Enantioselective Synthesis of Atropisomeric Biaryls using Biaryl 2,5-Diphenylphospholanes as Ligands for Palladium-Catalysed Suzuki-Miyaura Reactions

Article abstract of DOI:10.1002/adsc.202001211

Here we describe the development of biaryl 2,5-diphenylphospholanes as a new class of C₂-symmetric, monodentate ligands for asymmetric Suzuki-Miyaura (ASM) reactions. Screening of a series of exemplary phospholanes led to the identification of two ligands that were used to prepare a range of atropisomeric biaryl and heterobiaryl products with good to excellent levels of enantioselectivity (up to 97:3 e.r.) under mild conditions. DFT studies suggest that the formation of a constraining ligand pocket and coordination of one of the biaryl methoxy groups in the optimised ligands to the metal centre is crucial for restricting conformational freedom in the bond-forming step. (Figure presented.).

Full text of DOI:10.1002/adsc.202001211

Title: Enantioselective Synthesis of Atropisomeric Biaryls using Biaryl
2,5-Diphenylphospholanes as Ligands for Palladium-Catalysed
Suzuki-Miyaura Reactions
Authors: Liam Byrne, Christian Sköld, Per-Ola Norrby, Rachel Munday,
Andrew Turner, and Peter Smith
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001211
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10.1002/adsc.202001211
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Enantioselective Synthesis of Atropisomeric Biaryls using
Biaryl 2,5-Diphenylphospholanes as Ligands for Palladium-
Catalysed Suzuki-Miyaura Reactions
Liam Byrne,*a Christian Sköld,b Per-Ola Norrby,c Rachel H. Munday,d Andrew R.
Turner,a Peter D. Smith*a
a
Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, UK; e-mail:
liam.byrne@astrazeneca.com, peter.d.smith@astrazeneca.com.
b
c
d
Drug Design and Discovery, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
Data Science & Modelling, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: Here we describe the development of biaryl 2,5-diphenylphospholanes as a new class of C2-symmetric,
monodentate ligands for asymmetric Suzuki-Miyaura (ASM) reactions. Screening of a series of exemplary
phospholanes led to the identification of two ligands that were used to prepare a range of atropisomeric biaryl and
heterobiaryl products with good to excellent levels of enantioselectivity (up to 97:3 e.r.) under mild conditions. DFT
studies suggest that the formation of a constraining ligand pocket and coordination of one of the biaryl methoxy groups
in the optimised ligands to the metal centre is crucial for restricting conformational freedom in the bond-forming step.
Keywords: atropisomeric biaryls, phospholanes, palladium, Suzuki-Miyaura reaction, Density Functional Theory.
catalyst systems capable of effecting Suzuki-Miyaura
Introduction
cross-couplings of sterically-demanding substrates
for the synthesis of atropisomeric biaryls.[12]
Atropisomeric biaryls are a privileged structural class
Moreover, the introduction of a stereochemical
in asymmetric catalysis[1] and also feature in many
feature onto the biaryl core of the Buchwald ligands
biologically active
natural
products[2]
and
has engendered chiral monophosphine ligands that
induce high levels of atroposelectivity in such
reactions. Examples include KenPhos[13] and Cy-
MOP[8h,14] which contain
an axially chiral 1,1'-binaphthyl motif, and BI-
DIME[15] where constraint of the phosphorus atom in
a five membered ring gives rise to a P-stereogenic
centre.
pharmaceuticals,[3] including a growing number of
AstraZeneca’s portfolio of small molecules.[4] As a
result, significant efforts have been made to develop
methods for the atroposelective synthesis of these
valuable moieties.[5] Asymmetric transition-metal-
catalysed cross-couplings are strategically attractive
as the chiral axis can be forged directly from two pre-
formed fragments, and the Suzuki-Miyaura reaction[6]
offers additional practical advantages (air- and water-
stability, low toxicity, ready availability) with regards
to the coupling partners.[7] Although some
noteworthy advances have been made recently,[8] the
atroposelective variant of the Suzuki-Miyaura
reaction remains underdeveloped. The discovery of
new ligands for these transformations is therefore of
interest to medicinal chemists as well as the wider
synthetic community.
One of the major advances in transition-metal
catalysis was the development of the Buchwald
dialkylbiaryl phosphine ligands.[9] Owing to their
commercial availability and propensity to form air-
stable and highly active monodentate complexes, they
have found extensive use in palladium-catalysed C-
C[10] and C-X[11] bond-forming processes. Ligands
such as SPhos (Figure 1) have been shown to form
Figure 1. Examples of chiral monophosphine ligands
based on the Buchwald biaryl scaffold.
1
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10.1002/adsc.202001211
Advanced Synthesis & Catalysis
Cramer and co-workers recently reported a series of
ligands in which the dialkylphosphine groups (-PCy2,
-PtBu2) of the archetypal Buchwald ligands were
tolylboronic acid 6a. Whilst the commercially
available 1,2-bispho-
replaced with
a
trans-2,5-dialkylphospholane
fragment.[16] These C2-symmetric monodentate
ligands, exemplified by SagePhos (Figure 1), were
found to be highly enantioselective in Pd-catalysed
intramolecular C-H activation reactions. However, to
the best of our knowledge they have not been applied
in asymmetric cross-coupling reactions.
Table 1. Ligand screeninga
Results and Discussion
Entry Ligand
Yield e.r.
(%)b (S:R)c
(R,R)-iPr-BPE
We hypothesised that biaryl phospholane ligands of
this type might be capable of inducing
atroposelectivity in asymmetric Suzuki-Miyaura
(ASM) reactions. Preliminary molecular modelling
suggested that the presence of phenyl, rather than
alkyl substituents on the phospholane ring could be
beneficial in this context. In order to investigate this
experimentally we targeted the modular synthesis of a
series of novel P-arylated 2,5-diphenylphospholane
ligands (L, Scheme 1) and identified the known
phospholanic acid 1 as a key building block, which
can be prepared in enantiomerically pure form on
multigram scale.[17] Reduction of 1 allows access to
oxo-phospholane 2,[18] which can participate in
palladium-catalysed P-arylation reactions with aryl
halides and pseudohalides.[19] The resulting P(V)
oxides 4 can be reduced by a two-step procedure
involving activation with methyl triflate followed by
treatment with lithium aluminium hydride. On the
other hand, conversion of 2 to chlorophospholane 3
generates a P(III) electrophile which can be trapped
by a suitable aryl metal species. Although the use of
1,1'-dilithiated ferrocene has been reported in this
context,[18] we were cognizant that strongly basic aryl
lithiums could potentially epimerise the benzylic
stereocentres. For this reason, the less basic aryl
cuprates were used preferentially.
1
61
54
59
85
70d
62
82
74
78
49
16
54:46
58:42
48:52
26:74
65:35e
33:67
39:61
30:70
78:22
84:16
15:85
2
(R,R)-Ph-BPE
3
4
5
6
7
8
9
10
11
L1
L2
L3
L4
L5
L6
L7
L8
L9
a
Conditions: 0.10 mmol 5a, 0.15 mmol 6a, 0.30 mmol
K2CO3, 0.17 M in PrCN/H2O (4:1) at 85 °C in a glovebox
b
for 18-24 h; Solution yield determined by HPLC analysis
c
using an internal standard; Ratio determined by chiral
d
SFC; Isolated yield after the reaction was run with 0.30
mmol 5a; e The absolute configuration of the major product
was assigned by comparison of its optical rotation with
literature data. [20]
Scheme 1. Synthetic approaches to P-arylated 2,5-
diphenylphospholanes
spholanoethane (BPE) ligands and the P-o-thioanisyl
phospholane L1 all exhibited poor levels of
enantioselectivity (Table 1, entries 1-3), we were
encouraged to find that the MOP-type ligand L2
furnished o-tolyl naphthalene 7a with 74:26 e.r.
(entry 4). Employing diastereoisomeric ligand L3
Using these methods, phospholanes L1-9 were
synthesised and screened as ligands in the model
ASM reaction of bromonaphthalene 5a with o-
2
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10.1002/adsc.202001211
Advanced Synthesis & Catalysis
(entry 5) led to a switch in the major enantiomer
produced in the reaction from (R)- to (S)-7a
indicating that the phospholane rather than the chiral
axis is the dominant stereochemical feature. Varying
the steric and coordinating properties of the biaryl
unit in ligands L4-9 identified that ether substituents
on the distal aromatic ring were beneficial for
stereoselectivity, with methoxy groups giving the best
results (entries 6-11). Furthermore, the introduction
of a methoxy group ortho to the phospholane also had
a positive effect on selectivity (entry 10), which we
rationalise as a result of the substituent limiting the
conformational freedom of the phospholane by
restricting rotation about the C(sp2)-P bond. Direct
co-ordination of the ortho-methoxy group to Pd,
which has been observed in related ligands,[9a] has
been tested by DFT calculations and found to be less
favoured. The presence of a second methoxy group
gave no further improvement in selectivity and led to
a drastic reduction in reaction efficiency (entry 11).
Ligands L7 and L8 were selected for further
optimisation studies and synthesised on gram scale
using the two-step procedure outlined in Scheme
2A.[21] L7 was prepared by magnesium-halogen
exchange of bromobiphenyl 8a, followed by
transmetallation with copper(I) chloride and
treatment with chlorophospholane (R,R)-3. As well as
attenuating the basicity of the Grignard reagent, the
use of a stoichiometric quantity of CuCl facilitates
purification of the product through the formation of
complex 9 (Scheme 2B), which could be isolated by
flash silica chromatography. The structure of 9 was
determined by single crystal X-ray diffraction.
Subsequent decomplexation with ammonium
hydroxide followed by recrystallisation from n-BuOH
gave L7 as a crystalline air-stable solid.[22] Changing
the order of steps in the work-up (i.e. performing
decomplexation prior to chromatography) led to a ca.
20% reduction in yield, presumably via unwanted
oxidation to the phosphine oxide during purification.
For L8, the additional methoxy substituent thwarted
attempts to prepare the Grignard reagent from 8b
with either Mg turnings or i-PrMgCl.LiCl. Instead
lithium-halogen exchange with n-butyllithium was
18 h, 55%; L8: (a) (i) n-BuLi, THF, 0 °C - r.t., 2 h; (ii) 2,3-
dibromoanisole, –40 °C - r.t., 18 h; 61% for 8b; (b) (i) n-
BuLi, THF, –78 °C, 1.5 h, (ii) CuCl, -78 °C then (R,R)-3, –
40 °C to r.t., 18 h, 65%; (B) Work-up procedure and
structures of 9[23] and L7[24] determined by SC-XRD
analysis.
Table 2. Reaction optimisationa
a Conditions: 0.05 mmol 5a, 0.075 mmol 6a, 0.15 mmol
b
base, 0.17 M at 25 or 55 °C in a glovebox for 24 h;
Solution yield determined by HPLC analysis using an
c
d
internal standard; Ratio determined by chiral SFC;
Entry Base
Solvent
Temp Yieldb e.r.c
(°C)
55
55
55
55
55
25
25
25
25
25
25
25
(%)
68
51
68
73
53
32
96
93
66
25
76
82
1
K2CO3
PrCN
PrCN
PrCN
PrCN
79:21
80:20
80:20
81:19
79:21
81:19
72:28
72:28
72:28
75:25
83:17
90:10
2d
3
K2CO3
K3PO4
KOH
4
5
6
7
8
9
10
11
12e
DIPEA PrCN
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PrCN
THF
Dioxane
PhMe
EtOH
MeCN
MeCN
Pd2dba3 used; e L8 used.
generate a suitable precursor to the desired biaryl
cuprate.
With sufficient quantities of both ligands in hand
we set about identifying the relevant parameters of
the model ASM reaction using high throughput
experimentation (HTE), the results of which are
summarized in Table 2. Extensive screening of
palladium sources, bases and solvents (see SI for full
results) enabled us to conclude the following: (a)
changing the palladium source and base has little
effect with regards to asymmetric induction (entries
1-5); (b) the use of protic and non-polar aprotic
solvents results in a diminution of stereoselectivity
(entries 7-10); (c) running the reaction in acetonitrile
at room temperature is optimal (Entry 11) and (d) L8
exhibits the highest levels of enantioselectivity giving
(S)-7a with 90:10 e.r. (entry 12).
Next we applied our optimized conditions to the
synthesis of a variety of atropisomeric biaryl and
heterobiaryl products (Table 3). In all cases and in
line with previous results, the use of L8 led to
improved enantioselectivities compared with L7. o-
Tolyl products 7a-f were obtained with moderate to
good selectivities, although longer reaction times
required to
Scheme 2. (A) Gram-scale syntheses of L7 and L8: L7 (a)
(i) n-BuLi, THF, 0 °C - r.t., 2 h; (ii) 1-bromo-2-
chlorobenzene, 0 °C, 77% for 8a; (b) (i) Mg, (BrCH2)2,
THF, 65 °C, 2 h; (ii) CuCl, r.t. then (R,R)-3, –40 °C to r.t.,
3
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10.1002/adsc.202001211
Advanced Synthesis & Catalysis
were often required to achieve useful levels of
conversion. Naphthalene-1-boronic acid and its 4-
substituted congeners were found to be superior
coupling partners giving good to excellent yields and
enantioselectivities after stirring overnight at room
temperature (7g-r). Coupling of the more sterically
hindered
2-substituted
Table 3. Substrate scopea
a Conditions: 0.20 mmol 5, 0.30-0.40 mmol 6, 0.60 mmol K2CO3, 0.2 M in MeCN/H2O (9:1) at 25 °C in a glovebox for 24
d
e
f
h; b Reaction run for 48 h; c Reaction run for 72 h; Reaction run at 80 °C; Ar-BPin used; Reaction run at 40 °C.
napthalenylboronic acids proved to be challenging
under these conditions. As has been reported with
other catalyst systems,[8d,8n] poor reactivity at room
temperature and/or competitive protodeboronation
was observed. For tetra-ortho substituted binaphthyls
7u-w only trace amounts of product were obtained
intermediates after the oxidative addition (OA) and
transmetallation (TM) steps, and the transition states
for the reductive elimination (RE) steps, validated by
QRC calculations[25] to confirm the connection to the
preceding intermediate and the resulting enantiomer
of the final coupling product. Calculations were
after extended reaction times at elevated temperatures. performed at the B3LYP-D3/LACVP* level in
To investigate the source of the stereoselectivity
we studied the reaction pathways leading to product
7b by DFT, for ligands L7 and L8. Following a
report by Patel et al.,[8d] we have located all
Jaguar.[26]
Looking first at the OA product, the 2-Me-
naphthyl group (termed the “OA aryl”) strongly
prefers a position cis to the phosphine (Figure 2),
4
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10.1002/adsc.202001211
Advanced Synthesis & Catalysis
with the bromide trans to the phosphine. The biaryl
moiety acts as a chelating ligand in the fourth
position of the square plane around Pd. The
phospholane forms a floor, with stabilizing van der
Waals interactions to the naphthyl moiety. One
phenyl group of the phospholane protrudes into the
plane
of
the
naphthale-
Figure 2. Calculated relative energies (in kJ/mol) of the RE transition state structures for the two interconverting
ensembles of TM products with L7. The TM aryls for products 7b (o-tolyl) and 7h (1-naphthyl) are shown in black and
blue (dotted) respectively. The Pd-Br bond in the OA products is omitted for clarity.
ne inducing a twist. The main result of this twist is
that the biaryl will not coordinate through a carbon of
the aryl ring as has been observed previously,[9b, 27]
but rather with one of the methoxy substituents. The
biaryl ring forms a wall which, together with the
protruding phospholane substituent, restricts the
conformational freedom of the OA aryl. The naphthyl
moiety can adopt one of two conformations where the
extended -system takes either a “proximal” or
“distal” orientation with respect to the protruding
phospholane substituent. The two conformations
cannot interconvert; dihedral scans by DFT cause the
phosphine to dissociate, at a prohibitive cost in
energy. The phospholane prefers a conformation with
both phenyl groups in equatorial positions but, like
most cyclopentanes, are quite flexible. The phenyl
group pointing away from the naphthyl moiety can
adopt a more axial position. One major role of the
added OMe group in L8 is to limit the conformational
flexibility of the phospholane. For L8, an additional
conformation is possible where the biaryl moiety is
rotated away from Pd and the coordination site is
instead taken up by the added OMe group, as
observed by Buchwald and co-workers.[9a] However,
in our case, the alternative coordination mode is
disfavoured by 14-17 kJ/mol, excluding it from
consideration of viable pathways.
Transmetallation adds another aryl group (termed
“TM aryl”) to Pd, replacing the bromide. The full
mechanism of the transmetallation in a Suzuki
reaction is complex, generally involving replacement
of the bromide by a hydroxide, followed by boronic
acid coordination and actual transmetallation.[28]
However, in the current case, the o-tolyl in the TM
product can rotate with a low barrier of ca. 30 kJ/mol,
interconverting all possible conformations of the TM
aryl. The lowest RE barrier is ca. 65 kJ/mol, giving a
Curtin-Hammett situation, removing any possible
influence of the TM step on the final selectivity.
From each interconverting ensemble of TM
products, the sterically-induced skew in the transition
state for RE gives rise to four distinct paths to the
final products (Figure 2). Of these, the preferred ones
have the TM aryl oriented parallel to the biaryl wall.
Here, we will use the term “exo” to denote that the
ortho substituent of the transmetallated aryl points
away from the naphthalene core, towards Pd, and
“endo” if it is situated above the naphthalene. Note
that exo and endo conformers of the same TM
product will give rise to opposite atropisomers of the
5
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10.1002/adsc.202001211
Advanced Synthesis & Catalysis
final product in the reductive elimination. We will
use the term “syn” if the TM aryl substituent points
closer to the 2-Me-group of the naphthyl moiety, and
“anti” if it is closer to the fused benzene ring. For the
ensemble with the proximal OA aryl, the TS with the
syn-endo conformation is favoured over the anti-exo
by ca. 5-7 kJ/mol for both L7 and L8. This
corresponds well with experiment, where the Ra
isomer is favoured over the Sa isomer by ca. 4 kJ/mol,
for both ligands. In the distal ensemble, the difference
between the paths leading to opposite enantiomers is
smaller, with anti-endo being preferred over syn-exo
by only 1-2 kJ/mol.
To further test whether the high preference for RE
in the distal channel is due to selective OA or to
equilibration, we performed additional experiments
where the aryl bromide substrate was replaced by a
triflate, with or without added bromide in the form of
TBAB (Table 4). There was little influence on
selectivity when employing the o-tolyl coupling
partner to give product 7b, but together with the naph
thalene boronic acid, significant differences could be
seen in the selectivity for 7h. With both ligands L7
and L8, lower selectivities were seen with the aryl
triflate
Provided that the hypothesis of irreversible
selection of reaction channel at the OA step is correct,
and there is no crossover between channels after the
irreversible OA step, the channel selection should be
independent of selection of transmetallating partner.
We therefore also decided to investigate the more
sterically congested 1-naphthyl moiety (leading to 7h,
Table 3), showing the same sense of stereoinduction
as 7b, but with a much higher selectivity. The
experimental selectivity corresponds to ca. 9 kJ/mol
for L7, 10 kJ/mol for L8, in favour of the Ra product.
We first verified the barrier to rotation in the TM
product leading to 7h. At ca. 40 kJ/mol, this is still
low enough to give a true Curtin-Hammett situation,
with the RE as the selectivity-determining step within
each channel. Interestingly, it was found that the 1-
naphthyl group has a substantially higher inherent
torquoselectivity than the o-tolyl group. The penalty
for endo pathways is always at least 10 kJ/mol. As
before, the ligand scaffold will selectively favour
transition states where the TM aryl is parallel to the
biaryl “wall”. The outcome is that in each channel,
the pathways to one enantiomer of the product is
favoured over the alternative by at least 10 kJ/mol. In
the proximal channel, the favoured orientation is anti-
exo, leading to the Sa product. The distal pathway
instead gives an 11 kJ/mol preference for the
observed Ra product through the syn-exo TS.
Table 4. Effect of using ArOTf ± TBAB as an additivea
a
Conditions: 0.10 mmol 5, 0.15 mmol 6, 0.30 mmol
K2CO3, 0.2 M in MeCN/H2O (9:1) at 25 °C in a glovebox
b
for 24 h; TBAB = tetrabutylammonium bromide, 0.10
c
mmol used where +; Ratio determined by chiral SFC
analysis of the crude reaction mixtures.
(Table 4, entries 2 & 5) versus the aryl bromide
Entry
Ligand
X
TBABb e.r.
e.r.
7bc
7hc
1
2
3
4
5
6
Br
–
–
+
–
–
+
77:23
95:5
87:13
92:8
97:3
88:12
91:9
L7
L7
L7
L8
L8
L8
OTf
OTf
Br
OTf
OTf
77:23
77:23
80:20
81:19
81:19
(entries 1 & 4). Interestingly, the addition of TBAB
to the aryl triflate reactions (entries (3 & 6) led to a
partial recovery of the selectivity loss. The most
significant difference between bromide and triflate in
solution is that the former can act as a ligand to Pd,
temporarily replacing the phosphine and effecting
crossover between the proximal and distal channel.
On the other hand, the difference between entries 1 &
3, and 4 & 6, indicates that the nature of the leaving
group can also influence the selectivity of the OA
step, and that this selectivity has an influence on the
channel preference in the RE step.
The results strongly indicate that the major isomer
of 7h arises from the syn-exo pathway in the distal
channel. We also see that the lowest distal TS is 17
kJ/mol lower than the lowest proximal TS. Thus, two
different scenarios (or a combination of them) can
explain our observed selectivity. The OA step can be
highly selective for the distal channel and/or there is
crossover between the two channels before the RE
allowing a Curtin-Hammett situation also at this stage.
Equilibration of the distal and proximal ensembles
could occur via ligand dissociation, reversible
oxidative addition,[8d] or via the “oscillatory”
mechanism proposed by Buchwald and co-workers.
[13a]
Conclusion
Assuming that such a mechanism is also
operative for the o-tolyl product 7b, the lowest distal
TS is again favoured over the lowest energy proximal
TS, in this case by ~14 kJ/mol. However, the energy
differences for the TS structures in the distal
ensemble are low (1-2 kJ/mol) and within the
uncertainty range of DFT calculations.
To summarize, we have developed a new class of
chiral
monodentate
ligands,
P-aryl-2,5-
diphenylphospholanes, a selection of which have
been tested in the asymmetric Suzuki-Miyaura
(ASM) reaction, and with certain biaryl substituents
on phosphorous, produce axially chiral biaryls with
good to excellent yields and enantioselectivities. A
6
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10.1002/adsc.202001211
Advanced Synthesis & Catalysis
DFT study of the reaction has revealed a constraining
ligand pocket formed by the biaryl moiety together
with one of the phospholane phenyl substituents. The
high levels of enantioselectivity observed in reactions
with 1-naphthylboronic acids is determined by a high
exo preference in the reductive elimination. The
protruding phospholane phenyl group allows only
one of the biaryl methoxy groups to coordinate trans
to one of the Pd-aryl bonds. This coordination plays
an important role in restricting the conformational
freedom in the reductive elimination step, blocking
one of the otherwise favoured exo orientations in the
dominating distal pathway. Studies are ongoing to
further optimise the ligand structures, e.g. by
appropriate substitution of the phenyl rings on the
phospholane, and we anticipate that the
computational work outlined here will expedite the
design process.
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Experimental Section
In a glovebox, a 4 mL glass vial was charged with aryl
bromide (0.20-0.40 mmol), boronic acid (1.5 equiv.),
Pd(OAc)2 (5 mol%), L8 (6 mol%) and a tumble stirrer disc.
Acetonitrile (4.5 mL/mmol) was added followed by 6 M aq.
K2CO3 soln. (0.5 mL/mmol, 3 equiv.). The vial was sealed
and the reaction stirred at 25 °C for the stated time. The
vial was taken out of the glovebox and diluted with MTBE
(10 mL) and H2O (10 mL) and transferred to a separating
funnel. The layers were separated and the aqueous layer
extracted with MTBE (10 mL). The combined organics
were washed with 2 M aq. NaOH soln (2 x 10 mL) and
20% aq. NaCl soln. (10 mL), then dried (phase separator)
and concentrated under reduced pressure. The residue was
dryloaded onto SiO2 and purified by flash column
chromatography to give the desired biaryl product.
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Acknowledgements
LB is a fellow of the AstraZeneca postdoc programme. CS
acknowledges support from KLOSS Akademi Ut (INNOV
2015/29) and Vinnova (grant no. 2016-02110).
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Advanced Synthesis & Catalysis
FULL PAPER
Enantioselective Synthesis of Atropisomeric
Biaryls using Biaryl 2,5-Diphenylphospholanes as
Ligands for Palladium-Catalysed Suzuki-Miyaura
Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Liam Byrne,* Christian Sköld, Per-Ola Norrby,
Rachel H. Munday, Andrew R. Turner, Peter D.
Smith*
9
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