Two Stereoinduction Events in One C?H Activation Step: A Route towards Terphenyl Ligands with Two Atropisomeric Axes

Article abstract of DOI:10.1002/anie.201801130

Herein we disclose the synthesis of original chiral scaffolds—ortho-orientated terphenyls presenting two atropisomeric Ar–Ar axes. These unusual structures were built up by using the C?H activation approach, and remarkably, both chiral axes were controlled with excellent stereoselectivity in a single transformation. During the reaction, not only does atroposelective functionalization of a biaryl precursor occur to establish one stereogenic axis, but an unprecedented atropo-stereoselective C?H arylation also takes place to generate the second stereogenic element. These enantiomerically pure ortho-terphenyls show an original tridimensional structure and thus constitute a unique foundation for building up a library of enantiomerically pure bidentate ligands, such as the new ligands S/N-Biax and diphosphine BiaxPhos.

Full text of DOI:10.1002/anie.201801130

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Two Chiral Events in a Single C-H Activation Step: a route
towards terphenyl ligands with two atropisomeric axes.
Authors: Françoise Colobert, Quentin Dherbassy, Jean-Pierre Djukic,
and Joanna Wencel-Delord
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801130
Angew. Chem. 10.1002/ange.201801130
Link to VoR: http://dx.doi.org/10.1002/anie.201801130
http://dx.doi.org/10.1002/ange.201801130

10.1002/anie.201801130
Angewandte Chemie International Edition
COMMUNICATION
Two Chiral Events in One C-H Activation Step: a route towards
terphenyl ligands with two atropisomeric axes.
Quentin Dherbassy,[a] Jean-Pierre Djukic,[b] Joanna Wencel-Delord,*[a] and Françoise Colobert*[a]
Abstract: Herein we disclose the synthesis of original chiral
scaffolds - ortho-orientated terphenyls presenting two atropisomeric
Ar-Ar axes. These unusual structures are built up using the C-H
activation approach and remarkably both chiral axes are controlled
with excellent stereoselectivities in a single transformation. During
the reaction, not only atroposelective functionalization of a biaryl
precursor occurs imposing one chiral axis, but also an
unprecedented atropo-stereoselective C-H arylation takes place
generating the second chiral element. These enantiopure ortho-
terphenyls shows an original tridimensional structure and thus
constitute a unique ground to build-up a library of enantiopure
bicoordinating ligands such as new S/N-Biax and diphosphine
BiaxPhos.
necessary. Such a double stereocontrol can be achieved by
means of: 1) atroposelective introduction of an aryl substituent
on a configurationally unstable biaryl precursor (control of the
Ar1-Ar2 bond)[ 10 ] and 2) direct stereoselective Ar1-Ar3 bond
formation.
To access terphenyl precursors that can be used as a platform
to build up few families of unprecedented ligands, biaryl 1
(Figure 1) bearing a stereogenic sulfoxide moiety, appears as a
promising substrate. Few key parameters speak in favor of such
a substrate design: 1) the sulfoxide moiety is both, an efficient
directing group and a chiral auxiliary accessible in large scale[11]
from menthol as chiral pool, 2) traceless character of the
[ 12 ]
sulfoxide
should allow convenient installation of various
coordinating motifs via post-modifications, 3) chiral ligand-free
transformation may be expected as the chirality on the sulfur
atom is expected to induce chiral information, 4) access to
Axial chirality, arising from the hindered rotation about the Ar-Ar
axis, is an important feature of a variety of molecular scaffolds[1]
conferring unique properties to certain biologically active
compounds[2] and advanced materials.[3] But arguably the most
prominent application of the atropisomeric biaryls relates to their
use as stereogenic ligands.[4] Quite surprisingly, polyaromatic
structures presenting two ortho-orientated chiral Ar-Ar axes are
extremely rare (Figure 1). In 2006, Shibata astutely used
[2+2+2] cycloadditions to convert triynes into symmetrical ortho-
terphenyls[5] while Sparr et al. reported the synthesis of oligo-
1,2-naphthylenes bearing two atropocontrolled binaphthyl
axes.[6] Besides, molecules exhibiting both C-C and C-N axial
optically pure compounds is facilitated by
a convenient
purification of diastereomeric products.[13] Direct arylation of 1
with ortho-substituted iodoarenes bearing judiciously selected
and located functionalities should thus deliver the terphenyl
skeletons, the precursor of several various families of
stereogenic ligands with one or two coordination sites
(modification of red/orange sphere) and adjustable electronic
and steric properties (grey/black sphere). In order to warrant
atropostability of the desired terphenyls, important steric
hindrance around both Ar-Ar bonds is required (blue spheres).
Chiral compounds with two ortho-orientated atropisomeric axes
chiralities were also disclosed.[
atropisomeric, ortho-orientated dissymmetrical terphenyls
In contrast, doubly
7
]
O
NO2
Me
A
O
O
O
(Figure 1), exhibiting important structural diversity, remain
elusive although their unusual “open clam shell” geometry
seems highly appealing for stereogenic ligands design. To
address this synthetic challenge we embarked on designing a
general, step-economic and stereoselective protocol, focusing
on unprecedented atroposelective directed C-H arylation.[ 8],[ 9]
Such a C-H coupling presents however major difficulties: 1)
reacting together a metallacyclic intermediate resulting from a
challenging metallation at a sterically congested position and an
ortho-substituted iodoarene (recognized as difficult coupling
partner); 2) an inherent antagonism between efficiency and
atroposelectivity whereas such conditions are detrimental for
atropostability. Furthermore, as we target terphenyls with two
chiral axes, a perfect stereocontrol of both asymmetric events is
Cl
N
Me
Me
Me
O
OMe
NO2
H
Me
Cl
O
O
O
Hsung : 2007
Sparr : 2016
Shibata : 2006
New 3D scaffold
coordination site
Key step -
atroposelective
direct arylation
Ar2
tuning electronic
& steric properties
I
Ar1
+
O
S
H
Ar3
atropostability
1
2
A
Sulfoxide:
Challenges:
✔ traceless directing group
✔ handle to install various
1) efficient C-H arylation between two
sterically demanding partners
2) chiral induction/atropostability vs.harsh
reaction conditions
3) control of 2 chiral events in one step
coordinating motifs
✔ chirality from cheap & abundant pool
➜ no need for additional chiral ligand !
Figure 1. Concept of terphenyl scaffolds as precursor for original chiral ligands
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10.1002/anie.201801130
Angewandte Chemie International Edition
COMMUNICATION
Pd(TFA)2 (x mol%)
IPr-HCl (2x mol%)
Ag2CO3
(2+0.x equiv.)
AgTFA (1 equiv.)
R1
R1
Accordingly, coupling between 1a and ortho-iodotoluene 2A was
selected as a test reaction (Scheme 1). Although initial attempts
using standard reaction conditions for direct arylation failed,[14]
desired product 3aA was formed in small amount when using a
large catalyst loading of Pd(OAc)2 in combination with N-
heterocyclic carbene (NHC) ligand, Ag2CO3 salt and
trifluoroacetic acid (TFA) as additive. Detailed optimization of the
reaction conditions revealed that: 1) Pd(TFA)2 is more effective
catalyst than Pd(OAc)2 as side reactions are limited (formation
of 4a); 2) replacement of TFA by AgTFA salt is essential for
reactivity and 3) the coupling is highly water sensitive thus
addition of an optimized amount of 4Å molecular sieve is crucial
to prevent deactivation of the catalyst. Accordingly, under the
optimal reaction conditions, i.e. Pd(TFA)2 (25 mol%) and IPr-HCl
ligand, Ag2CO3 (2.5 equiv.) together with AgTFA (1 equiv.) and
4Å MS, in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at 85 °C, the
desired product was isolated in 49% yield within 4h. Remarkably,
1H NMR analysis of the crude reaction mixture shows formation
of 3aA with excellent diastereoselectivity (d.r. of 49 : 2 : 1) and
the purified product is a single atropisomer.
SOpTol
R3
SOpTol
SOpTol
Ar-I
+
H
4 Å MS, HFIP,
85 °C, 4 h
R2
R2
1a-h
2A-M
3
Me
Me
Me
SOpTol
Me
SOpTol
Me
Me
O
O
O
O
O
O
Me
OMe
3aA: 83% conv. (25 mol% Pd)
49 : 2 : 1 d. r. (crude)a
49% yield; ≥ 98 : 2 d. r.b
3aB: 96% conv. (15 mol% Pd) 3aC: 90% conv. (15 mol% Pd)
22 : 1 : 1 d. r. (crude)a
21 : 1 : 0 d. r. (crude)a
65% yield; ≥ 98 : 2 d.r.b
73% yield; ≥ 98 : 2 d. r.b
Me
Me
Me
SOpTol
SOpTol
SOpTol
Me
Me
Me
O
O
O
OMe
Me
3bA: 56% conv. (10 mol% Pd) 3bB: 80% conv. (10 mol% Pd)
3bC: 96% conv. (10 mol% Pd)
213 : 4 : 1 d. r. (crude)a
63% yield; ≥ 98 : 2 d. r.b
23 : 2 : 1 d. r. (crude)a
44% yield ; 98 : 2 d. r.b
45 : 2 : 1 d. r. (crude)a
62% yield; ≥ 98 : 2 d. r.b
Me
Me
Me
SOpTol
SOpTol
SOpTol
Me
Me
Me
O
O
O
OCF3
Br
Cl
3bD: 76% conv. (15 mol% Pd) 3bE: 95% conv. (20 mol% Pd) 3bF: > 95 conv. (25 mol% Pd)
Pdcat (x mol%)
iPr-HCl (2x mol%)
Agsalt (y equiv.)
62 : 2 : 0 d. r. (crude)a
49% yield; ≥ 98 : 2 d. r.b
Me
53 : 2 : 1 d. r. (crude)a
70% yield; 97 : 3 d. r.b
Me
20 : b : 1 d. r. (crude)a
49% yield; > 98 : 2 d. r.b
Me
Me
Me
Me
I
Me Additive (z equiv.)
pTol
SOpTol
SOpTol
OR
S
+
MeO
H
O
O
O
85 °C, 4 h
SOpTol
OMe
SOpTol
SOpTol
O
O
Me
3aA
Me
Me
Me
4a-OAc (R = Ac)
4a-OPiv (R = Piv)
1a
2A
6 equiv.
O
O
O
Me
Br
OMe
OMe
NPhth
3bH: 95% conv. (30 mol% Pd)c
3bG: > 95 conv. (20 mol% Pd)
20 : b : 1 d. r. (crude)a
3bI: 97% conv. (15 mol% Pd)
29 : 2 : 1 d. r. (crude)a
Scheme 1. Test reaction for the synthesis of terphenyls via asymmetric direct
arylation
51% yield; 97 : 3 d. r.b
53% yield; 98 : 2 d. r.b
72% yield; ≥ 98 : 2 d. r.b
Me
Me
Me
SOpTol
SOpTol
SOpTol
Cl
O
O
Next, the coupling of 1a with electron-rich 2-iodotoluene
derivatives 2A-C was completed delivering 3aA, 3aB and 3aC in
moderate to good yields, with no loss of the atroposelection
(Scheme 2). An additional electron donating substituent on 2
increased the reactivity of this coupling partner and therefore
catalytic loading for 3aB and 3aC could be decreased to 15
mol%. In contrast, less electron rich biaryl substrate 1b was
more effective than 1a as the desired arylation was achieved
with only 10 mol% of Pd (3bA-C). The reaction is compatible
with different heteroatoms; not only Cl- and Br-atoms were
tolerated but also coordinating motifs such as NPhth or OMe.
Besides, ortho-position of the aryl-iodide may be substituted by
Cl or OMe group (products 3bJ and 3bK, 3bL). More sterically
demanding Me substituent could also be introduced at the key,
meta position of Ar1 and 3cL and 3cK were isolated as
atropoisomerically pure compounds albeit in low yield. Finally,
electron donating and electron withdrawing substituents are well
tolerated on Ar2, delivering 3dG, 3eG, 3fG, 3gM and 3hG in 44-
68 % yield. Noteworthy, crystal structure of 3aC shows the
expected spatial proximity of Ar2 and Ar3 and the “cavity-like”
architecture of the molecule.[15]
O
O
O
OMe
Me
3bJ: 89% conv. (20 mol% Pd)
625 : 1 : 10 d. r. (crude)a
69% yield.; 97 : 3 d. r.b
3bL: 76% conv. (10 mol% Pd)
78 : 16 : 1 d. r. (crude)a
33% yield; 94 : 6 d. r.b
3bK: 84% conv. (10 mol% Pd)
6 : 1 : 1 d. r. (crude)a
66% yield; 97 : 3 d. r.b
CF3
Me
Me
Me
SOpTol
SOpTol
SOpTol
O
O
Me
Me
Me
O
OMe
Me
Br
3cL: 55% conv. (30 mol% Pd)d
15 : 2 : 0 d. r. (crude)a
3cK: 39% conv. (30 mol% Pd)d 3dG: > 95% conv. (20 mol% Pd)
24 : 2 : 0 (crude)a
16% yield; ≥ 98 : 2 d. r.b
64 : 2 : 3 (crude)a
24% yield; 94 : 6 d. r.b
49% yield; 98 : 2 d. r.b
Cl
OMe
Me
Me
Me
Me
SOpTol
SOpTol
SOpTol
Me
Me
Me
O
O
O
Me
Br
OMe
Br
Me
Br
3eG: > 95% conv. (20 mol% Pd) 3fG: > 95% conv. (20 mol% Pd) 3gM: > 95 % conv. (10 mol% Pd)
223 : 4 : 1 d. r. (crude)a
67% yield; ≥ 98 : 2 d. r.b
54 : 1 : 0 d. r. (crude)a
68% yield; ≥ 98 : 2 d. r.b
58 : 1 : b d. r. (crude)a
47% yield; > 95 d. r.b
Me
Me
(R)
2
SOpTol
SOpTol
Me
1
Me
O
(S)
3
O
O
Me
Br
OMe
3hG: > 95 % conv. (20 mol% Pd)
3aC
37 : 1 : 0 d. r. (crude)a
44% yield; 98 : 2 d. r.b
In order to unambiguously prove the optical purity of the
products, few fundamental tests were performed and the
rotational barriers were determined (Figure 2). Firstly, the
configurational stability of the sulfoxide was proved by chiral
HPLC analysis. Subsequently, the rotational barrier for the Ar1-
Scheme 2. Scope of the terphenyls with two axial chiralities (a)
4
diastereomers could be potentially obtained and 3 of them were identified in
“crude” 1H NMR spectra, b) 2 diastereomers detected on the 1H NMR spectra
of the purified products, c) for details see SI; d) reaction performed at 115 °C).
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10.1002/anie.201801130
Angewandte Chemie International Edition
COMMUNICATION
Ar2 axis of 3bN of +37 kcal/mol in the gas phase was computed
using Density Functional Theory studies (cf. SI) (calculated half-
life of c.a. 112 years at 85 °C) suggesting that the
Scheme 3. Mechanistic studies.
The originality of this transformation comes from the unique
possibility to control both axial chiralities in single
stereoinduction
is
kinetically
controlled.
Next,
a
atropodiastereomerically pure 3bB was subjected to thermal
treatment and partial racemization of the Ar1-Ar3 axis was
evidenced; ΔG‡ (32.4 ± 0.3) kcal/mol (413.15 K) for Ar1-Ar3 axis
of 3bB was determined (epimerization half-life of c.a. 73 days at
85 °C), in consistence with computed ΔG‡ of 33 kcal/mol.
Comparable stability of both atropo-diastereomers indicates that
the Ar1-Ar3 coupling is under kinetic control.
transformation (Scheme 4). Isolation of the atropisomerically
pure palladacyclic intermediate 6 and rapid racemization of the
substrate under the reaction conditions clearly suggest that the
stereoselectivity of Ar1-Ar2 axis is induced during the C-H
activation step. When diastereomer (aS,S)-1b reacts with NHC-
Pd catalyst, the interactions between the chiral auxiliary and the
NHC ligand are minimized (pTol moiety above the plane vs.
NHC ligand underneath the plane). In contrast, palladation of
(aR,S)-1b would require accommodation of the bulky ligand and
pTol group in the same plane and is yet disfavored and the
transformations implies Dynamic Kinetic Resolution. In contrast,
chirality of the Ar1-Ar3 linkage arises from the favored oxidative
addition of the Ar-I coupling partner from a sterically less
congested face of the metallacyclic intermediate, i.e. minimizing
a steric hindrance between the SOpTol moiety and ortho-
substituent of the Ar-I. In addition, reductive elimination from
such a sterically less congested Pd(IV) intermediate seems also
enhanced.
a) Ar1-Ar2
b) Ar1-Ar3
:
Me
Me
1
2
2
S
SOpTol
1
O
3
3
OMe
O
Me
Me
(aR1-2,aR1-3,SS)-3bB
(aR1-2,SS)-3bN
Δ G0 = 37 kcal/mol
(aS1-2,SS)-3bN
(aR1-2,aS1-3,SS)-3bB
‡
Δ G1 (413 K) = (32.5 ± 0.3) kcal/mol (experimental)
Δ G‡(413 K) = 33 kcal/mol (DFT calculations)
Figure 2. Determination of atropostability of terphenyl scaffolds.
Further mechanistic studies (Scheme 3a) revealed the
irreversibility of the C-H activation step (D/H scrambling test) and
KIE of 1.58 suggesting that the turnover-limiting step occurs
after the C-H cleavage.
H
O
S
Me SOpTol
S
O
H
O
O
O
(aS,S)-1b
(aR,S)-1b
Irreversible C-H
activation
×
Pd
Subsequently, in order to characterize the key intermediates, we
strove on preparation of the metallacyclic species (Scheme 3b).
Unfortunately all attempts of isolation of palladacycle
intermediate using substrate 1b failed but reaction between a
simplified substrate 1i and Pd(OAc)2, followed by ligand
exchange, delivered the complex 5. In presence of the NHC, 5
was easily converted into the well-defined, atropisomeric Pd-
NHC complex 6. The X-Ray structure of 6 clearly shows
coordination of Pd by the S-atom.[ 16 ] 1H NMR analysis of 6
indicates that the Ar1-Ar2 axis is perfectly controlled (d.r. > 98 :
2) during formation of the organometallic intermediate.[17] Finally,
while investigating reductive elimination from 6, the importance
of both Ag2CO3 and AgTFA salts to liberate the coupling product
was confirmed.
X
Me
L
I
Pd
S
S
O
O
S
S
O
Me
O
O
X
Pd
X
Pd
Pd
O
O
L
L
O
L
X
Me
X
X
Disfavored
L syn to the biaryl
crowded face
Favored
L anti to the biaryl
crowded face
Favored
Disfavored
Me-group anti to the Me-group syn to the
biaryl crowded face biaryl crowded face
Scheme 4. Proposed stereoinduction model.
As our goal is to access ligand precursors, a large-scale
synthesis of 3bE was undertaken (Scheme 5). 1b was prepared
at gram scale, in 3 steps (53% total yield) from inexpensive
starting materials, using only cheap reactants and catalysts and
with no need for silica gel column purifications. The large scale
direct atroposelective arylation with 2E furnished optically pure
3bE in 65% yield (774 mg).
Cond.
Scheme 2
2C (1 equiv.)
a)
Me
Me
SOpTol
D/H
SOpTol
D/H
kH/kD = 1.58
OMe
OMe
Reversibility test: 1b-D : 1b = 31 : 1
KIE: 1b-D : 1b = 1.6 : 1
1b-D : 1b = 31 : 1
Me
1b-D : 1b = 1.13 : 1
Br
Me
Me
O
S
O
S
+
+
b)
1i
Pd(OAc)2
+
Br
pTol
O
HO
pTol
ONa
OH
I
1) NaHCO3 (2.2 equiv.)
4Å MS, HFIP, RT
2) LiCl, (10 equiv.)
Acetone, RT, 1 h
<1€/mmol
<1€/mmol
50g synthesis
in one day
<1€/mmol
<1€/mmol
6
Ag2CO3
Pd(OAc) 2.5 mol%
n-Bu4NBr (1 equiv.)
Na2CO3 (3 equiv.)
H2O, 100 °C, 3 h
(2 equiv.)
AgTFA
(1 equiv.)
Me
Me
Me
Me
O
Me
Cond.
Scheme
2
Me
O
IMe-HCl
(1.5 equiv.)
O
B(OH)2
Br
+
SOpTol
Me
SOpTol
Ar
O
SOpTol
S
Ar-I,
HFIP,
85 °C
SOpTol
THF, RT,
2 h
S
pTol
2E
pTol
Cl
Pd
Pd
OMe
Cl
3
Ar
N
Cl
7
2 steps
1
crystallization
75% yield
3bE
65% yield
d.r. ≥ 98 : 2
N
8
1b
Ar
(2)
5
6
2 steps
85% yield,
2 crystallizations
70% yield, e.r. > 98 : 2
no chromatography
>1g prepared in 3 days
774 mg
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10.1002/anie.201801130
Angewandte Chemie International Edition
COMMUNICATION
Scheme 5. Large-scale synthesis of 3bE.
Scheme 7. BiaxPhos synthesis and its application in asymmetric
hydrogenation.
Next, in order to illustrate that the sulfoxide moiety is an useful
handle to install a variety of coordinating motifs while conserving
the optical purity of the scaffold, a sulfoxide/lithium exchange
Besides S/N-Biax 15 ligand, synthesized in two steps from 3fR,
showed good activity in 1,2-addition of Et2Zn to an aldehyde
(Scheme 8). Under non-optimized reaction conditions the
desired alcohol 17 was isolated in high yield and good e.r. of
93:7, comparable with a planar-chiral ferrocene-derived S/N
Me
CO2
CO2H
Me
ZnEt2 (2 equiv.)
15 (5 mol%)
PhMe, 25 °C,
15 h
1) H2NNH2
(50 equiv.)
THF/EtOH 1:1,
0-25 °C, 1h
O
Me
Me
Cl
OH
9: 74%, d.r. > 95 : 5
O
e.r. > 99 : 1
SOpTol
Me
SOpTol
Me
2) TsCl (1.05 equiv.)
pyridine (2.2 equiv.)
CHCl3, 25 °C, 2 h
Ar
H
Me
O
MeO2C
Me
Me
O
O
O
1. n-BuLi,
(4 equiv.)
NPhth
NHTs
16
(S)-17: 82% yield
e.r. = 93:7
HCO2Et
SOpTol
Me
15: 62% yield
S/N-Biax
3bH
R1
Me
CHO
Me
THF, -94 /
-78 °C,
3 min
ligand.[20]
O
Cl
Cl
R2
3bE
10: 56%, d.r. > 95 : 5
Scheme 8. S/N-Biax and its application in asymmetric reaction.
Me
ClPPh2
PPh2
Me
We present herein a new family of enantiopure skeletons,
terphenyls exhibiting two atropisomeric Ar-Ar axes. These
original compounds are built up via a challenging asymmetric C-
H activation route. This direct coupling is not only the first
example of highly atroposelective Ar-Ar bond formation, but also
two chiral elements are perfectly stereocontrolled during one
synthetic event. Hence accessed terphenyls present a unique,
tridimensional structure and by means of functional group
modifications they can be easily converted into an array of
unique bicoordinating ligands. Accordingly, diphosphine
BiaxPhos and S/N-Biax ligands were prepared and both
showed excellent stereoinduction in asymmetric hydrogenation
and 1,2 addition of Et2Zn respectively. These results clearly
showcase the potential of these chiral ligands for various
asymmetric transformations.
O
Cl
11: 74%, d.r. > 95 : 5
Scheme 6. Post-functionalization of terphenyl scaffolds.
followed by trapping with CO2, HCO2Et or PPh2Cl were
performed, delivering the corresponding enantiomerically pure
products 9,[18] 10 and 11 (Scheme 6).
The key application of these terphenyls with two chiral axes
concerns their use as chiral ligands. Based on the X-ray
structure of 9, it can be speculated that related ligands could
show a “pseudo-planar chiral” geometry if one coordinating
moiety is placed in ortho-position of Ar2 and the second
coordinating moiety in meta-position of Ar3. Accordingly,
brominated ortho-terphenyls 3bF, 3bG, 3(d-h)G, 3gN, all
obtained in decent yields and excellent stereoinduction, are
ligand precursors. As example, 3bF was subjected to double
lithium exchange followed by quenching with PPh2Cl and
delivered the diphosphine ligand BiaxPhos 12[19] in 54% yield
(Scheme 7). BiaxPhos, the first ligand presenting such “open
clam shell” tridimensional structure, revealed excellent reactivity
in Rh-catalyzed benchmark hydrogenation of the trisubstituted
methyl (Z)-α-acetamidocinnamate (MAC) 13 delivering the 14
with 99.5:0.5 e.r.
Acknowledgements
We thank the CNRS (Centre National de la Recherche
Scientifique), the “Ministere de l’Education Nationale et de la
Recherche“, and ANR (Agence Nationale de la Recherche) France
for financial support. Q. D. is very grateful to the “Ministere de
l’Education Nationale et de la Recherche“, France for a doctoral
grant. We are also very greatful to Dr. Lydia Karmazin and Dr.
Corinne Bailly for single crystal X-ray diffraction analysis.
Me
Me
1. tBuLi (5 equiv.)
-94 °C, Et2O,
20 min
Keywords: asymmetric C-H activation • axial chirality •
Me
Me
PPh2
PPh2
SOpTol
Br
2. ClPPh2 (4 equiv.)
-94 °C to -78 °C,
PhMe
terphenyl • chiral ligands • sulfoxide
OMe
OMe
3bF
12: 54% yield
CO2Me
NHAc
12/Rh(cod)2OTf
(1.5 mol%)
EtOH, 25 °C, 2 h
[1]
[2]
G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem. Rev.
2011, 111, 563.
CO2Me
NHAc
BiaxPhos
14: conv. > 99%
e.r. = 99.5 : 0.5
a) S. R. LaPlante, D. L. Fader, K. R. Fandrick, D. R. Fandrick, O. Hucke,
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7005; b) J. E. Smyth, N. M. Butler, P. A. A. Keller, Nat. Prod. Rep. 2015,
32, 1562.
Ph
Ph
13
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[3]
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[11] Easily accessible at 50g scale in 1 day using modified solvent-free
procedure.
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[14] For details see SI.
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supplementary crystallographic data for 3aC.
[16] CCDC 1557079 from the Cambridge Crystallographic Data contain the
supplementary crystallographic data for 6.
[17] The diastereopurity of 6 is also suggested by low temperature 1H NMR
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[9]
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supplementary crystallographic data for 9.
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[19] CCDC 1823772 from the Cambridge Crystallographic Data contain the
supplementary crystallographic data for 12.
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This article is protected by copyright. All rights reserved.