
CO Et
CO
2
Me
OAc
(
Table S1, entry 5, 99% ee). Detailed optimization of solvent
3p, 73%, 99% ee
3q, 45%, 99% ee
3r, 60%, 99% ee
revealed that HFIP/HOAc was the optimal (entry 7, 26%, 99% ee).
Other solvents totally inhibited the reaction, which suggests the
acidity of catalytic system was crucial for the occuring of the
reaction (entries 1-4). Intriguingly, the desired product 3a was
obtained in 59% yield with 99% ee when the reaction was
CO
2
Et
LG
CHO
CHO
LG = Br, 0%, --
LG = OH, 0%, --
LG = OCOEt, 60%, 99% ee
LG = OBz, 65%, 99% ee
LG = OBoc, 23%, 99% ee
2
CO Et
2
CO Et
OMe
3s,
51%, >99% ee
conducted in O
2
atmosphere. This result indicated the efficiency
3a
of the reaction was significantly affected by oxidant. We then
turned our attention to explore the effects of oxidants. BQ turned
out to significantly improve the yield with maintained
enantioselectivity (entry 12, 77%, 99% ee). Other amino acids,
however, suffered from lower reactivity and poor stereoselectivity
[
a] Reaction conditions: rac-1 (0.1 mmol), 2 (0.3 mmol), Pd(OAc) (0.01 mmol),
2
o
L-tert-leucine (0.02 mmol), BQ (0.1 mmol) HFIP/HOAc = 4:1 (1 mL), 60 C, air,
4
7
8 h. [b] L-tert-leucine (0.03 mmol). [c] L-tert-leucine (0.03 mmol), 70 oC, air,
2 h.
Table 2. Scope for Pd-catalyzed C‒H allylation with MBH/KR of biaryls[a]
(
entries 13-15 and Table S4).
Pd(OAc)
L-tert-leucine (30 mol%)
2
(10 mol%)
R
R
R
With the optimal conditions in hand, we sought to demonstrate
CHO
H
CHO
CHO
+
the generality of this protocol. A broad range of biaryls containing
substituents at either the 6- or 2’ positions underwent a dynamic
kinetic resolution (DKR) pathway (Table 1, 1a-1o, 1r). Various
substituted phenylnaphthalenes underwent the desired allylation
smoothly, indicating that the electronic properties of the
substituents on phenyl and naphthalene motiety did not affect the
reactivity and enantioselectivity (3a-3o, 33 to 74% yields, 96
to >99% ee). The reaction is compatible with different halogens,
such as fluoro and chloro. In addition to 2a, other allylation
reagents were also compatible with this strategy (3p and 3q).
Furthermore, we became interested in whether 3a could be
obtained wtih other allylic surrogates bearing with different leaving
groups. The outcomes showed that the leaving groups had a
great influence on the reactivity. No reaction happened when -Br
severed as the leaving group, indicating that β-bromo elimination
is difficult. Hydroxy is also an ineffective leaving group and allylic
reagents containing other leaving groups, such as -OCOEt, -OBz,
2a, 1.0 equiv BQ
CO Et
2
HFIP/HOAc = 4:1
R'
R'
R'
6
0 °C, 96 h
rac-4
4
5
R
1
CHO
Me
CHO
Me
CHO
Cl
CHO
R
R2
rac-4a, R = H
rac-4b, R = Me
rac-4c, R = Ph
rac-4d, R
1
= R
2
= H
rac-4g
rac-4h
rac-4e, R1 = H, R2 = Ph
rac-4f, R1 = F, R2 = H
4
5
entry
4
5
s[c]
yield (%)
ee (%)[b]
yield (%)
ee (%)[b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
5a
51
44
59
51
53
43
45
39
68
85
49
86
75
78
94
79
41
34
36
33
35
36
36
25
94
98
99
98
98
98
94
98
54
5b
5c
5d
5e
5f
270
324
276
236
88
-
OBoc show lower efficiency than 2a. It is also noteworthy that the
reaction can be applied to proaxially biaryl 3s via
desymmetrization process to give 3r in 51% yield and >99% ee.
a
4g
4h
5g
5h
115
240
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Angewandte Chemie International Edition
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COMMUNICATION
[
a] Reaction conditions: rac-4 (0.1 mmol), 2 (0.3 mmol), Pd(OAc) (0.01 mmol),
2
8
5% yield and >99% ee in a two-step sequence (see Supporting
o
L-tert-leucine (0.03 mmol), BQ (0.1 mmol), HFIP/HOAc = 4:1 (1 mL), 60 C, air,
6 h. Isolated yield. [b] The ee value was determined by HPLC. [c] s = ln[(1-
C)(1-ee )]/ln[(1-C)(1+ee )], C = ee /(ee +ee ).
Information for details).
9
4
4
4
4
5
The scope of biaryls were also examined with 2aa as the
reaction partner (Table 3). Although the yield was significant
affected by the electronic properties of the substituents, the
enantiocontrol remained remarkely high (6a-o, 96 to >99% ee).
Generally, the electron-donating aromatic substrates delivered
products more efficiently (6a-c, 6e, 6i, 6k-l), while those with
electron-deficient groups tended to afford products in a lower yield
Next, we examined whether the asymmetric C‒H allylation of
biarys could be applicable to kinetic resolution (KR) of biaryls
bearing sterically more bulky substituents at both the 6- and 2’
positions. To our delight, excellent selectivities were observed
under slightly modified conditions as shown in Table 2. The
allylated products 5 were obtained in 25%-41% yield with 94 to
(6d, 6f-h, 6j). However, biaryl bearing trimethoxy on Ar gave the
1
9
9% ee, and the starting materials were recovered in 39%-59%
desired product 6n in 38% yield with slightly decreased
enantioselectivity (90% ee). In comparison, with additional
yield with 49 to 94% ee (entries 1-7, s-factor = 54-324). It should
be noted that 3-chloro-biaryl 4h was found to be compatible with
methoxy substituents on Ar , the corresponding product 6o was
2
this reaction affording excellent selectivity (entry 8, s-factor = 240). isolated in 63% yield and 99% ee. The absolute configuration of
products 3k and 6j was unambiguously determined by X-ray
Table 3. Pd-catalyzed C‒H Allylation with 4-Vinyl-1,3-dioxolan-2-one /reduction
with Raney-Ni[a]
analysis and those of other biaryls were assigned by analogy.[23]
2
1) Pd(OAc) (10 mol%)
Ar
1
L-tert-leucine (30 mol%)
CHO i) C-H allylation
with
CHO
( )
CHO
HFIP:HOAc=9:1
OH
CHO
H
2aa
O
O
3Me
+
( )3 OH (1)
2
.0 equiv. nPrCO
2
Na
+
O
o
OH
ii) Pd/C, H2
60 C, air, 48 h
Ar
2
2
) Rany-(Ni) / H
THF, rt
2
rac-1a
3a', 20%, 99% ee
3b', 36%, >99% ee
rac-1a
2aa
6
R
In the interest of accessing more structurally diverse axially
chiral aldehydes, we explored the reduction of the allylated
product with other reducing agents. When Pd/C was used as the
catalyst, biaryl aldehydes 3a’ and 3b’ were obtained in excellent
enantioselectivities with 20% and 36% yield, respectively (eq 1).
R
OH
OH
OH
F
OH
OH
OH
6e, R = Me, 64%, 99% ee
f, R = Cl, 39%, 99% ee
6g, 36%, 99% ee
a, R= H, 85%, >99% ee
b, R = Me, 61%, >99% ee
c, R = OMe, 71%, >99% ee
6
a) Gram-scale synthesis
d, R = CF
3
, 33%, 99% ee[b]
F
OH
conditions
in Table 1
conditions
in Table 3
OH
CHO
CHO
H
OH
OH
CO
2
Et
OH
OH
OH
OH
R
3
a, 71, 99% ee
rac-1a
5.0 mmol
6a, 55%, >99 % ee
6
6
i, R = Me, 75%, >99% ee
j, R= F, 51%, 98% ee[b]
1.22 g
0.84 g
6
l, 64%, 96% ee
6h, 40%, 99% ee
b) Synthesis of axially chiral carboxylic acids
(
CCDC 1877121)
6
k, R = Ph, 66%, 96% ee
OMe
OMe
F
CO
2
H
CO
2
H
2
CO H
MeO
MeO
MeO
Me
OH
R
OH
OH
OH
MeO
MeO
CO
2
Et
OH
OH
7
a, 80%, >99% ee
7b, 30%, >99% ee
7c, R = CHO, 57%, 99% ee
d, R = CO H, 76%,>99% ee
OH
7
2
MeO
Scheme 2.Gram-scale synthesis and synthesis of axially chiral carboxylic acids.
Me
6n, 38%, 90% ee
OMe
6o, 63%, 99% ee[c]
6m, 49%, 92% ee
[
a] Reaction conditions: 1) rac-1 (0.1 mmol), 2aa (0.4 mmol), Pd(OAc)
2
(0.01
Gram-scale synthesis and synthetic transformations to various
axially chiral carboxylic acids were also conducted (Scheme 2).
Firstly, a 5 mmol-scale reaction of rac-1a and 2a was performed,
delivering 3a in 71% yield and 99% ee. Then the gram-scale
reaction of rac-1a with 2aa was conducted, the resulting product
could be easily reduced to 6a in 55% yield with maintained
enantioselectivity (>99% ee). Secondly, the oxidation of the
resulting chiral aldehydes all proceeded smoothly, affording the
desired axially chiral acids in satisfactory yields without erosion of
ee value (up to >99% ee, see supporting information for details).
In conclusion, a Pd-catalyzed atroposelective C‒H allylation via
β-O elimination using a transient auxiliary strategy was developed.
This protocol expands the asymmetric allylic alkylation (AAA)
reaction from central chirality to axial chirality. tert-Leucine served
as an efficient and catalytic transient chiral auxiliary. A broad
range of enantioenriched biaryls were obtained in synthetically
useful yields with excellent enantioselectivities (up to > 99% ee).
The axially chiral biaryl aldehydes could be further converted into
enantiomerically pure axially chiral carboxylic acids. Further
n
mmol), L-tert-leucine (0.03 mmol), PrCO
mL), 60 C, air, 48 h; 2) Rany-Ni/H
2
Na (0.2 mmol), HFIP/HOAc = 9:1 (1
o
o
2
. [b] Pd(OAc)
2
(0.015 mmol). [c] 70 C, 96 h.
These results prompted us to explore whether the mode of β-O
elimination could be applied to the use of other allylic surrogates,
which could enabled the synthesis of other type of non-C -
2
symmetric biaryls. We chose 4-vinyl-1,3-dioxolan-2-one 2aa as a
versatile coupling partner due to that it exhibits high activity on β-
O elimination with the evolution of CO
2
as a driving force.[ We
carried out the reaction of rac-1a with 2aa under our established
reaction conditions. Fortunately, we found that 2aa was amenable
to this transformation, albeit with a mixture of E/Z isomers. Further
optimizations revealed that the reaction proceeded most
efficiently with 4.0 equiv of 2a in the presence of 10 mol%
22]
2 2
Pd(OAc) , 30 mol% L-tert-leucine and 2.0 equiv of nPrCO Na in
HFIP/HOAc (9:1) at 60 °C for 48 h. To avoid the isolation of Z/E
isomers, the reaction mixture after C–H allylation was subjected
to the reduction with Raney-Ni to affored the alkylated biaryl 6a in
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Angewandte Chemie International Edition
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COMMUNICATION
applications of these axially chiral biaryl aldehydes and carboxylic
acids in asymetric synthesis are currently ongoing.
117, 8908; h) D.-W. Gao, Q. Gu, C. Zheng, S.-L. You, Acc. Chem. Res.
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Financial support from the NSFC (21772170, 21422206,
21572201), the National Basic Research Program of China
[15] a) T. Wesch, F. R. Leroux, F. Colobert, Adv. Synth. Catal. 2013, 355,
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2015CB856600), the Fundamental Research Funds for the
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Central Universities (2018XZZX001-02) and Zhejiang Provincial
NSFC (LR17B020001) is gratefully acknowledged.
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Keywords: atroposelective • C‒H allylation • biaryls • palladium
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Gang Liao, Bing Li, Hao-Ming Chen, Qi-
Jun Yao, Yu-Nong Xia, Jun Luo, and
Bing-Feng Shi*
Page No. – Page No.
Pd-Catalyzed Atroposelective C−H
Allylation via β-O Elimination: Diverse
Synthesis of Axially Chiral Biaryls
A Pd-catalyzed atroposelective C‒H allylation with two kinds of allylic surrogates
were reported. tert-Leucine was identified as an efficient, catalytic transient chiral
auxiliary. A wide range of enantioenriched biaryls were prepared in synthetically
useful yields with excellent enantioselectivities (up to >99% ee) via β-O elimination.
The reaction could be easily scaled up and the allylated axially chiral biary aldehydes
could be further converted to enantiomerically pure axially chiral carboxylic acids.
This article is protected by copyright. All rights reserved.