Atropselective Dibrominations of a 1,1′-Disubstituted 2,2′-Biindolyl with Diverging Point-to-Axial Asymmetric Inductions. Deriving 2,2′-Biindolyl-3,3′-diphosphane Ligands for Asymmetric Catalysis

Article abstract of DOI:10.1002/anie.201806294

On the ¹H NMR timescale, 2,2′-biindolyls with (R)-configured (1-alkoxyprop)-2-yl, (1-hydroxyprop)-2-yl, or (1-siloxyprop)-2-yl substituents at C-1 and C-1′ are atropisomerically stable at <0 °C and interconvert at >30 °C. A 2,2′-biindolyl (R,R)-17 a of that kind and achiral (!) brominating reagents gave the atropisomerically stable 3,3′-dibromobiindolyls (M)- and/or (P)-18 a at best atropselectively—because of point-to-axial asymmetric inductions—and atropdivergently, exhibiting up to 95 % (M)- and as much (P)-atropselectivity. This route to atropisomerically pure biaryls is novel and should extend to other substrates and/or different functionalizations. The dibromobiindolyls (M)- and (P)-18 a furnished the biindolyldiphosphanes (M)- and (P)-14 without atropisomerization. These syntheses did not require the resolution of a racemic mixture, which distinguishes them from virtually all biaryldiphosphane syntheses known to date. (M)- and (P)-14 acted as ligands in catalytic asymmetric allylations and hydrogenations. Remarkably, the β-ketoester rac-25 c was hydrogenated trans-selectively with 98 % ee; this included a dynamic kinetic resolution.

Full text of DOI:10.1002/anie.201806294

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Accepted Article
Title: Atropselective Dibrominations of a 1,1’-Disubstituted 2,2’-
Biindolyl With Diverging Point-to-Axial Asymmetric Inductions.
Deriving Diphosphane Ligands for Asymmetric Catalysis
Authors: Reinhard Brückner and Thomas Baumann
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10.1002/anie.201806294
Entry for the Table of Contents
Atropselective Synthesis
HO
HO
HO
HO
HO
1 2 3
(
R)
R)
N
(R)
(R)
(R)
(R)
N
T. Baumann, R. Brückner*
N
NBS,
PhI(OAc)2
Br
Br
PyrH Br3
_
_______________ Page – Page
Br
Br
(
N
ds = 95:5
N1' 2' 3'
ds = 5:95
N
HO
Atropselective Dibrominations of a 1,1’-
Disubstituted 2,2’-Biindolyl With Diverging
Point-to-Axial Asymmetric Inductions. De-
riving 2,2’-Biindolyl-3,3’-diphosphane Lig-
ands for Asymmetric Catalysis
(
R,R,M)-1
(R,R)-2
atropisomerically labile
(R,R,P)-1
atropisomerically stable
atropisomerically stable
From an atropisomeric bias to an atropisomeric lock: The biindolyl (R,R)-2 consists of
diastereomeric atropisomers. On the NMR time-scale, they interconvert at +30°C but not at
10°C. (R,R)-2 was dibrominated providing the biindolyls 1 (M)- or (!) (P)-selectively de-
pending on the reagent. They were elaborated into atropisomerically pure biindolyldiphos-
phanes. They accomplished higher ee’s in some Ru-catalyzed -ketoester hydrogenations
than BINAP.
1
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Angewandte Chemie International Edition
10.1002/anie.201806294
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Atropselective Synthesis
Atropselective Dibrominations of a 1,1’-Disubstituted 2,2’-Biindolyl
With Diverging Point-to-Axial Asymmetric Inductions. Deriving 2,2’-
Biindolyl-3,3’-diphosphane Ligands for Asymmetric Catalysis
†
,
Thomas Baumann and Reinhard Brückner *
Abstract: On an 1H-NMR time-scale, 2,2’-biindolyls with (R)-
configured (1-alkoxyprop)-2-yl, (1-hydroxyprop)-2-yl or (1-
siloxyprop)-2-yl substituents at C-1 and C-1’ are atropisomerically
stable at <0°C and interconvert at >30°C. A 2,2’-biindolyl (R,R)-
OMe
Me
N
N
S
Me
PPh2
R
PPh2
PPh2 MeO
MeO
PPh2
PPh2
PPh2
1
7a of that kind and achiral (!) brominating reagents gave the atro-
PPh2
R
PPh2
Me
pisomerically stable 3,3’-dibromobiindolyls (M)- and/or (P)-18a at
best atropselectively – because of point-to-axial asymmetric induc-
tions – and atropdivergently, exhibiting up to 95% (M)- and as much
S
Me
1[4]
R = Me: 2[5]
OMe
4[8]
5[9]
MeO: 3[6]
(P)-atropselectivity. Such a route to atropisomerically pure biaryls
is novel and should extend to other substrates and/or different func-
tionalizations. The dibromobiindolyls (M)- and (P)-18a furnished
the biindolyldiphosphanes (M)- and (P)-14a without atropisomeri-
zation. These syntheses entailed no resolution of a racemic mixture,
which makes them different than virtually all biaryldiphosphane
syntheses known to date. (M)- and (P)-14a acted as ligands in cata-
lytic asymmetric allylations and hydrogenations. Remarkably, the -
ketoester rac-25c was hydrogenated trans-selectively with 98% ee
due to a dynamic kinetic resolution.
O
X
N
PPh2
RN
PPh2
PPh2
N
N
PPh2
PPh2
PPh2
PPh2
PPh2
RN
X
N
O
X = NH: 6[10]
[11])
8[11]
9[12]
10[13]
R = Me: 11[14]
MOM: 12[14]
(O:
S:
7
Enantiomerically pure diphosphanes are widely used ligands in met-
this work
[
1 ]
al-catalyzed asymmetric synthesis. Two pioneers in that field,
[
2]
[3]
Knowles and Noyori, became Nobel laureates accordingly. The
R3SiO
R3SiO
R3SiO
R
R
R
R
N
N
single most influential ligand of this kind is BINAP (1), a 1,1’-
N
Me
PPh2
PPh2
PPh2
PPh2
PPh2
[
4]
[5]
binaphthyl (Figure 1).
It has been joined by BIPHEM (2) and
[6]
Me
PPh2
BIPHEP (3), two 1,1’-biphenyls. Biheteroaryls provide viable di-
phosphane scaffolds, too. P-Phos (4) is a bipyridyl. In contrast,
the diphosphanes 5-14 are non-benzenoid biheteroaryls. They com-
prise the 3,3’-bithiophenyl 5, the 3,3’-biindolyl 6,
bi(benzothiophenyl) 8,
the 2,2’-bi(benzoimidazolyl) 10, the 2,2’-biindolyls 11, 12,
and 13. The 3,3’-bi(benzofuryl) 7 is a member of this class as
well but not a worthwhile one because it atropisomerizes too easi-
N
N
N
[7]
[8]
R3SiO
[
9]
[10]
the 3,3’-
as well as
[11]
[12]
13[13]
3 2
(R,R,M)-14 R Si = tBu PhSi (R,R,P)-14
the 3,3’-bi(naphthofuryl) 9
[13]
[14]
[14]
[
13]
[11]
2
Figure 1. C -symmetric biaryl diphosphane ligands for asymmetric catalysis. Lig-
[
15]
ands 1-13 from the literature form (M)- (shown) and (P)-atropisomers which
are enantiomers; none of them has been synthesized atropselectively. Ligands (M)-
and (P)-14 from the current study are diastereomers; both were synthesized
atropselectively.
[
15]
[
[
11]
14]
ly.
As exemplified by the isomeric 2,2’-biindolyldiphosphanes
[13]
1
1
and 13,
certain bi(heteroaryls) may be phosphorylated in
more manners than their isocyclic counterparts.
Bi(heteroaryl)diphosphanes[16] also imply different syntheses, ge-
ometries and nucleophilicities than otherwise analogous binaphthyl-
or biphenyldiphosphanes. The present study enlarges the stock of
known 2,2’-biindolyl-3,3-diphosphanes which existed prior to our
[
†] Dipl.-Chem. T. Baumann, Prof. Dr. R. Brückner
Institut für Organische Chemie
[14]
[14]
work – i. e. compounds 11
and 12,
– by the diphosphanes
Albert-Ludwigs-Universität Freiburg
Albertstraße 21, D-79104 Freiburg (Germany)
Fax: (+) 49 761 203 6100
E-Mail: reinhard.brueckner@ocbc.uni-freiburg.de
Homepage: http://www.brueckner.uni-freiburg.de
(
R,R,M)- and (R,R,P)-14 (Figure 1). They resulted atropisomerically
pure in a fundamentally different manner than any of the diphos-
phanes 1-13, namely without resolving a racemic mixture. That is,
we obtained (R,R,M)- as well as (R,R,P)-14 by an atropselective
synthesis. In contrast, none of the diphosphanes (M)- or (P)-1-13 has
been synthesized atropselectively till date. Instead, each pure atrop-
[
] The authors thank Dr. Manfred Keller (Institut für Organische
Chemie, Albert-Ludwigs-Universität Freiburg) for the X-ray ana-
lysis and Alba Impelmann and Daniel Ebner for experimental
contributions.
[
15]
isomer thereof stemmed from resolving a racemic compound like
the diphosphane itself, the corresponding bis(phosphane oxide) or a
preceding bis(phenol).
Supporting information (experimental procedures, characterizati-
on data, copies of NMR spectra, and crystallographic details) for
this article is available on the WWW under
How we achieved atropselectivity was inspired by – but not analog-
ous to – the tribromination of phenol 15 (or derivatives containing
[17]
http://www.angewandte.org.
an ortho-C
6
H
3
RCO
2
H rather than -C
6
H
4
2
CO H group at C-3;
2
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201806294
substrate-control. In the following we present a combined answer to
the affirmative. We dibrominated type-(R,R)-17 biindolyls and ob-
tained type-(R,R,P)-18 dibromobiindolyls atropselectively because
the stereocenters of the latter exerted powerful point-to-axial asym-
Ref.[23]
atropisomerization[15]
(definitely unbiased) ... HO C
:
[
22]
metric inductions.
We also dibrominated a type-(R,R)-17 sub-
ortho
ortho
strate such that an (R,R,M)-configured type-18 dibromobiindolyl 18
formed selectively (see below). This alternative is noteworthy since
Miller´s best-performing catalyst gave tribromobiaryls 16 (P)-selec-
tively without a choice.
Our results exemplify a novel way of reaching biaryls atropselec-
tively. We used it for preparing atropisomerically pure diphosphane
ligands (M)- and (P)-14 for asymmetric catalysis (formulas: Figure
HO2C
2
2
4
2
4
HO
HO
6
6
... and NBS plus
(M)-15
asymmetric induction by
S,S,S)-configured catalyst

dynamic kinetic resolution
under catalyst control
(P)-15
(
1
1
). They contain the same biindolyl scaffold as the diphosphane
[
14]
[23,24,25]
1
which has a record in asymmetric catalysis already.
.
8
0%,
Miller´s tribromophenols are unlikely precursors of diphosphanes
yet led to one monophosphane atropisomer in three steps.
[
25]
[21a]
HO2C
Br
94% ae
HO2C
Br
no phos-
phane
Br
Br
OH
HO
HO
O
b)
R
d)
HO
HO
Br
Br
X
R
N
R
R
N
N
6
4%
70%
H
H
(
M)-16
no atropisomerization
This work:
(P)-16
X
R
a)
c)
NH2 L-alanine
HO C 20
2
80%
95%
atropisomerization[15]
(possibly biased) ...
Br
19
HOCH2 21
(R)R
(R)R
N
(R)R
N
H
H
H
H
(R,R)-17a
atropisomerizes[15] readily[37]
two 1H-NMR singlets at <0°C,
one 1H-NMR singlet at >30°C
:
(R)R
N
N
.
.. and NBS/PhI(OAc)2 plus
asymmetric induction by
Scheme 1. Synthesis of representative (R,R)-17a of the type-17 biindolyls (R,R)-
(R,R,M)-17
(R,R,P)-17
17 sketched in Figure 2. Reactions and conditions: a) HBr (48% in H O, 4.0 eq.),
2
(R,R)-configured bisindol
[26]
2
NaNO (2.0 eq.), aq. KBr, 0°C, 5 h (ref. : 95%). b) NaH (60%, 2.2 eq.), indole

[
27]
(
1.0 eq.), THF, 0°C, 1 h; 19 (1.1 eq.), 0°C50°C in 4 h (ref. : 48%). c)
dynamic kinetic resolution
under substrate control
28]
LiAlH
4
(4.4 eq.), THF, 56°C, 5 h; 95% ee.[  d) n-BuLi (2.2 eq.), TMEDA (2.2
2 2
eq.), Et O, rt, 2 h; CuCl
(1.0 eq.), 16 h; crystallization; 100% ee.[
30]
5
1%,
(R)R
(R)R
N
[24]
N
Br
Br
(R,R,P)-
diphos-
phane
Br
Br
90% ae
Synthesizing the diphosphanes (R,R,M)- and (R,R,P)-14 began with
[26]
(R)R
(R)R
converting L-alanine via the -bromoacid 19 into the indole-con-
N
N
[
27]
taining acid 20
(Scheme 1). Reduction ( alcohol 21, 95%
[
28]
[29]
ee ), ortho-lithiation, and oxidative dimerization gave the 2,2’-
[
30]
1
biindolyldiol (R,R)-17a (~100% ee ). 500 MHz H-NMR spectros-
copy in CDCl solutions revealed that the biindolyl 17a forms
NMR-stable atropisomers at ‒10°C which interconvert rapidly at
(R,R,M)-18
no atropisomerization
(R,R,P)-18
3
[
15]
Figure 2. (P)-selective brominations of the atropisomerization-labile biaryls 15
(
ref. ) and biindolyl 17 (this work) giving the atropisomerization-stable[15] biar-
[
17]
+50°C.
[31]
Coalescence at about room temp. implies rate constants
yls 16 and 18, respectively. Stereocontrol is due to the catalyst (15) or the sub-
strate (18).
katropisomerizations resembling the chemical shift differences at low tem-
perature (0.15 ppm) expressed in Hz, i. e. ca. 100 s . This is reflec-
1
tive of atropisomerization thresholds of about 11 kcal/mol.
We dibrominated this 2,2’-biindolyl (R,R)-17a under a variety of
conditions (Scheme 2).The respective 3,3’-dibromide (R,R)-18a re-
sulted as (M)/(P) mixtures which were separable. Accordingly, the
constituents – diastereomorphic atropisomers – did not atropisom-
erize. The dibromide, which dominated in 6 of the 8 experiments
was (M)-configured because its bis(benzenesulfonate) (R,R)-18c
Figure 2, top). These substrates, stoichiometric amounts of NBS or
another achiral brominating agent, and an enantiopure tripetide-
amide catalyst gave the tribromobiaryl (P)-16 or derivatives thereof
with up to 94% atropisomeric excess (“ae”[18]) because of the fol-
lowing: (1) Substrate 15 plus congeners are atropisomerization-
labile while the product 16 plus congeners are atropisomerization-
[32]
was (M)-configured in the crystal. By consequence the less abun-
dant dibromide (R,R)-18a must be (P)-configured. The following
[
15]
stable. (2) Bromine is shuttled from the achiral reagent to the sub-
strate via the (S,S,S)-configured catalyst. This makes the atropiso-
“
best procedures” furnished the dibromides (R,R,M)-18a and
[
19]
[33]
mer-determining transition state(s) diastereomeric  or, more spe-
cifically, “atropisomeric”  and thus their Free Enthalpies potential-
(R,R,P)-18a not only with high atropselectivites
but also in an
atropcomplementary – or “stereodivergent” – manner: (1) The
(M):(P) selectivity was 95:5 when the biindolyl (R,R)-17a was di-
[20]
ly distinct. In more general terms Miller effected the following:
The electron-rich aromatic 15, which is atropisomerization-labile,[15]
is attacked by an atropisomer-diffentiating electrophile. It gives rise
to a dynamic kinetic resolution which gives the functionalized aro-




brominated with nBu N Br or PyH Br in CH Cl ; purification
4
3
3
2
2
[
34]
by flash-chromatography on silicagel
rendered the atropisomeri-
cally pure dibromobiindolyl (R,R,M)-18a in 70% and 79% yield, re-
[
15]
[21]
[35]
matic 16, which is atropisomerization-stable, (P)-selectively.
spectively. (2) An opposite (M):(P) selectivity of 5:95 was real-
[
17]
The tribromination 15(P)-16 of Figure 2 is not unique. A num-
ized by dibrominating (R,R)-17a with NBS in CH
2
Cl
2
in the pres-
[
17]
[21]
[36]
ber of analogous as well as related tribrominations converted
other phenol-containing biaryls into single atropisomers by catalyst-
control, too. Accordingly, we wondered whether electrophilic (mul-
ti)functionalizations of phenol-free biaryls deliver single atropiso-
mers analogously. Moreover, we wondered whether the “catalyst-
2
ence of 3 equivalents of PhI(OAc) ;
flash-chromatography and
crystallization delivered the pure dibromide atropisomer (R,R,P)-
18a in 51% yield. This is a convincing demonstration of the value of
point-to-axial asymmetric inductions for synthesizing biheteroaryls
with a single twist about their biaryl axis.
[
17-21]
control of atropselectivity” exerted so far
might be replaced by
3
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Angewandte Chemie International Edition
10.1002/anie.201806294
Scheme 2 also shows how we carried the dibromobiindolyl (R,R,M)-
1
1
8a on to the atropisomerically pure biindolyldiphosphane (R,R,M)-
4. This was done by tert-butyldiphenylsilylating the OH groups, ef-
(
R,R)-17a
fecting two BrLi exchanges in the resulting disilylether (R,R,M)-
8b, and quenching with ClPPh . The last step displayed no atrop-
1
2
isomeric scrambling. The same is true for the analogous conversion
of the dibromobiindolyl (R,R,P)-18a via the disilylether (R,R,P)-18b
into the biindolyldiphosphane (R,R,P)-14. The main objective of our
study was accomplished thereby: making biheteroaryldiphosphanes
as single atropisomers without resolving a racemic mixture.
brominating agent: see body of Table;
isolation by flash-chromatography on
silica gel[40] and crystallization
RO
RO
RO
RO
R
R
best conditions: best conditions:
R
R
N
N
Br
Br
[39]
[39]
Br
Br
ds = 95:5;
ds = 5:95;
79%, d.r. = 100:0 51%, d.r. = 0:100
N
N
Table 1. Asymmetric allylic substitutions of nucleophiles 23a-d in trans-1,3-di-
phenylallyl acetate (rac-22). Grey backgrounds indicate where our ligands
(
R,R,M)-14 or (R,R,P)-14 effected more enantiocontrol than (M)-BINAP (1).
no atropisomerizations
(
(
R,R,M)-18a: R = H
(R,R,P)-18a: R = H
3
[
Pd( -C3H5)Cl]2 (1.0 mol-%),
a) 73%
c) 44%
b) 75%
d) 46%
OAc
Ph
Nu

R,R,M)-18b: R = tBuPh2Si
(R,R,P)-18b: R = tBuPh2Si
ligand (2.0 mol-%), nucleophile (2.4 eq.),
Ph
bis(trimethylsilyl)acetamide (2.4 eq.),
Ph
Ph
CH Cl , T, t
2
2
rac-22
24a-e
tBuPh2SiO
tBuPh2SiO
T,
t
(M)-BINAP
(1)
R
R
R
R
Nucleophile
(R,R,M)-14
(R,R,P)-14
N
N
PPh2
PPh2
PPh2
PPh2
O
O
O
O
N
N
MeO
Ph
OMe
MeO
Ph
OMe
O
O
tBuPh2SiO
tBuPh2SiO
‒40°C,
Ph
Ph
MeO
OMe
[a]
5
0 h
(S)-24a
(R)-24a
23a
(R,R,M)-14
e) 86%
(R,R,P)-14
8
8% (98% ee) 93% (83% ee) 99% (85% ee)
O
O
O
O
tBuO
OtBu
O
O
tBuO
OtBu
[
b]
2
2°C ,
Ph
Ph
tBuO
OtBu
Ph
Ph
[
c]
(R)-24b
1
6 h
(
S)-24b
2
3b
PhSO2O
PhSO2O
R
N
94% (51% ee) 99% (87% ee) 67% (65% ee)
Br
Br
O
O
O
O
R
Me
Me
N
O
O
EtO
Ph
OEt
EtO
Ph
OEt
2
2°C,
EtO
OEt
Ph
R)-24c
Ph
(S)-24c
[
d]
Me
23c
93 h
(
R,R,M)-18c[
38]
(
8
7% (22% ee) 95% (84% ee) 91% (70% ee)
O
O
O
O
Brominating agent
(R,R)-18a
Sol-
vent
O
O
2
2°C,

[33]
Br -
source
(M):(P)-ratio
Yield of isolated
[35]
Ph
Ph
Ph
Ph
Additive (eq.)
[e]
in crude product = major isomer
2 h
(
S)-24d
(R)-24d
2
3d
CH
DMF
toluene
2
Cl
2
85:15
55:45
50:50
73%
89% (89% ee) 92% (94% ee) 87% (84% ee)
[
a]
[b]
[c]
NBS

With (R,R,M)-14 26 h, with (R,R,P)-14 24 h. With (R,R,P)-14 20°C. With
[d] [e]
(
R,R,P)-14 72 h. With 1 45 h. With (R,R,M)-14 15 h, with (R,R,P)-14 10 h.

Having the diphosphanes (R,R,M)- and (R,R,P)-14 enantiopure at

nBu N
4
our disposal, we tested them – and compared them to (M)-BINAP



70%
Br
3
[37]
(
1) as a benchmark – in Pd-catalyzed asymmetric allylations with
CH
2
Cl
2
95: 5
the allyl acetate rac-22 (Table 1) and in Ru-catalyzed asymmetric
7
9%

PyH
[38,39]
hydrogenations of the -ketoesters
Allylating the dialkyl malonates 23a-c and acetylacetone (23d) with
,3-diphenylallyl acetate (rac-22), dimethyl malonate (23a) gave the
largest enantiomeric excess (98% ee), but only in the presence of
25a-c (Table 2).

Br
3
DMF
70:30
82:18
65:35

67%

1

PyridineH

OTs (4.0)
[
40]
(
M)-BINAP (1; Table 1 ). 94% ee, the second-highest value, re-
CollidineH
NBS

CH
2
Cl
2
sulted for acetylacetone (23d) and the ligand (R,R,M)-14. The low-
est ee values (51 and 22%) refer to the (M)-BINAP-catalyzed allyla-
tions of malonates 23b and c. In contrast, the same subset of reacti-
ons exhibited 87 and 84% ee using the ligand (R,R,M)-14 and 65
OTs (4.0)
PhI(OAc)
3.0)
2
5
:95
51%
(
[41]
Scheme 2. Top: Atropselective and -divergent syntheses of representatives
R,R,M)-18a and (R,R,P)-18a of the type-18 dibromobiindolyls (R,R)-18 sketched
in Figure 2. Center: Proof of the (M)-configuration of dibromobiindolyl (R,R,M)-
8a by an X-ray analysis of its bis(benzenesulfonate(R,R,M)-18c. In between:
Reaching the diphosphanes (R,R,M)-14 and (R,R,P)-14 stereospecifically. Reac-
tions and conditions: a) tBuPh SiCl (2.4 eq.), imidazole (3.0 eq.), DMF, rt, 24 h;
3%. b) Same as (a) but 75%. c) sBuLi (2.4 eq.), THF, −78°C, 1 h; ClPPh (2.6
eq.), −78°C  rt, 18 h; 44%. d) Same as (c) but tBuLi (4.4 eq.), 20 h; 46%. e)
PhSO Cl (3.0 eq.), CH Cl /pyridine (2:1), rt, 15 h; crystallization; 86%.
and 70% ee using (R,R,P)-14.
(
Ru(II)-catalyzed asymmetric hydrogenations of -ketoesters have
[
42]
[
32]
been a prime discipline of Noyori’s (M)-BINAP (1) ever since the
1
[
4]
latter had been designed. We performed such reactions at room
[
43]
2
temp. rather than 100°C
2
with 5 bar H , the -ketoesters 25a-c,
[
43]
7
2
and either “a mixture of Ru(1)Cl (DMF) and [Ru(1)Cl (DMF)] ”
2
2
2
n
[44]
or the presumed (R,R,M)-14- or (R,R,P)-14-based analogs thereof
2
2
2
4
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201806294
Keywords: asymmetric allyllations • asymmetric hydrogenations • atrop-
selectivities • biaryls • brominations • diphosphanes • indoles
(
Table 2).[45] (M)-BINAP (1) allowed to hydrogenate methyl aceto-
acetate (25a) with 99% ee while ligands (R,R,M)- and (R,R,P)-14
led to 86% and 82% ee, respectively. -Ketoesters derived from ar-
omatic ketones undergo BINAP-mediated hydrogenations with dis-
tinctly less enantiocontrol. Accordingly, in our hands, ethyl benzoyl-
acetate (25b) reacted with hydrogen in the presence of (M)-BINAP
[
1] Reviews of enantiomerically pure diphosphane ligands: a) J. Wencel-
Delord, A. Panossian, F. R. Leroux, F. Colobert, Chem. Soc. Rev.
2
015, 44, 3418-3430. b) M. M. Pereira, M. J. F. Calvete, R. M. B.
Carrilho, A. R. Abreu, Chem. Soc. Rev. 2013, 42, 6990-7027. c) J. A.
Gillespie, E. Zuidema, P. W. N. M. van Leeuwen, P. C. J. Kamer,
[
46]
(
1) with only 72% ee.
In contrast, ligand (R,R,M)-14 achieved
9
ee.
3% ee in the same hydrogenation and ligand (R,R,P)-14 even 97%
“Phosphorus Ligand Effects in Homogeneous Catalysis and Rational
[
47]
Hydrogenating ethyl tetralonecarboxylate (25c), a racemic
Catalyst Design”, in Phosphorus(III) Ligands in Homogeneous Catal-
ysis: Design and Synthesis (Eds.: P. C. J. Kramer, P. W. N. M. van
Leeuwen), John Wiley & Sons, Chichester 2012, 1-26. d) W. Li, X.
Zhang, “Chiral Phosphines and Diphosphines”, in Phosphorus(III)
Ligands in Homogeneous Catalysis: Design and Synthesis (Eds.: P. C.
J. Kramer, P. W. N. M. van Leeuwen), John Wiley & Sons, Chichester
substrate, entailed dynamic kinetic resolutions. They provided 76-
8
7% of the -hydroxyesters 26c as a 94:6 trans,cis mixture using
(
(
M)-BINAP (1) or with perfect trans-selectivities using (R,R,M)- or
R,R,P)-14. The ee’s of trans-26c were 84% employing 1, 98% em-
ploying (R,R,M)-14, and 96% employing (R,R,P)14. The last-
2
012, 27-80. e) T. Ohkuma, N. Kurono, “BINAP”, in Privileged
mentioned stereoselectivities are unmatched in the literature.[48]
Chiral Ligands and Catalysts (Ed. Q.-L. Zhou), 1-45 (Wiley-VCH,
2
[
7]
011). f) Ref. .
Table 2. Asymmetric hydrogenations of -ketoesters 25a-c at ambient tempera-
ture. Grey backgrounds indicate where our ligands (R,R,M)-14 or (R,R,P)-14 in-
duced better enantio- and diastereoselectivities than (M)-BINAP (1).
[2] W. S. Knowles, Angew. Chem. 2002, 114, 2096-2107; Angew. Chem.
Int. Ed. 2002, 41, 1998-2007.
[3] R. Noyori, Angew. Chem. 2002, 114, 2108-2123; Angew. Chem. Int.
Ed. 2002, 41, 2008-2022.
O
O
Ru(II)complex (1.0 mol-%)
of ligand,
OH
O
[4] A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, R.
Noyori, J. Am. Chem. Soc. 1980, 102, 7932-7934.
[5] R. Schmid, M. Cereghetti, B. Heiser, P. Schönholzer, H.-J. Hansen,
Helv. Chim. Acta 1988, 71, 897-929.
2
5a-c R1
OR2
R1

(
)
OR2 26a-c
*
H2 (5 bar), EtOH, 22°C, t
H/R
H/R
[a]
Ketoester
t
(M)-BINAP (1)
(R,R,M)-14
(R,R,P)-14
[6] R. Schmid, J. Foricher, M. Cereghetti, P. Schönholzer, Helv. Chim.
OH
O
OH O
Acta 1991, 74, 370-389.
O
O
[7] Reviews on enantiomerically pure diheteroaromatic-based diphos-
Me
OMe
Me
OMe
phane ligands: a) N. Arshad, C. O. Kappe, Adv. Heterocycl. Chem.
2
4 h
(R)-26a
(S)-26a
Me
OMe
2
010, 33-59. b) Y.-M., Li, W.-Y. Yu, A. S. C. Chan, “Atropisomeric
2
5a
8
9% (99% ee) 73% (86% ee) 35% (82% ee)
biheteroaromatic diphosphenes”, in Phosphorus Ligands in Asymmet-
ric Catalysis: Synthesis and Applications, Vol. 1 (Ed. A. Börner),
Wiley-VCH, Weinheim 2008, 260-283. c) J. Wu, A. S. C: Chan, Acc.
Chem. Res. 2006, 39, 711-720. d) T. T.-L. Au-Yeung, A. S. C. Chan,
Coord. Chem. Rev. 2004, 248, 2151-2164.- e) T. Benincori, S. Rizzo,
F. Sannicolò, J. Heterocycl. Chem. 2002, 39, 471-485.
OH
O
OH O
O
O
OEt
OEt
OEt 24 h
(
S)-26b
(R)-26b
2
5b
1
00% (72% ee) 98% (93% ee) 95% (97% ee)
[8] C.-C. Pai, C.-W. Lin, C.-C. Lin , C.-C. Chen, A. S. C. Chan, J. Am.
Chem. Soc. 2000, 122, 11513-11514.
OH
O
OH O
[
[
[
[
9] T. Benincori, E. Cesarotti, O. Piccolo, F. Sannicolò, J. Org. Chem.
2000, 65, 2043-2047.
10] U. Berens, J. M. Brown, J. Long, R. Selke, Tetrahedron: Asymmetry
1
2
OEt
1
2
OEt
O
O
OEt
1
996, 7, 285-292.
1
20 h
(1S,2R)-26c
(1R,2S)-26c
11] T. Benincori, E. Brenna, F. Sannicolò, L. Trimarco, P. Antognazza, E.
Cesarotti, F. Demartin, T. Pilati, J. Org. Chem. 1996, 61, 6244-6251.
12] N. G. Andersen, M. Parvez, R. McDonald, B. A. Keay, Org. Lett.
8
7%
82%
76%
rac-25c
trans/cis 94:6 trans/cis 100:0 trans/cis 100:0
trans: 84% ee) (trans: 98% ee) (trans: 96% ee)
(
2
000, 2, 2817-2820.
[
a]
[13] T. Benincori, E. Brenna, F. Sannicoló, L. Trimarco, L.; P. Antognazza,
In CDCl
3
solutions, the -ketoesters contained 6% enol (25a), 18% enol (25b), and
E. Cesarotti, G. Zotti, J. Organomet. Chem. 1997, 529, 445-453.
7
0% enol (25c), respectively.
[
14] T. Benincori, O. Piccolo, S. Rizzo, F. Sannicoló, J. Org. Chem. 2000,
5, 8340-8347.
6
Our ligands (R,R,M)-14 and (R,R,P)-14 turned each reactant pair of
Table 1 as well as each reactant of Table 2 into pairs of enantiomers.
Therefore, the twist of the biaryl moiety rules the sense of enantio-
control. The 6:2 lead of (R,R,M)-14 vs. (R,R,P)-14 as an inducer of
enantiocontrol in the catalyses of Tables 1-2 makes (R,R,M)-14 the
[
15] In this communication, “atropisomer”, “to atropisomerize”, and “atro-
pisomerization” refer to biaryls exchanging an (M)-conformation
about their biaryl axis for a (P)-conformation – or to the reverse pro-
cesses, by which “(P)-configured biaryl atropisomers“ render “(M)-
configured biaryl atropisomers“. This usage frees these terms and the
associated designations “conformation” and “configuration” from the
constraint that the respective Free Enthalphies of Activation supercede
“
better-matched” ligand design and (R,R,P)-14 the “less-matched”.
All in all, we synthesized two 2,2’-biindolyl-based diphosphane li-
2
0 kcal/mol (M. Oki, Top. Stereochem. 1983, 14, 1–81.
gands, (R,R,M)- and (R,R,P)-14, atropselectively. They showed
promising results in asymmetric allylations and hydrogenations and
outperformed (M)-BINAP (1) several times. The atropselectivity-
determining step was an aromatic dibromination. It exploited the
asymmetric induction of a single set of stereocenters but afforded ei-
ther atropisomer whereby it became stereodivergent. Accessing bi-
aryldiphosphanes atropselectively in this manner is novel. Our strat-
egy should yield other biaryls atropisomerically pure, too, and pos-
sibly by other axis-fixing steps than dibrominations as well.
[
16] While our own study was going on, bistriazolyl-based diphosphanes
were synthesized yet only as racemic mixtures: a) 5,5’-diphenyl-4,4'-
bis(1,2,4-triazolyl)-3,3’-bis(diphenylphosphane): A. A. Kirilchuk, A.
A. Yurchenko, Yu. G. Vlasenko, A. N. Kostyuk, A. B. Rozhenko,
Chem. Heterocycl. Comp. (Engl. Translation) 2015, 50, 1559-1566
(G
= 42.5 kcal/mol).‒ b) Three 3,3’-dialkyl-
calculated for atropisomerization
3H,3'H-4,4'-bis(1,2,3-triazolyl)-5,5’-bis(diphenylphosphanes): C. La-
borde, M.-M. Wei, A. van der Lee, E. Deydier, J.-C. Daran, J.-N.
Volle, R. Poli, J.-L. Pirat, E. Manoury, D. Virieux, Dalton Trans.
2
015, 44, 12539-12545..
[
17] J. L. Gustafson, D. Lim, S. J. Miller, Science 2010, 328, 1251-1255.
Received: ((will be filled in by the editorial staff))
[18] “Atropisomeric excess” ae = (yieldmajor atropisomer  yieldminor atropisomer) /
(yieldmajor atropisomer + yieldminor atropisomer)  100%.
Published online on ((will be filled in by the editorial staff))
5
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201806294
[
[
[
19] The atropisomer-determining step (steps) is (are) uncertain. There are
up to four possibilities, namely the 2- or 4-bromination of phenols 15
or 6-bromo-15.
2006, 39, 747-760. d) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921-2943.
[38] a) R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H.
Kumobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109, 5856-
5858. b) M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo, H.
Kumobayashi, S. Akutagawa, T. Ohta, H. Takaya, R. Noyori, J. Am.
Chem. Soc. 1988, 110, 629-631.
[39] Reviews: a) P.-G. Echeverria, T. Ayad, P. Phansavath, V. Ratove-
lomanana-Vidal, Synthesis 2016, 48, 2523-2539. b) F. D. Klingler,
Acc. Chem. Res. 2007, 40, 1367-1376. c) W. Zhang, Y. Chi, X.
Zhang, Acc. Chem. Res. 2007, 40, 1278-1290. d) M. Kitamura, R.
Noyori, “Hydrogenation and Transfer Hydrogenation” in Ruthenium
in Organic Synthesis (Ed. S.-I. Murahshi,) Wiley VCH Weinheim,
2004, 3-52. e) R. Noyori, M. Kitamura, T. Ohkuma, T. Proc. Natl.
Acad. Sci. 2004, 101, 5356-5362.

[19]
20] The difference(s) G fixation of the (P)- rather than (M)-axis of the pertinent
Free Activation Enthalpies must be around 2.1 kcal/mol for ac-
counting for as much as 94% ae of the tribromination 15  (P)-16.
21] Phenols with a 3-substituent different from ortho-C
6
H
3
RCO
2
H were
2
,4,6-tribrominated atropselectively by achiral N-bromoimides em-
[
21a-d]
ploying enantiopure tetrapeptide- (ref.
) or quinine-based catalysts
[
21e]
(
ref. ): a) 3-Substituent = C(=O)N(iPr) : K. T. Barrett, S. J. Miller,
2
Org. Lett. 2015, 17, 580-583. 3-Substituents
= 4-oxo-(3H)-
quinazolin-2-yls: b) M. E. Diener, A. J. Metrano, S. Kusano, S. J. Mil-
ler, J. Am. Chem. Soc. 2015, 137, 12369-12377.‒ c) A. J. Metrano, N.
C. Abascal, B. Q. Mercado, E. K. Paulson, S. J. Miller, Chem. Com-
mun. 2016, 52, 4816-4819.‒ d) A. J. Metrano, N. C. Abascal, B. Q.
Mercado, E. K. Paulson, A. E. Hurtley, S. J. Miller, J. Am. Chem. Soc.
[40] The ee-values of the products in Table 1 were determined by chiral
HPLC, and so were their absolute configurations (details: Supporting
Information).
2
017, 139, 492-516.‒ e) 3-Substituents = quinol-8-yls: R. Miyaji, K.
Asano, S. Matsubara, Chem. Eur. J. 2017, 23, 9996-10000.
22] a) This kind of asymmetric induction is often named “point-to-axial
chirality transfer” even when – like in Figure 1 – the inducing stereo-
center(s) persist(s) rather than vanish(es) in the atropisomer-
determining step, e. g. T. Qin, S. L. Skraba-Joiner, Z. G. Khalil, R. P.
Johnson, R. J. Capon, J. A. Porco, Jr., Nature Chem. 2015, 7, 234-
[
[41] Record-prone asymmetric allylations rac-22 + 23a (c or d)  24a (c
or d) were achieved in the presence of [Pd(allyl)Cl] (2 mol-%) and
2
the imine (5 mol-%) from (+)-camphor and (S)-1-[2-
(diphenylphosphanyl)phenyl)ethylamine by Q.-L. Liu, W.Chen, Q.-Y.
Jiang, X.-F. Bai, Z. Li, Z. Xu, L.-W. Xu, ChemCatChem 2016, 8,
1495-1499: yields = 99% (95% or 98%), ee = 99% (96% or 99%).
[42] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H.
Kumobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109, 5856-
5858.
2
40.– b) Example for atropselective biaryl syntheses by a genuine
point-to-axial chirality transfer: F. Guo, L. C. Konkol, R. J. Thomson,
J. Am. Chem. Soc. 2011, 133, 18-20.
[23] Ru(II)-catalyzed asymmetric hydrogenations of - and -ketoesters in
[
14]
the presence of (P)-11  up to 95% ee: ref.
.
[43] M. Kitamura, M. Tokunaga, T. Ohkuma, R. Noyori, Org.
Synth. 1993, 71, 1-13.
[24] Pd(II)-catalyzed DIELS-ALDER reactions of cyclopentadiene with N-
acryloyl- or N-[(E)-crotyl]-1,3-oxazolidin-2-one in the presence of
[44] We obtained these specimens by treating [RuCl
2
(benzene)]
2
with
(R,R,M)-14 – or with (R,R,P)-14 – as detailed in ref. for converting
[RuCl (benzene)] and (M)-1 into the quoted “mixture of
Ru(1)Cl (DMF) and [Ru(1)Cl (DMF)] ”.
[
43]
(P)-11 with up to 96% ee: G. Celentano, T. Benincori, S. Radaelli, M.
Sada, F. Sannicoló, J. Organomet. Chem. 2002, 643-644, 424-430.
2
2
[25] Ru(II)-catalyzed asymmetric hydrogenations of ,- or ,- diarylated
2
2
2
n

,-unsaturated nitrile in the presence of (P)-11 with up to 88% ee: T.
[45] The ee-values of the products in Table 2 were determined by chiral
HPLC, and so were their absolute configurations (details: Supporting
Information).
C. Wabnitz, S. Rizzo, C Götte, A. Buschauer, T. Benincori, O. Reiser,
Tetrahedron Lett. 2006, 47, 3733-3736.
[
26] C. H. Archer, N.R. Thomas, D. Gani, Tetrahedron Asym. 1993, 4,
[46] Selected precedence: a) Catalysis by 1 gave (S)-26b with 78.4% ee: Z.
Zhang, H. Qian, J. Longmire, X. Zhang, J. Org. Chem. 2000, 65,
6223-6226. b) Catalysis by ent-1 gave (R)-26b with 89% ee: L. Qiu,
F. Y. Kwong, J. Wu, W. H. Lam, S. Chan, W.-Y. Yu, Y.-M. Li, R.
Guo, Z. Zhou, A. S. C. Chan, J. Am. Chem. Soc. 2006, 128, 5955-
5965.
1
141-1152.
[
[
[
27] I. Nilsson, R. Isaksson, Acta Chem. Scand. B 1985, 39, 531-548.
28] Determined by HPLC (details: Suppporting Information).
29] a) Method: J. Bergman, N. Eklund, Tetrahedron 1980, 36, 1439-
[
14]
1
443. b) Recent application: ref.
.
[30] This compound was diastereomerically pure. It should have resulted
[47] A slightly superior asymmetric hydrogenation 25b  26b was
[
28]
with ee = 99.87% if the ee of its precursor 21 was exactly 95% be-
cause of the Horeau principle (J. P. Vigneron, M. Dhaenes, A. Horeau,
Tetrahedron 1973, 29, 1055-1059).
2
achieved in the presence of [Ir(COD)Cl] (0.05 mol-%) and (R)-N-[(3-
methylpyridin-2-yl)methyl]-7‘-[bis(3,5-di-tert-
butylphenyl)phosphanyl]-1,1‘-spirobiindanyl-7-amine (0.11 mol-%)
by J.-H. Xie, X.-Y. Liu, X.-H. Yang, J.-B. Xie, L.-X. Wang, Q.-L.
Zhou, Angew. Chem. 2012, 124, 205-207; Angew. Chem. Int. Ed. 2012,
1
[31] H-NMR shifts of protons drawn in blue color in Scheme 1 (500 MHz,
3
CDCl ): (R,R)-17a: ‒10°C = 6.56 ppm (92 rel-%) and 6.71 ppm
5
1, 201-203: yield = 98%, ee = 98%.
(8 rel-%), +50°C = 6.59 ppm (100 rel-%).
[
32] a) The crystallographic data of the bis(sulfonate) (R,R,M)-18f derived
from (R,R,M)-18a are contained in CCDC 1822186. They can be ob-
tained free of charge from the Cambridge Crystallographic Data Cen-
tre via www.ccdc.cam.ac.uk/data_request/cif.‒ b) The unit cell con-
tained two crystallographically independent molecules (details: Sup-
porting Informations).
[48] The -ketoester 25c has been hydrogenated with >99:1 cis-selectivity
and 99% ee in 90% yield (A. Ros, A. Magriz, H. Dietrich, J. M. Las-
saletta, R. Fernández, Tetrahedron 2007, 63, 7532-7537; Ru-catalyzed
transfer hydrogenation), with 97:3 cis:trans-selectivity and 99% ee in
51% yield (J. Li, Z. Lin, Q. Huang, Q. Wang, L.Tang, J. Zhu, J. Deng,
Green Chem. 2017, 19, 5367-5370; Rh-catalyzed transfer hydrogena-
tion), and with 99:1 cis:trans-selectivity and 45% ee but less than 10%
conversion (G. Gu, J. Lu, O. Yu, J. Wen, Q. Yin, X. Zhang, Org. Lett.
1
[33] The atropisomer ratio was determined H-NMR spectroscopically
(
500 MHz, CDCl
3
) from the integrals over the dublets of CHCH
3
2
018, 20, 1888-1892; Ir-catalyzed hydrogenation).
(

(R,R,M)-18a = 1.60 ppm, (R,R,P)-18a = 1.67 ppm), over the ddd’s of
1 2
CHCH H O ((R,R,M)-18a = 3.72 ppm, (R,R,P)-18a = 4.30 ppm), over the
ddd of CHCH H O ((R,R,M)-18a = 3.83 ppm), and over the multiplet
of CHCH H O ((R,R,P)-18a = 4.06-4.22 ppm).
1
2
1
2
[
[
34] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923-2925.
35] The dibromobiindolyl (R,R,M)-18a eluted from the flash-
[
34]
chromatography column after its atropisomer (R,R,P)-18a.
36] The exact role of PhI(OAc) remains unknown. The biindolyl (R,R)-
alone did not react. Related uses: a) Synthesis of
-amino-3-bromoindoles using 1,3-dibromo-5,5-dimethylhydantoin
: K. Moriyama, K. Ishida and H. Togo Chem. Commun.
[
2
1
7a and PhI(OAc)
2
2
and PhI(OAc)
2
2
015, 51, 2273-2276. b) Synthesis of oligobromoindoles using LiBr
2
and PhI(OAc) : H. Hamamoto, H. Umemoto, M. Umemoto, C. Ohta,
M. Dohshita, Y. Miki, Synlett 2010, 17, 2593-2596.
[37] Reviews: a) R. Ferraccioli, L. Pignataro, Curr. Med. Chem. 2015, 19,
1
5
06-120. b) B. M. Trost, D. R. Fandrick, Aldrichim. Acta 2007, 40,
9-72. c) B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem. Res.
6
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