Enantioselective cross-coupling for axially chiral tetra-ortho-substituted biaryls and asymmetric synthesis of gossypol

Article abstract of DOI:10.1021/jacs.0c02686

The axially chiral tetra-ortho-substituted biaryl skeleton exists in numerous biologically important natural products, pharmaceutical molecules, chiral catalysts, and ligands. The efficient synthesis of chiral tetra-ortho-substituted biaryl structures rem

Full text of DOI:10.1021/jacs.0c02686

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Article
Enantioselective Cross-Coupling for Axially Chiral Tetra-ortho-
Substituted Biaryls and Asymmetric Synthesis of Gossypol
He Yang, Jiawei Sun, Wei Gu, and Wenjun Tang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02686 • Publication Date (Web): 02 Apr 2020
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Journal of the American Chemical Society
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Enantioselective Cross-Coupling for Axially Chiral Tetra-ortho-
Substituted Biaryls and Asymmetric Synthesis of Gossypol
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He Yang,†,‡ Jiawei Sun,† Wei Gu,† and Wenjun Tang*,†,§
†State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences
‡Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, China
§School of Chemistry and Material Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of
Sciences
Supporting Information Placeholder
construction of sterically more hindered chiral tetra-ortho-
substituted biaryls remains a challenging and unsolved problem.
ABSTRACT: Axially chiral tetra-ortho-substituted biaryl
skeleton exists in numerous biologically important natural
products, pharmaceutical molecules, chiral catalysts and ligands.
The efficient synthesis of chiral tetra-ortho-substituted biaryl
structures remains a challenging but unsolved problem. Among
various asymmetric synthetic protocols, enantioselective Suzuki-
Miyaura cross-coupling represents one of the most
straightforward and versatile approaches. Herein we describe a
a) Axially chiral tetra-ortho-substituted natural
products and ligands
OH
O
OH
OH
OH
CHO OH
Me
OH
HO
HO
O
HO
powerful Suzuki-Miyaura coupling enabled by
a P-chiral
OH CHO
monophosphorus ligand BaryPhos, providing a broad range of
synthetically challenging chiral tetra-ortho-substituted biaryls in
excellent enantioselectivities and yields. In addition to the
enhanced reactivity for sterically hindered cross-coupling, the
rational design of BaryPhos also enabled a new catalysis mode of
asymmetric cross-coupling involving noncovalent interactions
between the ligand and two coupling partners, to effect efficient
stereoinduction. This protocol is robust and practical, allowing for
a concise enantioselective synthesis of therapeutically valuable
male contraceptive and antitumor agent gossypol.
OMe O
(M)-Knipholone
(S)-Gossypol
O
O
H
PPh2
PPh2
N
N
H
O
O
Bismurrayaquinone A
(S)-BINAP
R6
b)
R6
R4
R5
Pd-L*, base
R4
R1
R5
R2
[B]
Br
+
Introduction
R1
R2
R3
Axially chiral biaryl skeletons exist ubiquitously in numerous
therapeutic agents as well as biologically important natural
products.1 It is also a privileged backbone structure for thousands
of chiral catalysts and ligands in asymmetric catalytic reactions
(Figure 1a).2 Studies on such structures have gained significant
interests, resulting in a number of synthetic strategies.3 Among
them, the enantioselective transition-metal catalyzed cross-
coupling represents one of most straightforward, versatile, and
practical approaches to chiral biaryls with respect to the direct
formation of the C(sp2)C(sp2) axis.4 In particular, the
enantioselective Suzuki-Miyaura cross-coupling is most
convenient and reliable due to the ease of operation, nontoxic
nature, the ready availability and high stability of starting
materials. Nevertheless, most progresses in this field have been
focused on the synthesis of sterically less congested tri-ortho-
substituted biaryls (Figure 1b).5,6 In comparison with chiral tri-
ortho-substituted biaryl structure, the tetra-ortho-substituted
biaryl skeleton is a more common feature for axially chiral natural
products and many prominent ligands/catalysts. However, the
R3
Existing enantioselective Suzuki-Miyaura coupling
For tri-ortho-substituted biaryls
Limited access to tetra-ortho-
substituted biaryl compounds
R2
R1
Mostly naphthalene-based
biaryl structures
A general coupling method (this work)
Tetra-ortho-substitution
R4
R3
R2
R1
Biphenyl-type structures
Diversified biaryl products
Figure 1. Challenges in catalytic asymmetric cross-coupling for
the synthesis of axially chiral tetra-ortho-substituted biaryls.
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Most reported methods and catalysts suffer from low reactivities,
possess O and C substitution at the ortho positions of the axial
axis, which is a common structural feature in a wide range of
axially chiral tetra-ortho-substituted biaryl natural products and
pharmaceuticals. Secondly, the formyl group enables further
synthetic manipulations to various functional groups. Thirdly, the
formyl group can engage in a noncovalent interaction with other
moiety during the coupling process, which is important for the
proposed coupling protocol. As depicted in Table 1, the
employment of P-chiral monophosphorus ligand L1 (Entry 1,
Table 1) and L2 (Entry 2, Table 1), which were efficient for
enantioselective synthesis of tri-ortho-substituted biaryls in our
previous report, led to moderate yields and unsatisfactory ee’s.
Ligand L3 bearing a tertiary alcohol moiety was then designed in
hope to achieve enhanced reactivity and selectivity (Entry 3,
Table 1). Encouragingly, the improved enantioselectivity (64%
ee), compared with that using L2 (45% ee), indicated the
effectiveness of our proposal. More importantly, the use of L3 led
to a complete conversion and an excellent yield of 3 (90%),
demonstrating the increased reactivity with the tertiary alcohol
moiety in the ligand structure. Further protection of the hydroxyl
group in L3 was detrimental to the cross-coupling as the use of
L4 afforded diminished enantioselectivity (36% ee) and yield
(78%) (Entry 4, Table 1). Structural modification was made at the
2,6-dimethoxyphenyl moiety of the ligand. The installation of two
iPr groups remarkably improved the enantioselectivity. When L5
was employed, 86% ee was achieved (Entry 5, Table 1). Further
modifications of the ligand structure led to L6, an air-stable and
synthetically convenient ligand named as BaryPhos. The Suzuki-
Miyaura coupling reaction using L6 produced 3 in 93% yield and
92% ee (Entry 6, Fig. 2). These results demonstrate the
importance of the tertiary alcohol moiety in ligand structure for
both reactivity and enantioselectivity.
1
2
3
4
5
6
7
8
unsatisfactory enantioselectivities, or a limited substrate scope.6u-
6z,7
For example, the existing coupling reactions are limited to
substrates with extended π system, such as 2-substituted-1-
naphthyl derivatives, to produce axially chiral naphthalenes and
related biaryl structures. The synthesis of axially chiral tetra-
ortho-substituted biphenyls remains ellusive.8 Furthermore, a
general and practical coupling protocol is to be developed to
tolerate different functional groups and substrate skeletons, as
well as to diversify the valuable axially chiral tetra-ortho-
substituted biaryl structures.
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The
importance
of
non-covalent
interactions
to
enantioselectivity in asymmetric catalysis has been well studied
and documented.9 The beneficial effects of weak interactions have
also been emphasized in enantioselective Suzuki-Miyaura cross-
coupling for the synthesis of axially chiral tri-ortho-substituted
biaryls.6b,6o We realized previously a highly enantioselective
Suzuki-Miyaura cross-coupling for the synthesis of axially chiral
tri-ortho-substituted biaryl naphthalenes by using P-chiral
monophosphorus ligands and exploiting a secondary interaction
(polar-π) between two coupling partners (Figure 2a).6j,6k,10
However, this paradigm would not be reliable for the synthesis of
axially chiral tetra-ortho-substituted biphenyls due to the absence
of extended π-system in substrates. New chiral catalyst and
coupling mode need to be developed for the efficient
discrimination of the two ortho substituents in phenyl substrates
during the coupling process. In this report, we established a
general and efficient Suzuki-Miyaura coupling protocol for the
synthesis of axially chiral tetra-ortho-substituted biphenyls and
related biaryls by rational design of
a
new P-chiral
monophosphorus ligand possessing a hydrogen-bond donor. The
utilization of double non-covalent interactions between ligand and
the two coupling partners are crucial to bolster the chiral
translation from the ligand to the axial chirality of the biaryl
Table 1. Ligand effect on cross-coupling reaction. a
MeO
product in
a highly enantioselective fashion (Figure 2b).
BF3K
Br
Pd2dba3 (0.5 mol %)
Meanwhile, the employment of the sterically hindered
monophosphorus ligand promises high reactivity of the
palladium-catalysed cross-coupling. An enantioselective synthesis
of therapeutically valuable gossypol was achieved for the first
time to demonstrate the utility and robustness of this method.
MeO
MeO
CHO
Ligand (1.5 mol %) MeO
MeO
CHO
CHO
CHO
+
MeO
K3PO4, 60 oC, 12 h
Tol/H2O (5:1, v/v)
1
2
3
yield[a]
ee[b]
entry
ligand
a) For chiral tri-ortho-substituted biaryls, previous study
L1
L2
L3
1
2
3
68%
73%
90%
30%
45%
64%
O
R
Ar
P
tBu
*P Pd Ar'
MeO
OMe
R = Me, iPr
L4
L5
L6
4
5
6
78%
89%
93%
36%
86%
92%
2nd interaction
b) For chiral tetra-ortho-substituted biaryls, this report
a
O
1
Reaction conditions: Aryl bromide (0.10 mmol, 1.0 equiv.), trifluoroarylborate
2
(1.5 equiv.), Pd2(dba)3 (0.5 mol%), ligand (1.5 mol%) and K3PO4 (3.0 equiv.)
in toluene (1.0 mL) and H2O (0.20 mL) at 60 oC for 15 h.
Ar
P
OH
tBu
OMe
*P Pd Ar'
MeO
O
H-bond
donor
O
P
O
P
R1
tBu
OR2
P
OH
2nd interaction
tBu
tBu
MeO
OMe
R3
MeO
OMe
MeO
OMe
R3
Figure 2. Reaction modes for enantioselective cross-coupling.
R
R
3 = iPr
3
L5
L6
L1
L3
L4
R
1 = H (BIDIME)
1 = iPr
R
R
2 = H
2 = Me (NitinPhos)
BaryPhos
= cyclopentyl (
)
L2
R
Results and Discussion
Reaction development
Synthesis of axially chiral tetra-ortho-substituted biaryls
At the outset of our study on asymmetric Suzuki-Miyaura
cross-coupling, we selected substrates with alkoxy and formyl
groups at the ortho positions of the coupling site, such as 1 and 2,
for three reasons. Firstly, the corresponding coupling product will
Axially chiral tetra-ortho-substituted biphenyls remain
challenging targets by transition-metal catalyzed asymmetric
cross-couplings with scarce successful examples.8 In the presence
of 1 mol % Pd-L6 catalyst, a broad range of chiral biphenyls were
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Table 2. Chiral tetra-ortho-substituted biaryls by asymmetric Suzuki-Miyaura coupling. a
1
2
3
4
R6
O
Br
R6
Pd2dba3 (0.5 mol%)
General protocol
P
R1
R2
OH
R4
R1
R5
R2
(S,S)-BaryPhos (1.5 mol%)
tBu
OMe
R4
R5
+
MeO
R3
Diversified axially
chiral biaryls
K3PO4 (3 eq), 60 oC, 15 h
[B]
5
6
7
R3
(S,S)-BaryPhos
a
Axially chiral tetra-ortho-substituted biphenyls
MeO
MeO
MeO
MeO
MeO
8
9
BnO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
BnO
MeO
CHO
CHO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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36
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40
41
42
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60
MeO
MeO
NHPiv
F
MeO
MeO
NO2
OMe
9
4
5
3
6
7
8
88%, 93% ee
79%, 93% eeb
78%, 90% ee
84%, 90% ee
80%, 94% ee
83%, 92% ee
76%, 92% ee
71%, 90% ee
MeO
MeO
MeO
MeO
CHO
CHO
MeO
CHO
CHO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
MeO
MeO
CHO
CHO
F
OMe
MeO
MeO
Ph
(S)-15
10
83%, 92% ee
11
12
69%, 89% eec
13
86%, 91% ee
14
80%, 91% ee
83%, 92% ee
73%, 87% ee
CHO
OMe O
OMe
CHO
OMe
CHO
OMe
OMe
Me
MeO
Me
OMe
OMe
MeO
N
N
N
MeO
CHO
Me
OBn
CHO
OHC
OMe
OHC
OMe
OHC
OHC
MeO
O
16
93%, 67% ee
17
87%, 83% ee
18
19
20
51%, 95% eec
63%, 91% ee
90%, 91% ee
b
Axially chiral tetra-ortho-substituted phenyl-naphthyls
OMe
OMe
OMe
OHC
OMe
OMe
OHC
OMe
OMe
OHC
N
OMe
OMe
OHC
OMe
OMe
OMe
OBn
OHC
OMe
OMe
OHC
OHC
MeO
HO
OMe
21
90%, 93% ee
22
84%, 90% ee
OMe
23
79%, 91% ee
24
80%, 89% ee
25
92%, 91% de
26
87%, 96% ee
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OHC
OHC
OMe
OMe
OHC
OHC
PivHN
OMe
OHC
F
N
OMe
OMe
OMe
OMe
28
91%, 93% ee
27
82%, 91% ee
29
83%, 91% ee
30
(S)-31
89%, 92% ee
92%, 81% ee
c
Axially chiral tetra-ortho-substituted binaphthyls
Ph
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OSO2F
N
OHC
Ph
OMe
32
33
34
81%, 90% ee
35
36
37
89%, 87% ee
65%, 93% ee
92%, 91% ee
87%, 87% ee
90%, 95% ee
CF3
MeO
MeO
Ar
R
=
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
CF3
O
O
TMS
R
=
Ar
88%, 90% ee
38
79%, 92% ee
(S)-39
86%, 96% ee
40
41
75%, 92% ee
aReaction conditions: Aryl bromide (0.10 mmol, 1.0 equiv), trifluoroarylborate or arylboronic acid (1.5 equiv), Pd2(dba)3 (0.5 mol%),(S,S)-BaryPhos (1.5 mol %) and
K3PO4 (3.0 equiv) in toluene (1.0 mL) and H2O (0.20 mL) at 60 oC for 15 h. The yields are isolated yields. bAryl chloride was used in place of aryl bromide. cA one-
pot domino Miyaura-borylation/Suzuki-coupling was employed with reaction conditions as follows: Aryl bromide (0.10 mmol, 1.0 equiv), Pd2(dba)3 (1.0 mol%), (S,S)-
BaryPhos (2.0 mol%), bis(pinacolato)diboron (0.6 equiv) and K3PO4 (3.0 equiv) in toluene (1.0 mL) at 60 oC for 15 h.
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formed in excellent enantioselectivities and yields (Table 2a). The
arylated naphthalene (40) as well as a substrate with a
1
2
3
4
5
6
7
8
method was compatible with aryl bromides bearing electron with-
drawing fluoro (4) and nitro groups (5), providing the
corresponding biphenyls in high yields and 90% ee. Electron-rich
substrates were well-tolerated in the coupling reaction (6-9). Aryl
chloride could be employed as the electrophile to afford the
corresponding product without sacrifice in enantioselectivity,
albeit in a slightly lower yield than using aryl bromide (3). Phenyl
substituted substrate could also participate in the coupling
reaction, leading to the formation of (S)-15, whose absolute
configuration was confirmed by its X-ray structure. Besides non-
C2 symmetric biphenyls, axially chiral C2-symmetric products
were efficiently synthesized from the coupling between aryl
bromides and the corresponding potassium trifluoroarylborates
(10 and 11). It is worth noting that a domino Miyaura
borylation/Suzuki-coupling protocol was reliable for the synthesis
of C2 symmetric biaryls from aryl bromides in the presence of
bis(pinacolato)diboron, giving comparable enantioselectivities to
cross-coupling reactions (12). This tandem coupling cascade
provides a practical synthetic approach to symmetrical axially
chiral natural products. Further study demonstrated that the ortho-
alkoxy substitution was not a necessity. Aryl bromides with fluoro
or alkyl (Me) groups at the ortho position of the coupling site
were suitable substrates to provide axially chiral 13 and 14,
respectively. When the formyl group in one of the coupling
partners was replaced with a methyl group, a diminished
enantioselectivity was obtained (67% ee for 16). This control
example indicated the important role of the formyl groups in both
coupling partners for high enantioselectivity (more control
examples are provided in S65). Structurally complex aryl
bromides based on 2-naphthyl, naphthoquinone and carbazole
skeletons served successfully as electrophiles to provide the
corresponding enantioenriched biaryls with significant synthetic
utilities (17-19). Furthermore, the enantioselective domino
Miyaura borylation/Suzuki-coupling of a carbazole substrate
afforded C2 symmetric biaryls 20 in 95% ee, which possesses
close structural resemblance to pharmacologically intriguing
biscarbazole alkaloids such as bismurrayaquinone A.11
benzopyranone unit (41), generating structurally diverse chiral
binaphthyls. The efficient construction of both C2-symmetric and
non-C2-symmetric chiral BINOL derivatives provided
a
convenient, robust, and reliable method to a diverse set of
BINOL-based ligands and catalysts.12
Mechanistic considerations
In order to gain the structural information of the Pd-L6 catalyst
and illuminate the stereochemical process of the enantioselective
cross-coupling, an oxidative addition Pd(II) complex (42)
containing (R,R)-L6 was prepared with benzaldehyde substrate
and its X-ray crystal structure revealed a dimeric and C2-
symmetric structure at solid state (Figure 3a). Besides the P–Pd
coordination, the O atom of tertiary alcohol in BaryPhos also
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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42
43
44
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60
coordinates to the Pd center to form
a five-membered
oxapalladacycle [Pd–O = 2.15 Å]. As high temperature or a strong
base such as KOH or KOtBu is normally required for sterically
demanding Suzuki-Miyaura cross-couplings,13,14 the Pd-L6
catalyst allowed the current coupling reaction to proceed under
very mild reaction conditions (K3PO4/60 oC). The superior
reactivity observed with the Pd-L6 catalyst is largely attributed to
the presence of the tertiary alcohol moiety in L6 which acts likely
as an internal base during the coupling process. Presumably, the
organoboron transmetalation undergoes a 4-membered oxo-metal
transmetalation pathway facilitated by the Pd–O bond within the
five-membered oxapalladacycle (see S66 for further details).15 In
the solid state of complex 42, because of the presence of the Pd–O
coordination, the aryl group from the substrate was pushed to the
position opposite to the Pd–O coordination, but adjacent to the
lower aryl ring of the BaryPhos. The formyl group of the phenyl
moiety orientates towards one of cyclopentyl units of the ligand.
A weak noncovalent interaction between the O atom of the formyl
group and the nearest C(sp3)–H atom of cyclopentyl moiety was
observed, with the O–H distance of 2.59 Å.6b,16
a) Oxidative addition Pd(II) complex
b) Proposed stereochemical model
hydrogen bonding
(R,R)-BaryPhos
O
O
H
O
O
O
The generality of the enantioselective Suzuki-Miyaura coupling
was further exemplified by the efficient synthesis of phenyl-
O
P
Pd
Ar2
naphthyl type products (Table 2b).
bromonaphthalenes reacted with
A
range of 1-
H
O
C
O
various potassium
Ar1
weak O-H interaction
trifluorophenylborates under current conditions to generate
phenyl-naphthyls in high yields and excellent enantioselectivities
(21-23). The method was compatible with heteroaryl substrates,
such as substituted bromo-isoquinoline and pyridine, leading to
enantioenriched biaryls 24 and 29, respectively. Axially chiral
biaryl 25 containing (S)-naproxol moiety was also synthesized in
92% yield and 91% de by asymmetric coupling between (S)-
O
O
reductive
elimination
O
O
H
P
O
O
O
O
P
Ar2
Pd
O
2.15 Å
Pd
O
Cl
MeO
MeO
CHO
CHO
O
H
C
O
2.68 Å
O
Ar1
O
bromonaproxol
and
the
corresponding
potassium
Ar1
MeO
O
trifluorophenylborate. Interestingly, the reactions proceeded in a
smooth manner to afford axially chiral phenyl-naphthyls in
reliable yields and enantioselectivities (26-31) by simply
swapping the aryl moieties of the two coupling partners, further
demonstrating the generality and robustness of the asymmetric
cross-coupling protocol. The synthesis of chiral tetra-ortho-
substituted binaphthyls was also realized in highly
enantioselective fashion (Table 2c). A series of C2-symmetric (32,
36, 37, 39) and non-C2-symmetric (34 and 38) BINOL derivatives
were produced from enantioselective naphthyl-naphthyl coupling.
Bromoisoquinoline and naphthalene possessing fluorosulfonate
functionality were also converted successfully to enantioenriched
35 and 33 in excellent ee’s and yields, respectively. Notably, the
enantioselective Suzuki-Miyaura coupling was applicable to an
42
3
(R)-
Figure 3. Stereochemical model for enantioselective cross-
coupling.
On the basis of the X-ray structure of complex 42 as well as the
experimental results, a stereochemical model for phenyl-phenyl
cross-coupling is proposed (Figure 3b). Two significant
noncovalent interactions would presumably exist. A weak O···H
interaction between the O atom of the formyl group in Ar1 and
one aliphatic H atom of the cyclopentyl ring, as observed in the
oxidative addition complex 42, would guide the disposition of Ar1
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group. On the other hand, the hydroxyl group in L6 liberated after
1
transmetallation, would interact with the formyl group of Ar2 in
2
3
Scheme 1. Enantioselective synthesis of gossypol
4
5
6
7
8
9
Br
N
3.
OMe O
OMe
OMe
O
OTMS
2. BF3 OEt2, Et3SiH;
then AcCl
O
Br
OMe
OMe
1. DCM, rt
then HOAc
Br
OMe
OMe
Br
OMe
OMe
OMe
OMe
Br
N
O
AIBN
OMe
Br
+
OHC
MeCN, 80 oC;
then NMO
65%
84%
82%
O
45
OAc
46
OH
O
47
43
44
4. TMBBr
K2CO3
96%
[Pd(cinnamyl)Cl]
K3PO4 H2O
rac-
OTf
8.
2
OTMB
MeO
MeO
OMe
10
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43
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45
46
47
48
49
50
51
52
53
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55
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57
58
59
60
5. Pd2(dba)3 (2.5 mol%)
(R,R)-BaryPhos (5 mol%)
6. Pd/C, H2,
CHO
OMe
L9
OMe
Br
OMe
OMe
THF/HOAc
OMe
OMe
MeO
OMe
B(OH)2
56%
MeO
B2pin2, K3PO4, DCE
62%, 83% ee
OMe
50
7. Tf2O,Et3N
71% (2 steps)
OHC
OMe
OHC
49
(-)-
OMe
OTMB
48
OTf
43%, >99% ee after
recrystallization TMB = 3,4,5-trimethoxylbenzyl
(-)-
OTMB
MeO
MeO
HO
HO
HO
10. Cl2CHOMe,
TiCl4
OMe
OH
OH CHO
9. BBr3
O
P
O
P
tBu
tBu
OMe
OMe
OH
OH
OH
OH
HO
94%
46%
OMe
OH
CHO OH
tBu
NMe2
L9
52
(-)- apogossypol
(-)-gossypol
51
(-)- gossypol hexamethyl ether
(1.0 equiv.), DCM, HOAc (2.2 equiv.), 25 oC; 2) BF3 OEt2 (2.0 equiv.), Et3SiH (2.0 equiv.), DCM, 15 h, 25 oC, then AcCl (2.0 equiv.), 0 o
44
C
43
Conditions: 1)
(2.0 equiv.),
to 25 oC; 3) 1,3-bibromo-5,5-dimethylhydantoin (1.1 equiv.), AIBN (5.0 mol%), MeCN, 80 oC, 8 h, then NMO (4.0 equiv.), 80 oC;(4) TMBBr (1.4 equiv.), K2CO3 (1.2 equiv.),
MeCN, 60 oC; (5) Pd2dba3 (2.5 mol%), (R,R)-BaryPhos ( ) (5.0 mol%), B2pin2 (0.6 equiv.), K3PO4 (3.0 equiv.), DCE, 60 oC; 6) 10% Pd/C (10.0 wt%), H2 (1.0 atm), THF,
L6
HOAc, 25 oC; 7) Tf2O (2.5 equiv.), Et3N (3.0 equiv.), DCM, 0 oC to 25 oC; 8) [Pd(cinnamyl)Cl]2 (2.0 mol%), rac- (6.0 mol%), isopropylboronic acid (6.0 equiv.), K3PO4 H2O
L9
(5.0 equiv.), toluene, 100 oC, 5 h; (9) BBr3 (6.0 equiv.), DCM, -78 oC to -10 oC; 10) Cl2CHOMe (4.0 equiv.), TiCl4 (2.0 equiv.), 0 oC to 20 oC.
proximity through a hydrogen-bonding interaction, which should
guide the disposition of Ar2. Reductive elimination via the
proposed favourable transition state gives (R)-3, which is
consistent with the experimental result. Overall, the noncovalent
interactions, in combination with the steric effect arising from the
rigid conformation of L6 enable the high enantioselectivity of
phenyl-phenyl coupling, which was not possible previously. For
asymmetric coupling of substituted 1-naphthyl halides or boronic
acids, the steric effect was presumably operative during the
asymmetric cross-coupling event.
treatment with N-methylmorpholine N-oxide, with concomitant
removal of acetyl group. After the protection of the phenolic
hydroxyl groups in 47 with TMB (3,4,5-trimethoxybenzyl), the
domino Miyaura-borylation/Suzuki-coupling reaction of 48
proceeded smoothly to afford binaphthyl compound 49 in 62%
yield and 83% ee by using Pd-(R,R)-L6 catalyst. Enantiopure (-)-
49 was obtained after recrystallization and was elaborated to
bistriflate (-)-50 via hydrogenolysis and subsequent treatment
with Tf2O/Et3N. The installation of two isopropyl groups was
achieved by conducting a Suzuki-Miyaura coupling between (-)-
50 and isopropylboronic acid using catalyst Pd-L9,20 leading to
gossypol hexamethyl ether (-)-51. Global demethylation afforded
apogossypol (-)-52, which was converted to (-)-gossypol after a
Rieche formylation. This concise, 10-step synthetic route provides
a practical and reliable approach to enantiomerically pure
gossypol and related derivatives for biological and clinical studies.
Synthetic applications
Gossypol is a polyphenolic axially chiral biaryl natural product
with various biological activities such as male antifertility,
antioxidation, treatment of bronchitis, inhibition of HIV, antiviral
and anticancer effects.17 It has also been applied to clinical studies
as AT-101 [(-)-gossypol acetic acid].18 Access to enantiomerically
pure gossypol relies majorly on chemical resolution. To date, the
only asymmetric synthesis of this natural product was reported by
Conclusions and Outlook
A general, practical, and efficient asymmetric Suzuki-Miyaura
aryl–aryl cross-coupling was established, providing convenient
access to a wide range of axially chiral tetra-ortho-substituted
biaryls with significant structural diversity in high yields and
excellent enantioselectivities. The success of this coupling
protocol is attributed to the judicious design and development of a
sterically bulky P-chiral monophosphorus ligand BaryPhos, which
have not only solved the reactivity issue of sterically hindered
coupling for the synthesis of tetra-ortho-substituted biaryls, but
also enabled a new catalysis mode involving noncovalent
interactions between the ligand and two coupling partners to
provide excellent enantioselectivities. Application of this reliable
coupling method is exemplified by a concise and enantioselective
synthesis of male contraceptive and antitumor agent gossypol.
This coupling protocol is expected to present broad synthetic
utilities for chiral ligands, catalysts, materials as well as bioactive
natural products and therapeutic agents.
Meyers using
a chiral auxiliary-assisted diastereoselective
Ullmann coupling to forge the axially chiral biaryl structure.19
The lengthy synthetic route and tedious auxiliary manipulations
make it impractical for ample supply.
A concise and
enantioselective synthesis of gossypol is highly desirable.
Facilitated by the asymmetric Suzuki-Miyaura coupling, an
efficient synthesis of (-)-gossypol was accomplished (Scheme 1).
The synthesis commenced with the Diels-Alder reaction between
easily accessible quinone 43 and diene 44, providing
naphthoquinone 45 in 84% yield. Regioselective reduction of the
naphthoquinone moiety using BF3·OEt2/Et3SiH and in situ quench
with acetyl chloride afforded naphthylene 46. The conversion of
the benzylic methyl group in 46 to a formyl group was necessary
for a highly enantioselective Suzuki-Miyaura coupling. The
transformation was realized through a one-pot two-step sequence
comprising of benzylic dibromination of 46 and subsequent
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Journal of the American Chemical Society
Page 6 of 8
recent advances. Coord. Chem. Rev. 2015, 286, 1-16. (b) Baudoin, O. The
Asymmetric Suzuki Coupling Route to Axially Chiral Biaryls. Eur. J.
Org. Chem. 2005, 4223-4229.
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ASSOCIATED CONTENT
Supporting Information
(6) For selected examples on asymmetric Suzuki-Miyaura coupling
reactions: (a) Yin, J. J.; Buchwald, S. L. A Catalytic Asymmetric Suzuki
Coupling for the Synthesis of Axially Chiral Biaryl Compounds. J. Am.
Chem. Soc. 2000, 122, 12051-12052. (b) 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. (c) Cammidge, A. N.; Crépy, K. V. L. The First
Asymmetric Suzuki Cross-Coupling Reaction. Chem. Commun. 2000,
1723-1724. (d) Mikami, K.; Miyamoto, T.; Hatano, M. A highly efficient
asymmetric Suzuki-Miyaura coupling reaction catalyzed by cationic chiral
palladium(II) complexes. Chem. Commun. 2004, 2082-2083. (e) Ji, W.;
Wu, H, -H.; Zhang, J. Axially Chiral Biaryl Monophosphine Oxides
Enabled by Palladium/WJ-Phos-Catalyzed Asymmetric Suzuki-Miyaura
Cross-Coupling. ACS Catal. 2020, 10, 1548-1554. (f) Bermejo, A.; Ros,
A.; Fernández, R.; Lassaletta, J. M. C2-Symmetric Bis-Hydrazones as
Ligands in the Asymmetric Suzuki-Miyaura Cross-Coupling. J. Am.
Chem. Soc. 2008, 130, 15798-15799. (g) Ros, A.; Estepa, B.; Bermejo, A.;
Álvarez, E.; Fernández, R.; Lassaletta, J. M. Phosphino Hydrazones as
Suitable Ligands in the Asymmetric Suzuki-Miyaura Cross-Coupling. J.
Org. Chem. 2012, 77, 4740-4750. (h) Jumde, V.; Iuliano, A. Deoxycholic
acid derived monophosphites as chiral ligands in the asymmetric Suzuki-
Miyaura cross-coupling. Tetrahedron: Asymmetry 2011, 22, 2151-2155.
(i) Yamamoto, T.; Akai, Y.; Nagata, Y.; Suginome, M. Highly
Enantioselective synthesis of Axially Chiral biarylphosphonates:
Asymmetric Suzuki-Miyaura Coupling Using High-Molecular-Weight,
Helically Chiral Polyquinoxaline-Based Phosphines. Angew. Chem., Int.
Ed. 2011, 50, 8844-8847. (j) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.;
Savoie, J.; Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci, A. G.; Wei, X.;
Zhang, Y.; Gao, J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K.;
Senanayake, C. H. Efficient Chiral Monophosphorous Ligands for
Asymmetric Suzuki-Miyaura Coupling Reactions. Org. Lett. 2012, 14,
2258-2261. (k) Xu, G.; Fu, W.; Liu, G.; Senanayake, C. H.; Tang, W.
Efficient Syntheses of Korupensamines A, B and Michellamine B by
Asymmetric Suzuki-Miyaura Coupling Reactions. J. Am. Chem. Soc.
2014, 136, 570-573. (l) Zhang, S.-S.; Wang, Z. Q.; Xu, M.-H.; Lin, G.-Q.
Chiral Diene as the Ligand for the Synthesis of Axially chiral Compounds
via the Palladium-Catalyzed Suzuki-Miyaura Coupling Reaction. Org.
Lett. 2010, 12, 5546-5549. (m) Sawai, K.; Tatumi, R.; Nakahodo, T.;
Fujihara, H. Asymmetric Suzuki-Miyaura Coupling Reactions Catalyzed
by Chiral Palladium Nanoparticles at Room Temperature. Angew. Chem.,
Int. Ed. 2008, 47, 6917-6919. (n) Wang, S.; Li, J.; Miao, T.; Wu, W.; Li,
Q.; Zhuang, Y.; Zhou, Z.; Qiu, L.-Q. Highly Efficient Synthesis of a Class
of Novel Chiral-Bridged Atropisomeric Monophosphine Ligands via
Simple Desymmetrization and Their Applications in Asymmetric Suzuki-
Miyaura Coupling Reaction. Org. Lett. 2012, 14, 1966-1969. (o) Zhou, Y.;
Zhang, X.; Liang, H.; Cao, Z.; Zhao, X.; He, Y.; Wang, S.; Pang, J.; Zhou,
Z.; Ke, Z.; Qiu, L.-Q. Enantioselective Synthesis of Axially Chiral Biaryl
Monophosphine Oxides via Direct Asymmetric Suzuki Coupling and DFT
Investigations of the Enantioselectivity. ACS Catal. 2014, 4, 1390-1397.
(p) Xia, W.; Li, Y.; Zhou, Z.; Chen, H.; Liang, H.; Yu, S.; He, X.; Zhang,
Y.; Pang, J.; Zhou, Z.; Qiu, L.-Q. Synthesis of Chiral-Bridged
Atropisomeric Monophosphine Ligands with Tunable Dihedral Angles
and their Applications in Asymmetric Suzuki-Miyaura Coupling
Reactions. Adv. Synth. Catal. 2017, 359, 1656-1662. (q) Benhamou, L.;
Besnard, C.; Kündig, E. P. Chiral PEPPSI Complexes: Synthesis,
Characterization, and Application in Asymmetric Suzuki-Miyaura
Coupling Reactions. Organometallics 2014, 33, 260-266. (r) Li, Y.; Tang,
J.; Gu, J.; Wang, Q.; Sun, P.; Zhang, D. Chiral 1,2-CyclohexaneBridged
Bis-NHC Palladium Catalysts for Asymmetric Suzuki-Miyaura Coupling:
Synthesis, Characterization, and Steric Effects on Enantiocontrol.
Organometallics 2014, 33, 876-884. (s) Wu, L.-L.; Salvador, A.; Ou, A.;
Shi, M.-W.; Skelton, B. W.; Dorta, R. Monodentate Chiral N-Heterocyclic
Carbene-Palladium-Catalyzed Asymmetric Suzuki-Miyaura and Kumada
Coupling. Synlett 2013, 24, 1215-1220. (t) Kamei, T.; Sato, A. H.;
Iwasawa, T. Asymmetric Suzuki-Miyaura cross-coupling of aryl chlorides
with enhancement of reaction time and catalyst turnover. Tetrahedron
Lett. 2011, 52, 2638-2641. (u) Patel, N. D.; Sieber, J. D.; Tcyrulnikov, S.;
Simmons, B. J.; Rivalti, D.; Duvvuri, K.; Zhang, Y.; Gao, D. A.; Fandrick,
K. R.; Haddad, N.; Lao, K. S.; Mangunuru, H. P. R.; Biswas, S.; Qu, B.;
The Supporting Information is available free of charge on the
ACS Publications website.
Detailed experimental procedures and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
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*tangwenjun@sioc.ac.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the Strategic Priority Research
Program of the Chinese Academy of Sciences (XDB20000000),
CAS (QYZDY-SSW-SLH029), NSFC (21725205, 21432007,
21572246), and the K.C. Wong Education Foundation.
REFERENCES
(1) Recent reviews: (a) Bringmann, G.; Gulder, T.; Gulder, T. A. M.;
Breuning, M. Atroposelective total synthesis of axially chiral biaryl
natural products. Chem. Rev. 2011, 111, 563-639. (b) Kozlowski, M. C.;
Morgan, B. J.; Linton, E. C. Total synthesis of chiral biaryl natural
products by asymmetric biaryl coupling. Chem. Soc. Rev. 2009, 38, 3193-
3207. (c) Smyth, J. E.; Butler, N. M.; Keller, P. A. A twist of nature-the
significance of atropisomers in biological systems. Nat. Prod. Rep. 2015,
32, 1562-1583. (d) LaPlante, S. R.; Fader, L. D.; Fandrick, K. R.; Fandrick,
D. R.; Hucke, O.; Kemper, R.; Miller, S. P. F.; Edwards, P. J. Assessing
atropisomer axial chirality in drug discovery and development. J. Med.
Chem. 2011, 54, 7005-7022.
(2) (a) Zhou, Q.-L. Privileged chiral ligands and catalysts (Wiley-VCH,
Weinheim, 2011). (b) Yoon, T. P.; Jacobsen, E. N. Privileged chiral
catalysts. Science 2003, 299, 1691-1693.
(3) Recent reviews on asymmetric synthesis of axially chiral biaryls: (a)
Wang, Y,-B.; Tan, B. Construction of axially chiral compounds via
asymmetric organocatalysis. Acc. Chem. Res. 2018, 51, 534-547. (b)
Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. Recent
advances and new concepts for the synthesis of axially stereoenriched
biaryls. Chem. Soc. Rev. 2015, 44, 3418-3430. (c) Metrano, A. J.; Miller,
S. J. Peptide-Based Catalysts Reach the Outer Sphere through Remote
Desymmetrization and Atroposelectivity. Acc. Chem. Res. 2019, 52, 199-
215. (d) Loxq, P.; Manoury, E.; Poli, R.; Deydier, E.; Labande, A.
Synthesis of Axially Chiral Biaryl Compounds by Asymmetric Catalysis
Reactions with Transition Metals. Coord. Chem. Rev. 2016, 308, 131-190.
(e) Zilate, B.; Castrogiovanni, A.; Sparr, C. Catalyst-Controlled
Stereoselective Synthesis of Atropisomers. ACS Catal. 2018, 8, 2981-
2988. (f) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivaguru, J.
Nonbiaryl and Heterobiaryl Atropisomers: Molecular Templates with
Promise for Atropselective Chemical Transformations. Chem. Rev. 2015,
115, 11239-11300.
(4) For selected reviews on transition-metal catalyzed cross-coupling
reactions in chiral biaryl synthesis: (a) Cherney, A. H.; Kadunce, N. T.;
Reisman, S. E. Enantioselective and enantiospecific transition-metal-
catalyzed cross-coupling reactions of organometallic reagents to construct
C−C bonds. Chem. Rev. 2015, 115, 9587-9652. (b) Yang, H.; Yang, X.;
Tang, W. Transition-metal catalyzed asymmetric carbon–carbon cross-
coupling with chiral ligands. Tetrahedron 2016, 72, 6143-6174.
(5) For selected reviews on asymmetric Suzuki-Miyaura coupling: (a)
Zhang, D.; Wang, Q. Palladium catalyzed asymmetric Suzuki-Miyaura
coupling reactions to axially chiral biaryl compounds: Chiral ligands and
6
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Page 7 of 8
Journal of the American Chemical Society
Grinberg, N.; Pennino, S.; Lee, H.; Song, J. J.; Gupton, B. F.; Garg, N. K.;
Suzuki-Miyaura coupling: Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 1162-1163.
Kozlowski, M. C.; Senanayake, C. H. Computationally Assisted
Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric
Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-
Substituted Biaryl Synthesis. ACS Catal. 2018, 8, 10190-10209. (v)
Genov, M.; Almorín, A.; Espinet, P. Efficient Synthesis of Chiral 1,1’-
Binaphthalenes by the Asymmetric Suzuki-Miyaura Reactions: Dramatic
Synthetic Improvement by Simple Purification of Naphthylboronic Acids.
Chem. -Eur. J. 2006, 12, 9346-9352. (w) Uozumi, Y.; Matsuura, Y.;
Suzuka, T.; Arakawa, T.; Yamada, Y. M. A. Palladium-Catalyzed
Asymmetric Suzuki-Miyaura Cross Coupling with Homochiral Phosphine
Ligands Having Tetrahydro-1H-imidazo-[1,5-a]indole Backbone.
Synthesis 2017, 49, 59-68. (x) Shen, D.; Xu, Y.; Shi, S, -L. A Bulky Chiral
N-Heterocyclic Carbene Palladium Catalyst enables Highly
Enantioselective Suzuki-Miyaura Cross-Coupling Reactions for the
Synthesis of Biaryl Atropisomers. J. Am. Chem. Soc. 2019, 141, 14938-
14945. (y) Castanet, A. S.; Colobert, F.; Broutin, P. E.; Obringer, M.
Asymmetric Suzuki cross-coupling reaction: Chirality reversal depending
on the palladium-chiral phosphine ratio. Tetrahedron: Asymmetry 2002,
13, 659-665. (z) Uozumi, Y.; Matsuura, T.; Arakawa, T.; Yamada, Y. M.
1
2
3
4
5
6
7
8
(15) (a) Thomas, A. A.; Denmark, S. E. Pre-transmetalation
intermediates in the Suzuki-Miyaura reaction revealed: the missing link.
Science 2016, 352, 329-332. (b) Thomas, A. A.; Zahrt, A. F.; Delaney, C.
P.; Denmark, S. E. Elucidating the Role of the Boronic Esters in the
Suzuki-Miyaura Reaction: Structural, Kinetic, and Computational
Investigations. J. Am. Chem. Soc. 2018, 140, 4401-4416. (c) Miyaura, N.
Cross-Coupling reaction of organoboron compounds via base-assisted
transmetalation to palladium(II) complexes. J. Organomet. Chem. 2002,
653, 54-57.
(16) Desiraju, G. R. & Steiner, T. The weak hydrogen bond in
structural chemistry and biology (Oxford University Press, New York,
1999).
(17) Selected reviews on the bioactivities of gossypol: (a) Adams, R.;
Geissman, T. A.; Edwards, J. D. Gossypol, a pigment of cottonseed.
Chem. Rev. 1960, 60, 555-574. (b) Lu, Y.; Li, J.; Dong, C. -E.; Huang, J.;
Zhou, H. -B.; Wang, W. Recent advances in gossypol derivatives and
analogs: A chemistry and biology view. Future Med. Chem. 2017, 9,
1243-1275. (c) Keshmiri-Neghab, H.; Goliaei, B. Therapeutic potential of
gossypol: An overview. Pharm. Biol. 2014, 52, 124-128.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A. Asymmetric Suzuki-Miyaura Coupling in Water with
a Chiral
Palladium Catalyst Supported on an Amphiphilic Resin. Angew. Chem.,
Int. Ed. 2009, 48, 2708-2710.
(18) Selected clinical studies of gossypol enantiomer: (a) Liu, G.;
Kelly, W. K.; Wilding, G.; Leopold, L.; Brill, K.; Somer, B. An open-
label, multicenter, phase I/II study of single-agent AT-101 in men with
castrate-resistant prostate cancer. Clin. Cancer Res. 2009, 15, 3172-3176.
(b) Baggstrom, M. Q.; Qi, Y.; Koczywas, M.; Argiris, A.; Johnson, E. A.;
Millward, M. J.; Murphy, S. C.; Erlichman, C.; Rudin, C. M.; Govindan,
R. A phase II study of AT-101 (gossypol) in chemotherapy-sensitive
recurrent extensive-stage small cell lung cancer. J. Thorac. Oncol. 2011,
6, 1757-1760.
(19) (a) Meyers, A. I.; Willemsen, J. J. The synthesis of (S)-(+)-
gossypol via an asymmetric Ullmann coupling. Chem. Commun. 1997,
1573-1574. (b) Meyers, A. I.; Willemsen, J. J. An oxazoline based
approach to (S)-gossypol. Tetrahedron 1998, 54, 10493-10511.
(20) (a) Si, T.; Li, B.; Xiong, W.; Xu, B.; Tang, W. Efficient cross-
coupling of aryl/alkenyl triflates with acyclic secondary alkylboronic
acids. Org. Biomol. Chem. 2017, 15, 9903-9909. (b) Li, C.; Chen, T.; Li,
B.; Xiao, G.; Tang, W. Efficient synthesis of sterically hindered acyclic
secondary alkyl arenes by Suzuki-Miyaura cross-couplings. Angew. Chem.
Int. Ed. 2015, 54, 3792-3796.
(7) For selected examples on the asymmetric synthesis of axially chiral
tetra-ortho-substituted binaphthalenes via asymmetric Negishi and
Kumada coupling: (a) Genov, M.; Fuentes, B.; Espinet, P.; Pelaz, B.
Asymmetric Negishi reaction for sterically hindered couplings: synthesis
of chiral binaphthalenes. Tetrahedron: Asymmetry 2006, 17, 2593-2595.
(b) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. Asymmetric Synthesis
Catalyzed by Chiral Ferrocenylphosphine-Transition-Metal Complexes. 6.
Practical Asymmetric Synthesis of 1,1’-Binaphthyls via Asymmetric
Cross-Coupling
with
a
Chiral
[(Alkoxyalkyl)ferrocenyl]monophosphine/Nickel Catalyst. J. Am. Chem.
Soc. 1988, 110, 8153-8156.
(8) An example on the asymmetric synthesis of axially chiral tetra-
ortho-substituted biphenyls via asymmetric Ullmann coupling: Chen, W.-
W.; Zhao, Q.; Xu, M.; Lin, G.-Q. Nickel-catalyzed asymmetric Ullmann
coupling for the synthesis of axially chiral tetra-ortho-substituted biaryl
dials. Org. Lett. 2010, 12, 1072-1075.
(9) (a) Neel, A. J.; Hilton, M. J.; Sigman, M. S.; Toste, F. D. Exploiting
non-covalent π interactions for catalyst design. Nature 2017, 543, 637-
646. (b) Davis, H. J.; Phipps, R. J. Harnessing non-covalent interactions to
exert control over regioselectivity and site-selectivity in catalytic
reactions. Chem. Sci. 2017, 8, 864-877. (c) Mahmudov, K. T.; Gurbanov,
A. V.; Guseinov, F. I.; Guedes da Silva, M. F. C. Noncovalent interactions
in metal complex catalysis. Coord. Chem. Rev. 2019, 387, 32-46.
(10) (a) Xu, G.; Senanayake, C. H.; Tang, W. P-chiral phosphorus
ligands based on
a 2,3-dihydrobenzo[d][1,3]oxaphosphole motif for
asymmetric catalysis. Acc. Chem. Res. 2019, 52, 1101-1112. (b) Yang, H.;
Tang, W. Efficient enantioselective syntheses of chiral natural products
facilitated by ligand design. Chem. Rec. 2020, 20, 23-40.
(11) (a) Tasler, S.; Bringmann, G. Biarylic biscarbazole alkaloids:
Occurrence, stereochemistry, synthesis, and bioactivity. Chem. Rec. 2002,
2, 113-126. (b) Schmidt, A. W.; Reddy, K. R.; Knolker, H. J. Occurrence,
Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids.
Chem. Rev. 2012, 112, 3193-3328.
(12) (a) Shen, Y.; Yekta, S.; Yudin, A. K. Modified BINOL ligands in
asymmetric catalysis. Chem. Rev. 2003, 103, 3155-3212. (b) Brunel, J. M.
BINOL: A versatile chiral reagent. Chem. Rev. 2005, 105, 857-898. (c)
Pereira, M. M.; Calvete, M. J. F.; Carrilho, R. M. B.; Abreu, A. R.
Synthesis of binaphthyl based phosphine and phosphite ligands. Chem.
Soc. Rev. 2013, 42, 6990-7027.
(13) For examples of using strong bases in sterically hindered Suzuki-
Miyaura coupling: (a) Zhao, Q.; Li, C.; Senanayake C. H.; Tang, W. An
efficient method for sterically demanding Suzuki-Miyaura coupling
reactions. Chem. Eur. J. 2013, 19, 2261-2265. (b) Organ, M. G.; Çalimsiz,
S.; Sayah, M.; Hor, K. H.; Lough, A. J. Pd-PEPPSI-IPent: An active,
sterically demanding cross-coupling catalyst and its application in the
synthesis of tetra-ortho-substituted biaryls. Angew. Chem. Int. Ed. 2009,
48, 2383-2387. (c) Stambuli, J. P.; Weng, Z.; Incarvito, C. D.; Hartwig, J.
F. Reductive elimination of ether from T-shaped, monomeric
arylpalladium alkoxides. Angew. Chem. Int. Ed. 2007, 46, 7674-7677.
(14) Weak bases such as K3PO4 were employed in sterically demanding
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CHO OH
HO
HO
Asymmetric Suzuki-Miyaura Coupling
OH CHO
for
Axially Chiral Tetra-ortho-Substituted Biaryls
(S)-gossypol
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