Enantioselective Synthesis of Axially Chiral Biaryls via Cu-Catalyzed Acyloxylation of Cyclic Diaryliodonium Salts

Article abstract of DOI:10.1021/acscatal.9b00695

We report here a Cu-catalyzed enantioselective acyloxylation of cyclic diaryliodonium salts. With readily available cyclic diaryliodonium salts and ubiquitous aliphatic or (hetero)aromatic carboxylic acids as the starting materials, various axially chiral

Full text of DOI:10.1021/acscatal.9b00695

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Article
Enantioselective Synthesis of Axially Chiral Biaryls via Cu-
Catalyzed Acyloxylation of Cyclic Diaryliodonium Salts
Kai Zhu, Kai Xu, Qi Fang, Yi Wang, Bencan Tang, and Fengzhi Zhang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00695 • Publication Date (Web): 22 Apr 2019
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Page 1 of 8
ACS Catalysis
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Enantioselective Synthesis of Axially Chiral Biaryls via Cu-
Catalyzed Acyloxylation of Cyclic Diaryliodonium Salts
5
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Kai Zhu, †, ‡ Kai Xu, † Qi Fang, † Yi Wang, † Bencan Tang§ and Fengzhi Zhang*, †, ‡
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9
†
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, P. R. China
‡
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou, 310014, P. R. China
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§
Department of Chemical and Environment Engineering, The University of Nottingham Ningbo China, Ningbo, 315100
ABSTRACT: We report here a Cu-catalyzed enantioselective acyloxylation of cyclic diaryliodonium salts. With readily available
cyclic diaryliodonium salts and ubiquitous aliphatic or (hetero)aromatic carboxylic acids as the starting materials, various axially
chiral acyloxylated 2-iodobiaryls were prepared in
excellent yields and enantioselectivity (mostly 99%
yield and 99% ee). DFT calculations were conducted
to reveal the stereo- and regioselectivity. This simple
reaction protocol can be employed for the late stage
modification of some drug molecules. Finally, by
diversity-oriented transformations these acyloxylated
2-iodobiaryl products can be easily transformed into
R2
R1
enantioselective
acyloxylation
R1
R2
I
O
CO2H
+
> 40 examples
mostly 99% yield
and 99% ee
I
O
OTf
Readily available carboxylic acids
and cyclic diaryliodonium salts
Valuable functionalized
axially chiral biaryls
diverse valuable functionalized biaryls which could be used as chiral ligands or functional materials.
KEYWORDS: diaryliodonium salts, axially chiral biaryl, copper catalysis, acyloxylation, diversity oriented synthesis
Atropisomerism, a dynamic type of axial chirality arising from
a large degree of hindrance to rotation about a bond, exists in
many common scaffolds including biaryls, benzamides,
anilides, diaryl ethers and diaryl amines.1 In drug discovery,
the prevalence of atropisomerism has been increasing over the
last decade.2 It has become increasingly appreciated that each
possible atropisomeric conformation of a molecule can
possess different drug properties and target profiles.3 Several
research groups have demonstrated that the selectivity of a
promiscuous compound can be improved by rigidifying it into
the relevant conformation for the desired binding target.4 As
atropisomerism becomes more prevalent, it’s highly important
to develop novel and improved methods to obtain enantiopure
atropisomers.
Although several strategies including metal-catalyzed and
organo-catalytic processes have been developed for the
1,9,10
construction of biaryl atropisomers,
there are still some
challenges need to be addressed. First, how to make the
reaction happen in excellent yield and full enantiocontrol
under mild conditions with low catalyst loading; Second, how
to control the regioselectivity in the presence of other reaction
sites; Third, how to increase the functional group tolerance
and the structural diversity of the axially chiral biaryls.
Recently we completed the copper-catalyzed acyloxylation of
cyclic diaryliodonium salts for the construction of racemic
biaryls.11 We envisioned that the above challenges might be
addressed by developing our enantioselective version of
acyloxylation for the access of axially chiral biaryls.
Compared to the linear diaryliodonium salts which have been
widely employed as the arylating reagents in (non)asymmetric
reactions,12,13 the research especially the asymmetric synthesis
involved with the cyclic diaryliodonium salts are very rare.14,15
In 2004, the Hayashi group reported the palladium-catalyzed
Heck and carbonylation reactions of cyclic diaryliodonium salt,
which opened a new window for the access of enantiopure
biaryl atropisomers although only one asymmetric example
reported with 38% yield and 28% ee (Scheme 1a).16 During
our investigation, the Gu group reported excellent examples
about the enantioselective amination and thiolative of cyclic
diaryliodonum salts for the access of axially chiral biaryls
(Scheme 1b).17 In addition, the Gu group also reported an
asymmetric ring-opening reaction of diaryliodoniums to
access molecules with center chirality.18 In continuation of
our interest in the diaryliodonium salt chemistry,19 herein we
report our enantioselective acyloxylation of cyclic
diaryliodonium salts for the efficient preparation of axially
chiral biaryls under economical, mild and scalable conditions
(Scheme 1c), and demonstrate that they can be served as
platform molecules for the divergent synthesis of various
valuable chiral ligands or building blocks.
Biaryl atropisomerism is the most typical type of axial
chirality arising from a large degree of hindrance to rotation
about the aryl-aryl single bond, which is ubiquitous in
pharmaceuticals (such as vancomycin5 used as antibiotic),
bioactive natural product (such as gossypol6 used as Bcl-2
inhibitor), functional materials (such as the dopants7 used in
nematic liquid crystals) and chiral ligands8 (Figure 1).
O
R
OH
OH
HO
OH
OH
O
H2N
O
HO
O
O
Me Me
O
O
O
R
Cl
O
O
chiral ligand dopant in liquid crystals
HO
OH
H
Cl
O
H
O
O
H
NH
N
N
O
H
OH
OH
N
N
H
O
N
OH
O
H
H
O
O
NH
HO
HO
HOOC
NH2
OH
O
H
vancomycin
antibiotic
gossypol
Bcl-2 inhibitor
HO
OH
OH
Figure 1: Representative molecules containing axially
chiral biaryl skeleton
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We laid special stress on screening the effects of various
Page 2 of 8
(a) Hayash's Pd-catalyzed asymmetric carboxylation
Pd(OAc)2
1
2
3
4
5
6
7
8
chiral ligands. First, the chiral phosphoramidite L1 and
phosphine L2 were tested which gave either no or very poor
enantioselectivity, albeit virtually quantitative yields of the
desired product 3a were obtained (Table 1, entries 1 and 2).
The pyridine oxazoline ligands L2-7 were then screened. The
reaction using pyridine oxazoline ligand L3 gave only 3% ee
(Table 1, entry 3). The C2-symmetric pyridine bis(oxazoline)
ligands (PyBOX) L4-7 led to 66-70% ee (Table 1, entries 4-6).
Finally, the bis(oxazoline) ligands (BOX) L8-10 with an
isopropyl linker were screened. To our pleasant surprise, it
was found the ee was increased dramatically to 99% in almost
quantitative yield when L8 was used (Table 1, entry 8). The
reaction with phenyl-substituted ligand L9 was almost equally
effective (Table 1, entry 9). However, the ee was decreased to
67% when the tert-butyl-substitued bisoxazoline L10 was used
(Table 1, entry 10). Further investigation with L8 identified
that the loading of catalyst and ligand could be reduced to 5
mol% without compromising the yield or enantioselectivity of
3a (Table 1, entries 11-12). The control experiment showed
that no reaction happened in the absence of copper catalyst
(not shown here).
I
+
CO
MeOH +
CO2Me
(R)-BINAP
I
Et3N, DMF
OTf
38% yield, 28% ee
(b) Gu's Cu-catalyzed asymmetric amination and thiolation
R2
R1
Cu(PyBox)2PF6
R1
R2
I
Z
R X
+
or Cu(CH3CN)4PF6,
(S)-(Ph)-Box
up to 99% yield
and 99% ee
I
Y
9
X = NH2/COSK
Y = OTf or PF6
Z = NHR/SCOR
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(c) This work: Cu-catalyzed asymmetric acyloxylation
R2
R1
Cu(OAc)2
chiral Box ligand
R1
R2
I
O
CO2H
+
> 40 examples
mostly 99% yield
and 99% ee
I
O
OTf
Readily available carboxylic acids
and cyclic diaryliodonium salts
Valuable functionalized
axially chiral biaryls
Scheme
1:
Asymmetric
synthesis
with
cyclic
diaryliodonium salts.
We started our investigation by reacting benzoic acid 1a
with cyclic diaryliodonium salt 2a in DCM at 30 C with
o
Cu(OAc)2 (10 mol%) as the catalyst (Table 1).
Table 1: Optimization of the reaction conditions
COOH
With the optimal conditions in hands, we first examined the
scope of carboxylic acids for this enantioselective
acyloxylation reaction (Table 2).
Table 2: Substrate scope of carboxylic acids
Cu(OAc)2
I
O
+
chiral ligand
Na2CO3, DCM
I
Cu(OAc)2 (5 mol%)
OTf
O
I
O
R COOH
+
3a
1a
2a
L8 (5 mol%), Na2CO3 (3 eq.)
DCM, 30 oC, 12 h
I
2a
R
OTf
1
O
O
3
O
O
O
(0.1 mmol)
(0.12 mmol)
Ph
Ph
P
Ph
O
O
N
P
P
N
Ph
N
Cl
F
I
O
I
O
I
O
I
O
L2
L3
L1
O
O
O
O
N
O
O
O
N
O
O
N
N
N
N
N
3a
3b
, 99%, 99% ee
, 99%, 99% ee
3c
, 98%, 99% ee
3d
, 99%, 99% ee
N
N
Ph
Ph
L5
L4
L6
O
O
Br
OMe
O
O
I
O
I
O
I
O
O
I
O
H
N
O
O
N
O
O
N
N
N
N
N
N
N
O
O
OH
O
O
Bn
Bn
Ph
Ph
L7
L9
L8
L10
3e
, 98%, 99% ee
3f
, 99%, 99% ee
3g
, 99%, 95% ee
3h
, 98%, 97% ee
Entrya
Cat/mol% Ligand/mol%
Yieldb
99
eec
0
I
I
I
O
I
1
2
10
10
10
10
10
10
10
10
10
10
5
L1/20
L2/20
L3/20
L4/20
L5/20
L6/20
L7/20
L8/20
L9/20
L10/20
L8/10
L8/5
O
O
O
O
NO2
99
8
O
O
O
O
3l
, 95%, 99% ee
3i
3j
3k
, 98%, 99% ee
, 98%, 99% ee
, 98%, 99% ee
3
99
3
4
99
66
64
67
70
99
97
67
99
99
I
O
S
I
O
I
O
I
O
5
93
N
O
O
6
99
O
O
3o
, 98%, 99% ee
3p
, 98%, 98% ee
3n
, N.R.
3m
, 94%, 99% ee
7
90
8
99
I
I
I
I
9
99
O
O
O
O
Ph
O
O
O
O
10
11
12
98
3q
3r
3s
3t
, 95%, 99% ee
, 91%, 99% ee
, 99%, 99% ee
, 91%, 95% ee
99
5
99
I
O
I
O
I
O
I
O
Ph
Cl
NHCbz
Br
aReaction conditions: benzoic acid 1a (0.1 mmol), iodonium
salt 2a (0.12 mmol), Cu(OAc)2 (x mol%), chiral ligand
(x mol%), Na2CO3 (0.3 mmol), DCM (2.0 mL), 30 C, 12 h.
b Isolated yields. cDetermined by chiral HPLC.
O
O
O
O
3u
, 94%, 99% ee
3w
3v
, 82%, 99% ee
, 89%, 99% ee
3x
, 97%, 98% ee
o
Generally the benzoic acid derivatives with either simple
alkyl (3b), halogen (3c-e), strong electron-donating (3f and 3g)
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ACS Catalysis
or withdrawing (3h and 3i) substituents all gave excellent
carboxylic acid attacking from the less hindered side of the
diaryliodonium salts. Again, all kinds of functional groups
such as halide, nitro, ester or even the hydroxyl group are
tolerated under this mild reaction conditions.
1
yields and ee (>98% yield, >95% ee). 1-Naphthoic acid (3j)
and 2-naphthoic acid (3k) also proceed steadily to give perfect
stereo induction. The reactions with heteroaromatic carboxylic
acids such as 2-furoic acid (3l) and 2-thiophenecarboxylic acid
(3m) afforded the corresponding products in excellent yields
and ee. However, 2-quinolinecarboxylic acid (3n) was
negative for this reaction probably because of the strong
coordinate effect of nitrogen. Alkyl carboxylic acids also
worked smoothly and delivered the corresponding products in
excellent yields and ee (3o-x) except the one with chlorine
substituent (3v) giving a slightly decreased yield. Lots of
functional groups such as hydroxyl, formyl, nitro, alkynyl,
alkenyl, halogen and amide were tolerated under these mild
conditions, which provide functional handles for further
transformations. It is worth mentioning that the reaction, with
carboxylic acids bearing with hydroxyl or unsaturated
functional groups as substrates, took place regioselectively on
the carboxylic acid position without touching either hydroxyl
(3g), alkynyl (3r) or alkenyl (3s) groups which are normally
reactive in the copper catalyzed reactions involved with linear
diaryliodonium salts.20
2
3
4
5
6
7
8
9
To gain more understanding of this reaction, we further
conducted the following competition experiments (Scheme 2).
First, the reactivity of the linear 5 and cyclic diaryliodonium
salt 2a was compared (Scheme 2, equation 1). Treatment of
the benzoic acid 1a with the same amount of 5 and 2a under
the optimized conditions, only the axially chiral product 3a
was obtained in 85% yield, which demonstrated the cyclic
diaryliodonium salt 2a is much more reactive than the linear
one 5 under these conditions. We then examined the
electronic effect of the substituents on the carboxylic acids
(Scheme 2, equation 2). The reaction with a mixture of 1i, 1f
and 2a gave the product 3h as the major product which
showed the electron deficient carboxylic acid reacts much
faster than the electron rich one. It gave almost equal amount
of products 3a and 3p by reacting the mixture of acids 1a and
1p with 2a (Scheme 2, equation 3).
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OTf
optimized
I
I
O
+
+
(1)
conditions
I
Next, we examined the scope of substituted cyclic
diaryliodoniums salts (Table 3). First, the symmetric cyclic
diaryliodonium salts were tested (4a-e). When additional
methyl substituents were introduced to the meta- or para-
position of the C-I bond, the reactions gave the corresponding
COOH
OTf
O
5
1a
0.2 mmol
2a
0.2 mmol
3a
, 85%
0.2 mmol
OMe
NO2
+
NO2
OMe
optimized
conditions
I
O
I
+
(2)
O
I
COOH
COOH
OTf
2a
0.2 mmol
O
O
0
products in almost quantitative yields and ee at 0 C (4a-d).
1i
1f
3h
, 69%
3f
, 16%
0.2 mmol
0.2 mmol
The reaction of dinaphthaleneiodonium salt gave the product
4e in 99% ee and an un-optimized moderate yield. The non-
symmetric cyclic diaryliodonium salts were then examined
(4f-p). It was found that all of them with either a methyl,
fluorine or chlorine atom at the adjacent position of the C-I
bond delivered the axially chiral products efficiently (>93%
yield, >97% ee), which took place regioselectively with the
Table 3: Substrate scope of cyclic diaryliodonium salts
optimized
conditions
+
(3)
+
I
O
I
O
+
COOH
COOH
I
OTf
O
O
1a
0.2 mmol
1p
2a
0.2 mmol
3a
, 46%
0.2 mmol
3p
, 44%
Scheme 2: Competition experiments
The single crystal X-ray diffraction analysis of 4j was then
performed to determine the stereoselectivity of this reaction.21
R2
R1
Cu(OAc)2 (5 mol%)
R1
R2
I
O
R COOH
+
The stereochemistry of 4j was determined to be
R
R
L8 (5 mol%), Na2CO3 (3 eq.)
DCM, 30 oC, 12 h
I
configuration. In terms of the regioselectivity, surprisingly it
was found that the acid 1j only attacked the salt 2 from the
phenyl ring without fluorine (Figure 2).
1
2
O
OTf
4
(0.1 mmol)
(0.12 mmol)
I
I
I
I
O
Ph
O
O
Ph
O
O
O
O
O
F
NO2
4a [a]
4b [a]
4c [a]
4d [a]
,
99%, 99% ee
,
99%, 99% ee
,
99%, 99% ee
I
,
99%, 99% ee
F
O
I
O
I
O
I
O
O
I
O
Ph
Ph
4j
O
O
O
O
4h
, 98%, 99% ee
4f
4j
4g
Figure 2: X-ray structure of 4j
, 99%, 99% ee
,99%, 99% ee
4e
, 52%, 99% ee
F
F
Cl
I
Cl
NO2
I
I
O
I
O
O
Ph
O
Ph
O
O
O
O
4i
, 96%, 99% ee
4l
, 95%, 99% ee
4k
, 99%, 99% ee
, 97%, 99% ee
I
I
I
I
O
Ph
HO
O
Ph
O
Ph
O
O
O
O
O
O
O
4p
, 96%, 97% ee
4o
, 93%, 99% ee
4n
, 96%, 99% ee
4m
, 98%, 99% ee
aReaction temperature: 0 oC,
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Page 4 of 8
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Figure 3: DFT-calculated free-energy profile (kcal/mol) for Cu-catalyzed acyloxylation of cyclic diaryliodonium salt.
All hydrogen atoms in transition-state geometries are not shown for clarity. Key distances are indicated in Å. Figures
of the transition-state geometries were prepared using CYLview.
To reveal the possible reaction mechanism and the origin of
enantio-/regioselectivity, the DFT calculations were
conducted.22 The possible reaction pathway might involve
three steps (Figure 3): a Cu-catalyzed ring-opening step of the
cyclic diaryliodonium salt, an exergonic reorientation of the
carboxyl group, and the final acyloxylation that generates the
desired product. The pathway leading to the major (R)-
enantiomer has an overall barrier of 9.7 kcal/mol, which is 5.3
kcal/mol lower in energy than that of minor (S)-enantiomer
(see SI, Figure S1). The high barrier for TS1-S is probably
caused by the steric repulsion between the indeno group in the
ligand and the cyclic diaryliodonium salt (See SI, Figure S2).
In terms of the regioselectivity, DFT calculations show the
bond cleavage between iodine and phenyl ring is preferred
over the one between iodine and fluorine-substituted phenyl
ring by 4.9 kcal/mol in energy (See SI, Figure S3), explaining
why only one single product 4j was obtained.
To further demonstrate the utility of these axially chiral
acyloxylated products, the gram-scale reaction was conducted,
and the platform molecule 3a (1.7 g, 99% yield and 99% ee)
was prepared efficiently with further reduced amounts of
copper catalyst and chiral ligand (1 mol%). Compound 3a was
then converted into various valuable functionalized biaryls by
diversity-oriented transformations (Scheme 4). The
alkenylated biaryl 11 was prepared in 71% yield and 99% ee
under the Heck coupling conditions with styrene. By cross
coupling with pyridine-3-boronic acid or diphenylphosphine
the chiral bidentate pyridine (12) and phosphino ligands (13)
could be prepared in good yields and excellent ee respectively.
Functional groups such as phenyl could be introduced to give
14 efficiently by a Pd-catalyzed C-H activation/arylation with
the ester as the directing group. Finally, the ester 3a could be
hydrolyzed to give the monophenol 15 and then biphenol 16 in
excellent yields and enantioselectivities. Treated biphenol 16
with phosphoryl chloride afforded the axially chiral
phosphoric acid 17 which is a highly valuable chiral ligand
and might be difficult to access by other methods.8,24
Given that the carboxylic acid motifs are present in a range
of small-molecule drugs or pre-clinical candidates, the late-
stage functionalization of such molecules would be a powerful
demonstration of the utility of this process. To confirm this
strategy, we selected five of most prescribed drugs
(Indometacin, febuxostat, furosemide, diclofenac and
naproxen) and treated them to the reaction conditions (Scheme
3). Each of these drug molecules underwent smooth reaction
with the cyclic diaryliodonium salt 2a and furnished the
desired drug-like products 6-10 respectively in excellent
enantioselectivities with an axially chiral biaryl moiety, which
might have different bioavailability and target profiles.23
PPh2
OH
I
N
OH
OH
12
, 80%, 95% ee
15
, 98%, 99% ee
13
, 52%, 99% ee
e
b
c
f
Ph
Ph
OH
OH
I
O
O
Ph
a
O
OMe
O
CN
N
16
, 84%, 99% ee
I
I
3a
11
, 71%, 99% ee
O
O
O
S
g
N
O
O
d
Cl
O
7
(from febuxostat)
O
O
6
(from indometacin)
I
O
98%, 99% ee
80%, 99% ee
NH2
P OH
O
Ph
Cl
O
O S O
Cl
Ph
I
O
HN
I
O
I
O
14
, 73%, 99% ee
17
, 85%
Cl
O
aStyrene, Pd(OAc)2, AgOAc, AcOH, 110 oC; bPyridine-3-
O
O
O
HN
O
boronic acid, Pd(PPh3)4, K2CO3, DMF, 110 oC;
c
10
(from naproxen)
99%, dr 99:1
9
(from diclofenac)
99%, 99% ee
8
(from furosemide)
88%, 99% ee
o
d
Diphenylphosphine, CuI, Cs2CO3, toluene, 100 C; Ph2IOTf,
Pd(OAc)2, Ac2O, TfOH, DCE, 50 oC; eLiOH,
Scheme 3: Late stage modification of drug molecules
o
f
.
THF/MeOH/H2O, 40 C; Cu(OAc)2 H2O, D-glucose, KOH,
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ACS Catalysis
DMSO/H2O, 110 oC; g1. POCl3, TEA, DCM, 45 oC; 2.
THF/H2O, 60 C.
Scheme 4: Diversity oriented transformations of product
3a.
B. Construction of Axially Chiral Compounds via Asymmetric
Organocatalysis. Acc. Chem. Res. 2018, 51, 534-547.
(2) Toenjes, S. T.; Gustafson, J. L. Atropisomerism in Medicinal
Chemistry: Challenges and Opportunities. Future. Med. Chem. 2018,
10, 409-422.
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Challenge of Atropisomerism in Drug Discovery. Angew. Chem., Int.
Ed. 2009, 48, 6398-6401.
o
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In summary, we have developed an efficient protocol for the
construction of axially chiral biaryls via copper-catalyzed
acyloxylation of cyclic diaryliodonium salts with
(4) (a) Laplante, S. R.; Fader, L. D.; Fandrick, K. R.; Fandrick, D. R.;
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Zhu, J. P. Palladium-Catalyzed Enantioselective Desymmetrizing
Aza-Wacker Reaction: Development and Application to the Total
Synthesis of (−)-Mesembrane and (+)-Crinane. Angew. Chem., Int. Ed.
2018, 57, 1995-1999.
(9) For selected metal-catalyzed examples, see: (a) Guo, Q. X.; Wu, Z.
J.; Luo, Z. B.; Liu, Q. Z.; Ye, J. L.; Luo, S. W.; Cun, L. F.; Gong, L.
Z. Highly Enantioselective Oxidative Couplings of 2-Naphthols
Catalyzed by Chiral Bimetallic Oxovanadium Complexes with either
Oxygen or Air as Oxidant. J. Am. Chem. Soc. 2007, 129, 13927-
13938. (b) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka, K.
Asymmetric Assembly of Aromatic Rings to Produce Tetra-ortho-
Substituted Axially Chiral Biaryl Phosphorus Compounds. Angew.
Chem., Int. Ed. 2007, 46, 3951-3954. (c) Shen, X.; Jones, G. O.;
Watson, D. A.; Bhayana, B.; Buchwald, S. L. Enantioselective
Synthesis of Axially Chiral Biaryls by the Pd-Catalyzed Suzuki-
Miyaura Reaction: Substrate Scope and Quantum Mechanical
Investigations. J. Am. Chem. Soc. 2010, 132, 11278-11287. (d) Zheng,
J.; Cui, W. J.; Zheng, C.; You, S. L. Synthesis and Application of
Chiral Spiro Cp Ligands in Rhodium-Catalyzed Asymmetric
Oxidative Coupling of Biaryl Compounds with Alkenes. J. Am. Chem.
Soc. 2016, 138, 5242-5245. (e) Pan, C. Q.; Zhu, Z. X.; Zhang, M. K.;
Gu, Z. H. Palladium-Catalyzed Enantioselective Synthesis of 2-Aryl
Cyclohex-2-enone Atropisomers: Platform Molecules for the
Divergent Synthesis of Axially Chiral Biaryl Compounds. Angew.
Chem., Int. Ed. 2017, 56, 4777-4781. (f) Newton, C. G.; Braconi, E.;
Kuziola, J.; Wodrich, M. D.; Cramer, N. Palladium-Catalyzed
Enantioselective Synthesis of 2-Aryl Cyclohex-2-enone Atrop Axially
commercially
available
carboxylic
acids.
Various
functionalized biaryl acetates were prepared in excellent yields
and enantioselectivity, and a wide range of functional groups
are tolerated under the mild and scalable reaction conditions.
DFT calculations were conducted to reveal the stereo- and
regioselectivity of this reaction. This simple reaction protocol
can be applied for the late stage modification of some drug
molecules to give the novel drug-like atropisomers. Finally,
we further demonstrated that various valuable axially chiral
biaryl ligands or functional molecules can be accessed
efficiently by diversity-oriented transformations of the biaryl
acetate products. We expect this highly efficient atropisomer
conformation controlling work will become a more prevalent
strategy in asymmetric synthesis and drug discovery.
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■
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhangfengzhi@zjut.edu.cn
ORCID
Fengzhi Zhang: 0000-0001-9542-6634
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENT
This research was supported by the NSFC under grant No.
21871234, and Zhejiang Provincial NSFC for Distinguished
Young Scholars under grant No. LR15H300001. We
appreciate the help from Prof. Guilin Zhuang of Zhejiang
University of Technology for X-ray analysis.
■
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Enantioselective Synthesis of Axially Chiral Biaryls via Cu-
Catalyzed Acyloxylation of Cyclic Diaryliodonium Salts
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Kai Zhu, †, ‡ Kai Xu, † Qi Fang, † Yi Wang, † Bencan Tang§ and Fengzhi Zhang*, †, ‡
In the presence of catalytic amount of Cu(OAc)2 and chiral Box ligand, the reactions of (hetero)aromatic or aliphatic carboxylic acids with
cyclic diaryliodonium salts afforded the valuable axially chiral biaryls in excellent yields and enantioselectivities.
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R2
R1
Cu(OAc)2,
chiral Box ligand
R1
R2
I
O
CO2H
+
> 40 examples
mostly 99% yield
and 99% ee
I
O
OTf
Readily available carboxylic acids
and cyclic diaryliodonium salts
Valuablefunctionalized
axially chiral biaryls
8
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