Reducing Diastereomorphous Bis(phosphane oxide) Atropisomers to One Atropisomerically Pure Diphosphane: A New Ligand and a Novel Ligand-Preparation Design

Article abstract of DOI:10.1002/chem.201704800

1,1′-Biphenyl-2,2′-diphosphanes with an achiral bridge spanning C-5 and C-5′ form atropisomers that are enantiomers. Accessing them in an atropisomerically pure form requires resolving a racemic mixture thereof or of a bis(phosphane oxide) precursor. 1,1′-Biphenyl-2,2′-diphosphanes with a homochiral bridge spanning C-5 and C-5′ form atropisomers that are diastereomers. We synthesized the first compound of this kind 1) atropselectively and 2) under thermodynamic control—seemingly a first-time exploit in diphosphane synthesis. The selectivity-inducing step was a high-temperature reduction of two non-interconverting bis(phosphane oxide) atropisomers (60:40 mixture). It furnished the desired diphosphane atropisomerically pure (and atropconvergently because the yield was 67 %). This diphosphane proved worthwhile in Tsuji–Trost allylations, the Hayashi addition of phenylboronic acid to cyclohexenone, and the asymmetric hydrogenation of methyl acetoacetate (up to 95 % yield and 95 % ee).

Full text of DOI:10.1002/chem.201704800

DOI: 10.1002/chem.201704800
Communication
&
Diphosphane Chemistry
Reducing Diastereomorphous Bis(phosphane oxide) Atropisomers
to One Atropisomerically Pure Diphosphane: A New Ligand and a
Novel Ligand-Preparation Design
[a, c]
[a, d]
[b]
[a]
Frank Sartorius,
Marc Trebing,
Charlotte Brꢀckner, and Reinhard Brꢀckner*
Abstract: 1,1’-Biphenyl-2,2’-diphosphanes with an achiral
bridge spanning C-5 and C-5’ form atropisomers that are
enantiomers. Accessing them in an atropisomerically pure
form requires resolving a racemic mixture thereof or of a
bis(phosphane oxide) precursor. 1,1’-Biphenyl-2,2’-diphos-
phanes with a homochiral bridge spanning C-5 and C-5’
form atropisomers that are diastereomers. We synthesized
the first compound of this kind 1) atropselectively and
2) under thermodynamic control—seemingly a first-time
exploit in diphosphane synthesis. The selectivity-inducing
step was a high-temperature reduction of two non-inter-
converting bis(phosphane oxide) atropisomers (60:40 mix-
ture). It furnished the desired diphosphane atropisomeri-
cally pure (and atropconvergently because the yield was
6
7%). This diphosphane proved worthwhile in Tsuji–Trost
Figure 1. 1,1’-Biaryl-2,2’-diphosphanes for transition-metal mediated asym-
metric catalysis (usually, R is for aryl, occasionally, for alkyl). In order to per-
form their role these ligands must be atropisomerization-stable. This is guar-
anteed by being 6,6’-disubstituted.
allylations, the Hayashi addition of phenylboronic acid to
cyclohexenone, and the asymmetric hydrogenation of
methyl acetoacetate (up to 95% yield and 95% ee).
single configuration 1) by additive control and 2) in catalytic
[
4]
In 1980 Noyori et al. enriched the early field of asymmetric syn-
thesis by introducing (aR)- and (aS)-1,1’-binaphthyl-2,2’-bis(di-
phenylphosphane) (BINAP, 1; Figure 1) as a ligand for transi-
amounts. BINAP revolutionized synthesis, continues to be a
gold standard for the performance of asymmetric catalysis,
and has shaped these fields so profoundly that its originator
[
1]
[5]
tion-metal-mediated asymmetric catalysis. Accessing enantio-
gained the Nobel Prize in Chemistry in 2001. The structure
[
2]
merically pure BINAP was studied in detail and re-opti-
and virtues of BINAP have inspired the development of a con-
[
3]
mized. This allowed the two enantiomers to become the
most important ligand for establishing stereocenters with a
siderable variety of related 1,1’-biaryl-2,2’-bis(diarylphosphanes)
for almost 30 years.
[6,7]
We have designed, synthesized, and
tested a novel bis(diarylphosphane) of this kind (16) as de-
scribed from here onward.
[
a] Dr. F. Sartorius, Dr. M. Trebing, Prof. Dr. R. Brꢀckner
Institut fꢀr Organische Chemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstr. 21, 79104 Freiburg (Germany)
E-mail: reinhard.brueckner@organik.uni-freiburg.de
Homepage: http://www.brueckner.uni-freiburg.de
Most 1,1’-biaryl-2,2’-bis(diaryl- or dialkylphosphanes) known
to date form atropisomers that are enantiomers. Obtaining
them in an atropisomerically pure form—as required for any
[8–11]
application in asymmetric catalysis—almost always
includes
[
b] Dr. C. Brꢀckner
the resolution of a racemic precursor (e.g., for obtaining the di-
Institut fꢀr Physikalische und Theoretische Chemie
Julius-Maximilians-Universitꢁt Wꢀrzburg
Emil-Fischer-Str. 42, 97074 Wꢀrzburg (Germany)
[1–3,12–16]
phosphanes 1–6 shown in Figure 1
). We found how
such a resolution can be avoided while an enantiomerically
pure 1,1’-biaryl-2,2’-bis(diphenylphosphane) results neverthe-
less: if its atropisomers are diastereomers.
[
c] Dr. F. Sartorius
McKinsey & Company, Inc.
Taunustor 1, 60310 Frankfurt (Germany)
Figure 2 shows two 1,1’-biaryl-2,2’-bis(diaryl- or dialkylphos-
phane) designs of the last-mentioned kind, namely the struc-
tures 7 and 8. They are 6,6’-unsubstituted compounds—that
is, a priori atropisomerization-labile—yet 5,5’-disubstituted. The
placement of one homochiral substituent at C-5 or the place-
ment of two homochiral substituents at both C-5 and C-5’ de-
[
d] Dr. M. Trebing
Corden Pharma Switzerland LLC
Eichenweg 1, CH-4410 Liestal (Switzerland)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
chem.201704800.
Chem. Eur. J. 2017, 23, 1 – 7
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Communication
The diphosphane (R,R)-16 was obtained as a pure (M)-atrop-
isomer in seven steps (Schemes 1 and 2). 4-Aminoacetophe-
none (8) was monobrominated in 97% yield (Scheme 1). The
[23]
resulting aminobromoacetophenone 9 was transformed into
Figure 2. 1,1’-Biaryl-2,2’-diphosphanes which are 6,6’-unsubstituted but 5,5’-
disubstituted by at least one homochiral substituent. The latter uplifts 1) the
mirror symmetry between the respective atropisomers and thus 2) their en-
ergetic degeneracy. The involvement of two stereocenters is shown here
Scheme 1. Reagents and conditions: a) NBS, NH
0 min; 97%. b) Br , hn, no solvent, reflux, 90 min; 58% (ref. [30]: 45–55%).
c) NaNO
, conc. HCl, 08C, 45 min; KI, 08C!RT, 16 h; 72%. d) Concomitant
addition of 12 and BH ·THF to (3aS)-1-Methyl-3,3-diphenyltetrahydro-3H-pyr-
rolo[1,2-c][1,3,2]oxazaborole (20 mol%) in THF, 08C, 3 h; RT, 2 h; 98%.
e) NaH, THF, RT, 20 h; 81%. f) (i) iPrMgCl·LiCl, THF, ꢀ308C, 45 min; ClPPh
RT, 6 h; 94%; (ii) H , 15 min; 96%.
4
OAc (5 mol-%), MeCN, RT,
(like in our proof-of-principle compound 16), but one stereocenter or more
6
2
than two stereocenters might act similarly.
2
3
[
27]
fines diphosphane 7. Alternatively, a single homochiral sub-
stituent between C-5 and C-5’ characterizes diphosphane 8.
2
; !
2
O
2
[17]
Unbridged diphosphane 7 should atropisomerize readily
without delivering atropisomerically pure material. This is be-
cause the Gibbs free-energy difference between (R,R,P)-7 and
[
18–20]
(
R,R,M)-7 is expected to be relatively small.
A 5,5’-bridged
diphosphane 8 might (!) be atropisomerization-labile, too. If
so, it looks more likely that 8 occurs as a single atropisomer
under thermodynamic control—because DDG is sufficiently
f
large (“case 1”)—than a type-7 diphosphane would. Such a
preference might result from the differential restraints, which a
[
21]
bridge between C-5 and C-5’ imposes. On the other hand, a
bridged diphosphane (R,R,P)-8 or (R,R,M)-8 might be atropiso-
merization-stable (“case 2”). If so, even a synthesis of 8 lacking
atropselectivity might provide atropisomerically pure materi-
al(s) after standard purifications (like crystallization or flash-
[
22]
chromatography on silica gel ). Finally (“case 3”), an appropri-
ate preparation protocol might furnish an atropisomerization-
stable diphosphane 8 atropselectively right away. This would
6
be due to kinetic control and to DDG being sufficiently large.
f
Any of these “cases 1–3” would work without resolving a race-
mic intermediate. This is worth noting, since exactly this is in-
dispensable for reaching any of the diphosphanes 1–6 shown
in Figure 1 in an atropisomerically pure form.
We are interested in atropisomerically unique type-8 1,1’-
biaryl-2,2’-bis(diaryl- or dialkylphosphanes) corresponding to
any of the three “cases”. The first compound of this kind that
we identified—diphosphane (R,R,M)-16 (formula: Scheme 2)—
represents an “in-between type”: It is conformationally labile at
around 1508C (“case-1” diphosphane) and conformationally
stable below 1008C (“case-2” diphosphane; details: below).
Scheme 2. Reagents and conditions: a) Cu (100 mesh), DMF, 1408C, 20 h;
0%. b) DMF, 1278C, 24 h. c) HSiCl (10 equiv), NEt (10 equiv), toluene,
reflux, 5 h; 67%. d) H , THF, RT, 30 min; 98%.
8
3
3
2
O
2
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Communication
[
24]
the bromoiodoacetophenone 12 by diazotation and treat-
[
25–27]
ment with KI. A Corey–Itsuno reduction
ensued. It provid-
of carbinol 11 in 90% yield with
8% ee. Successive exposures to NaH and ortho-bis(bromo-
methyl)benzene (10; from a double bromination of ortho-
[
28]
ed the (R)-enantiomer
[
29]
9
[
30]
xylene ) furnished the diether 13. It was purified by flash-
[
22]
[31]
chromatography on silica gel as a seemingly pure (R,R)-
isomer. A Br-tolerating I!Mg exchange with iPrMgCl·LiCl at
[
32]
ꢀ
308C, quenching the resulting mixture with ClPPh , and an
2
H O oxidation performed in situ gave 90% of the bis(phos-
2
2
[
31]
phane oxide) (R,R)-14.
Exposing the bis(phosphane oxide) (R,R)-14 (0.01m solution
in DMF) to vacuum-dried copper powder (100 mesh) at 1408C
induced an Ullmann cyclization (Scheme 2). It led to up to
8
0% of an inseparable mixture of the atropisomers (R,R,P)-15
[
31]
(ca. 40%) and (R,R,M)-15 (ca. 60%). Reduction of this mixture
with HSiCl /NEt in refluxing toluene furnished 67% of the di-
3
3
phosphane (R,R,M)-16. It was obtained as a single atropisomer
and possessed the (M)-configuration according to X-ray crystal-
[
33]
[34]
lography. This finding implies that a near-complete (P)!
M) atropisomerization occurred during the reduction. It
became feasible after the bulky P(=O)Ph groups had given
[
35]
(
2
[
36]
way to the smaller PPh groups.
2
Figure 3. The four most stable stereostructures of the 5,5’-bridged 1,1’-
biaryl-2,2’-diphosphane (R,R)-16 in toluene and three ways to interconvert
them, all by DFT calculations [B3LYP-D3/cc-pVDZ]. The differences between
The uniqueness of our ligand design and its variability—as
the “ligand cases 1–3” above—called for a thorough analysis.
We performed it by DFT calculations on the B3LYP-D3/cc-pVDZ
level of theory. The environment was taken into account by
means of a dielectric continuum (PCM). Figure 3 summarizes
a) (R,R,P)-16C2
-
symmetric and (R,R,P)-16C1
- -
symmetric or b) (R,R,M)-16C1 symmetric and
(
[
R,R,M)-16C2 symmetric are hard to visualize.
a] Etransitionstate =9.61 kcalmol . [b] Etransitionstate =48.53 kcalmol [not compet-
-
ꢀ
1
ꢀ1
ꢀ1
itive for realizing (P)/(M) interconversions]. [c] Etransitionstate =32.01 kcalmol
[
.
[
37]
ꢀ1
the essence of our insights. Diphosphane (R,R)-16 possesses
two Epotat0K minima both for its (P)- and its (M)-atropisomer.
Both (P)-atropisomers are less stable (Erel at 0K =2.94 and
d] Etransitionstate =11.00 kcalmol .
ꢀ
1
[39]
5
0
.52 kcalmol ) than both (M)-atropisomers (E
=0.00 and
19a–g do not atropisomerize—that is, racemize—within as
rel at 0K
ꢀ
1
[38–40]
.86 kcalmol ). The (P)-atropisomer is more stable when C -
much as 12 h
(Figure 4). That is, our diphosphane 16,
1
rather than C -symmetric, whereas the opposite holds true for
which contains a 14-membered ring, atropisomerizes faster
2
the (M)-atropisomer. Equaling these Erel values with Gibbs free
energies, atropisomerically equilibrated (R,R)-16 should consist
of (R,R,M)-16C2
(mainly), (R,R,M)-16C1
(secondarily),
symmetric
-symmetric
-
and (R,R,P)-16C1
rise to a 73.1:25.3:1.6 mixture
(a little). At 110.68C, this should give
-
symmetric
[
34]
and thus an atropisomeric
excess of 96.7% of the (M)-atropisomers.
We also identified four transition structures (Figure 3 alludes
ꢀ
1
to them). The most stable (Erel at 0K =9.61 kcalmol ) belongs to
the interconversion of the (P)-atropisomers and the second-
ꢀ
1
most stable (Erel at 0K =11.00 kcalmol ) to that of the (M)-atro-
ꢀ
1
pisomers. A third transition structure (Erel at 0K =32.01 kcalmol )
allows the C -symmetric atropisomers to interconvert. The least
1
ꢀ
1
stable transition structure (Erel at 0K =48.53 kcalmol ) prevents a
one-step interconversion of the C -symmetric atropisomers.
2
The combined atropisomerizations (R,R,P)-16C1
!(R,R,M)-
-
symmetric
16C1
and (R,R,M)-16C1-symmetricQ(R,R,M)-16C2-symmetricshould
-
symmetric
proceed with a half-lifetime of 56 min at 110.68C (details: Sup-
porting Information, Section 14). Its shortness explains the
atropconvergence of the phosphane oxide reduction of
[
35]
Scheme 2.
At 1108C the 5,5’-bridged 1,1’-biaryl-2,2’-bis(diphenylphos-
phane) 16 atropisomerizes—that is, diastereomerizes—within
a few hours, whereas the analogous compounds 17a-e and
[38]
Figure 4. The 5,5’-bridged 1,1’-biaryl-2,2’-diphosphanes (M)-17a–e and
[38]
[39]
(M)-19a–g from Wanbin Zhang’s laboratories and (R,R,M)-16 from ours.
Chem. Eur. J. 2017, 23, 1 – 7
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Communication
than the diphosphanes 17 or 19, which contain 15- to 18- and
0-membered rings. Perhaps the shorter and stiffer 5,5’-bridge
In summary we designed and gained an enantiopure 1,1’-
biaryl-2,2’-bis(diphenylphosphane) (R,R)-16 of diastereomorphic
atropisomers. Under equilibrating conditions (!) the (M)-atro-
pisomer(s) dominated over their (P)-counterpart(s) approxi-
mately 60-fold. This allowed (R,R)-16 to be employed in asym-
metric catalyzes and to achieve up to 95% ee. The design prin-
ciple behind diphosphane 16 appears highly variable. This
nourishes hopes that 16 might represent a lead structure for a
2
in the diphosphane 16 imposes a greater resemblance to the
transition structure of atropisomerization than the longer and
more flexible bridges in the diphosphanes 17 and 19 do. Sus-
pecting such an effect to pair with more strain in the diphos-
phane 16 than in 17 or 19, we estimated the strain in the
ꢀ
1
former as 9.4 kcalmol . This value equals the extra-energy li-
[51]
berated when ligand 16 is ring-opened by hydrogenolysis
novel type of “privileged ligands ”. These are adoptable for
several if not many applications.
ꢀ
1
(
!20+21; DE
=ꢀ39.9 kcalmol ) compared to when
potat0K
its backbone model 18 is hydrogenolyzed (!20+2ꢂ22;
DE
ꢀ
1
=ꢀ30.5 kcalmol ), both in silico (B3LYP-D3/
potat0K
Acknowledgements
cc-pVDZ ).
Diphosphane (R,R)-16 acts sufficiently as an (M)-atropisomer
for behaving like Noyori’s (M)-configured ligand (aR)-BINAP
This research was supported by the DFG (IRTG 1038 “CCROS”).
F.S. is thankful to the Stiftung der Deutschen Wirtschaft for a fel-
lowship. We are indebted to Prof. Dr. Bernd Engels (Institut fꢀr
Physikalische und Theoretische Chemie, Julius-Maximilians-Uni-
versitꢃt Wꢀrzburg) for providing C.B. the time and the compu-
tational capacity for joining this cooperation. We thank Dr.
Daniel Kratzert (Institut fꢀr Anorganische Chemie, Albert-Lud-
wigs-Universitꢃt Freiburg) for the single-crystal X-ray analysis.
[
1–3]
(
1)
in typical transition-metal-catalyzed transformations, al-
though not quite as well (Scheme 3). Pd-complexed (R,R)-16
[
41]
catalyzed a Tsuiji–Trost allylation at 08C—at which fully equi-
librated (R,R)-16 would have approximately 99.3% atropiso-
[
42,43]
meric excess
—and provided 89% of the malonate (ꢀ)-
[
44]
23
with 88% ee. (aR)-BINAP (1) delivered the same product
in 88% yield and with 98% ee in our group
[
45a]
and in 84%
yield and with 99% ee using the corresponding zinc enola-
[
45b]
te.
Rh-complexed (R,R)-16 catalyzed the phenylborylation of
Conflict of interest
[
46]
cyclohexenone
at 1008C—at which the fully equilibrated
R,R)-16 would have approximately 97.2% atropisomeric
(
The authors declare no conflict of interest.
[
42,43]
[47]
excess
—and provided 95% of the 1,4-adduct (+)-25
with 93% ee. (aR)-BINAP (1) delivered the same product in
Keywords: asymmetric catalysis · asymmetric induction ·
atropisomerism · biaryls · diphosphanes
83% yield and with 99% ee according to reference [48] and in
2% yield and with 96% ee in own hands. Ru-complexed (R,R)-
9
1
6 catalyzed the asymmetric hydrogenation of the b-ketoest-
[
1] A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, R. Noyori,
J. Am. Chem. Soc. 1980, 102, 7932.
[
49]
er 26 at room temperature—at which the fully equilibrated
(
R,R)-16 would have approximately 98.9% atropisomeric
[2] a) H. Takaya, K. Mashima, K. Koyano, M. Yagi, H. Kumobayashi, T. Taketo-
mi, S. Akutagawa, R. Noyori, J. Org. Chem. 1986, 51, 629; b) H. Takaya, S.
Akutagawa, R. Noyori, Org. Synth. 1989, 67, 20.
[
42,43]
[50]
excess
—and provided 78% of the hydroxyester (ꢀ)-27
with 95% ee. (aR)-BINAP (1) delivered the same product in
6% yield and with 98% ee in our hands.
[
3] a) D. Cai, J. F. Payack, D. R. Bender, D. L. Hughes, T. R. Verhoeven, P. J.
Reider, Org. Synth. 1998, 76, 6; b) D. Hughes, Org. Synth. 2014, 91, 1.
4] R. Noyori, H. Takaya, Acc. Chem. Res. 1990, 23, 345.
8
[
[
5] R. Noyori, Angew. Chem. Int. Ed. 2002, 41, 2008; Angew. Chem. 2002,
114, 2108.
[
6] Reviews of enantiomerically pure biaryldiphosphane ligands: a) T.
Ohkuma, N. Kurono, in Privileged Chiral Ligands and Catalysts (Ed.: Q.-L.
Zhou), Wiley-VCH, Weinheim, 2011; b) M. Berthod, G. Mignani, D. Wood-
ward, M. Lemaire, Chem. Rev. 2005, 105, 1801; c) T. T. L. Au-Yeung, S.-S.
Chan, A. S. C. Chan, Adv. Synth. Catal. 2003, 345, 537; d) P. Kocovsky, S.
Vyskocil, M. Smrcina, Chem. Rev. 2003, 103, 3213.
[
7] Reviews covering all kinds of enantiomerically pure diphosphane li-
gands: a) J. Wencel-Delord, A. Panossian, F. R. Leroux, F. Colobert, Chem.
Soc. Rev. 2015, 44, 3418; b) M. M. Pereira, M. J. F. Calvete, R. M. B. Carril-
ho, A. R. Abreu, Chem. Soc. Rev. 2013, 42, 6990; c) J. A. Gillespie, E. Zui-
dema, P. W. N. M. van Leeuwen, P. C. J. Kamer in Phosphorus(III) Ligands
in Homogeneous Catalysis: Design and Synthesis (Eds.: P. C. J. Kamer,
P. W. N. M. van Leeuwen), Wiley, Chichester, 2012; d) W. Li, X. Zhang in
Phosphorus(III) Ligands in Homogeneous Catalysis: Design and Synthesis
(
Eds.: P. C. J. Kamer, P. W. N. M. van Leeuwen), Wiley, Chichester, 2012;
e) N. Arshad, C. O. Kappe, Adv. Heterocycl. Chem. 2010, 99, 33.
Scheme 3. Reagents and conditions: a) Dimethyl malonate (1.2 equiv), bis(-
[8] The only exceptions are syntheses based on ring-closing aryl/aryl bond
3
[9]
trimethylsilyl)acetamide (2.2 equiv), NaOAc (5.0 mol%), [Pd(h -C
3
H
5
)Cl]
, 08C, 1 h. b) Similarly as (a) but using (R)-
(2.5 equiv), [Rh(acac)(C ] (1.0 mol%), 16
2
1.2 mol%), dioxane:H O=9:1, 1008C, 5 h. d) Same as (c) but using (R)-
2
]
formations in enantiomerically pure bis(arenes). With a view on reach-
(
0.50 mol%), 16 (1.0 mol%), CH
2
Cl
2
ing 1,1’-biaryl-2,2’-diphosphanes eventually such ring-closures furnished
6,6’-bridged 2,2’-disubstituted biaryls at first and, ideally, atropisomeri-
cally pure. If phosphorus is present both at C-2 and C-2’ these com-
pounds gave atropisomerically pure 6,6’-bridged biaryl-2,2’-diphos-
[
45a]
BINAP at ꢀ408C.
c) PhB(OH)
2
2 4 2
H )
(
ꢁ
ꢂ
BINAP. e) H
2
(5 bar), [Et
2
NH
2
]
{[ClRu(16)]
2
(m-Cl)
3
}
(0.5 mol%), EtOH, RT, 20 h.
ꢁ
ꢂ
[10a]
[10b]
f) Same as (e) but using [Et
2
NH
2
]
{[ClRu((R)-BINAP)]
2
(m-Cl)
3
}
(0.5 mol%).
phanes in another 1
or 2 steps.
Related ring-closure products
&
&
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Communication
devoid of phosphorus were transformed into atropisomerically pure
Hirao, S. Nakahama, J. Chem. Soc. Perkin Trans. 1 1985, 2039; d) S.
Itsuno, M. Nakano, K. Ito, A. Hirao, M. Owa, N. Kanda, S. Nakahama, J.
Chem. Soc. Perkin Trans. 1 1985, 2615.
1
,1’-biaryl-2,2’-diphosphanes in 3 steps—by liberating two aryl-bound
[10c]
2
OH groups, making their bis(triflate), and coupling with HPAr .
[
9] Quite generally, “the coupling of two aryls units, pre-fixed through a
chiral bridge, is a popular strategy in asymmetric biaryl synthesis” ac-
cording to the introductory words of Section 3.1 of a pertinent review:
a) G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J. Garner,
M. Breuning, Angew. Chem. Int. Ed. 2005, 44, 5384; Angew. Chem. 2005,
[26] E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen, V. K. Singh, J. Am. Chem.
Soc. 1987, 109, 7925.
[27] (3aS)-1-Methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazabor-
[
26]
ole was obtained from BASF Corporation.
[28] Alcohol 11 was dextrorotatory. It should be (R)-configured because its
(R)-debromo and its (R)-deiodo analogs are dextrorotatory, too (details:
Supporting Information).
[29] This ee value was determined by HPLC analysis using an enantiomeri-
cally pure stationary phase (details: Supporting Information).
[30] Procedure: a) R. Brꢀckner, S. Braukmꢀller, H.-D. Beckhaus, J. Dirksen, D.
Goeppel, M. Oestreich, Praktikum Prꢁparative Organische Chemie—Or-
ganisch-Chemisches Grundpraktikum, Spektrum, Heidelberg, 2008,
pp. 83; analytical data: b) R. P. Kreher, J. Kalischko, Chem. Ber. 1991, 124,
645.
117, 5518. According to reference [9a] atropselectivity in a ring-closure
as characterized in the first sentence of reference [8], but not targeting
a biaryldiphosphane, was first reported by b) S. Miyano, M. Tobita, H.
Hashimoto, Bull. Chem. Soc. Jpn. 1981, 54, 3522.
[
10] First transformation of an atropisomerically pure 6,6’-bridged biaryl-
2,2’-bis(phosphane oxide) into a 6,6’-bridged biaryl-2,2’-diphosphane:
a) L. Qiu, J. Wu, S. Chan, T. T.-L. Au-Yeung, J.-X. Ji, R. Guo, C.-C. Pai, Z.
Zhou, X. Li, Q.-H. Fan, A. S. C. Chan, Proc. Natl. Acad. Sci. USA 2004, 101,
5815; first transformation of an atropisomerically pure 6,6’-bridged
biaryl-2,2’-bis(diethyl phosphonate) into a 6,6’-bridged biaryl-2,2’-di-
phosphane: b) X. Sun, L. Zhou, W. Li, X. Zhang, J. Org. Chem. 2008, 73,
[31] Alcohol (R)-11 (98% ee) and dibromide 10 should have afforded a 98:2
mixture of diether (R,R)-13 (99.98% ee) and its meso diastereomer. We
observed neither the latter nor the meso isomer of any of the follow-up
products. It is possible that we removed the meso compund(s) flash-
chromatographically (reference [22]).
[32] Br(!)/Mg exchange reactions with this reagent: A. Krasovskiy, P. Knochel,
Angew. Chem. Int. Ed. 2004, 43, 3333; Angew. Chem. 2004, 116, 3396.
[33] 8% of the P atoms of diphosphane (R,R,M)-16 had been oxidized (inad-
vertently) in the crystals, which we studied after months of storage:
1143; first transformation of an atropisomerically pure 1,1’-biaryl with a
6,6’-bridge via a 1,1’-biaryl-2,2’-diol into a 1,1’-biaryl-2,2’-diphosphane:
c) G. Michaud, M. Bulliard, L. Ricard, J.-P. GenÞt, A. Marinetti, Chem. Eur.
J. 2002, 8, 3327.
[
11] The cyclizations to which reference [8] alludes or which underlie the
studies of reference [10] were atropselective and gave 5,5’-di-unsubsti-
tuted 6,6’-disubstituted 1,1’-biaryl-2,2’-diphosphanes in the end. In stark
contrast the cyclization giving bis(phosphane oxide) 15 is not atropse-
lective. Irrespective thereof, it sets the stage for reaching the 5,5’-
bridged 6,6’-di-unsubstituted 1,1’-biaryl-2,2’-diphosphane 16 atropcon-
vergently. This makes our ligand design fundamentally distinct from lit-
erature precedence.
2
They pertained to P(=O)Ph units. It is noteworthy that this left the C,
O, and P atom sites unaffected throughout the crystal. Therefore, re-
finement was possible as if the material had been homogeneous. De-
tails and ORTEP plots: Supporting Information. CCDC 1475863 contains
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre.
[
[
[
[
[
12] R. Schmid, M. Cereghetti, B. Heiser, P. Schçnholzer, H.-J. Hansen, Helv.
Chim. Acta 1988, 71, 897.
13] R. Schmid, J. Foricher, M. Cereghetti, P. Schçnholzer, Helv. Chim. Acta
[34] At equilibrium in toluene solution of 110.68C the diphosphanes (R,R,M)-
1991, 74, 370.
16C2
(Keq =47.4; details: Supporting Information, Section 10.1). The diphos-
phanes (R,R,M)-16C2
prevail over (R,R,P)-16C1
Supporting Information, Section 10.3).
[35] At 110.68C in toluene solution, a 60:40 mixture of a mixture of the di-
phosphanes (R,R,M)-16C2
pure (R,R,P)-16C1 symmetric should provide a 96.4:3.6 mixture within 4 h
- -
symmetric and (R,R,P)-16C1 symmetric should represent a 97.9:2.1 mixture
14] X. Zhang, K. Mashima, K. Koyano, N. Sayo, H. Kumobayashi, S. Akutaga-
wa, H. Takaya, Tetrahedron Lett. 1991, 32, 7283.
15] T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura, H. Kumo-
bayashi, Adv. Synth. Catal. 2001, 343, 264.
16] S. Jeulin, S. Duprat de Paule, V. Ratovelomanana-Vidal, J.-P. GenÞt,
Angew. Chem. Int. Ed. 2004, 43, 320; Angew. Chem. 2004, 116, 324.
17] G. Storch, F. Maier, P. Wessig, O. Trapp, Eur. J. Org. Chem. 2016, 5123.
18] G. Storch, O. Trapp, Angew. Chem. Int. Ed. 2015, 54, 3580; Angew. Chem.
-
symmetric and (R,R,M)-16C1
-
symmetric combined should
-
symmetric in a 98.4:1.6 ratio (Keq =59.7; details:
- -
symmetric and (R,R,M)-16C1 symmetric combined vs.
[
[
-
(details: Supporting Information, Section 13). This alone may have left
2
015, 127, 3650.
(R,R,P)-16 undetected. Assistance by having decreased its proportion
[
22]
[
[
19] The diphosphane design 7 can have some potential for asymmetric cat-
alysis nevertheless. This was shown impressively in reference [18].
during purification by flash-chromatography is conceivable.
[36] Oxidation of the diphosphane (R,R,M)-16 with H gave 98% of the bi-
2
O
2
20] An atropisomerization-labile 1,1’-biaryl-2,2’-bis(diphenylphosphane), the
s(phosphane oxide) 15 (Scheme 2). It was pure (R,R,M)-15, without a
trace of (R,R,P)-15, and remained atropisomerically pure while heating a
DMF solution thereof at 1278C for 24 h. This inertness could be due to
an insurmountable atropisomerization barrier and/or to a lack of driv-
ing force.
“
atropisomers” of which would be enantiomers, converged to an atro-
II
pisomerically pure Pd complex in the presence of an enantiopure dia-
mine ligand. The complex stayed atropisomerically pure even after re-
moval of this diamine by protonation: a) K. Mikami, K. Aikawa, Y. Yusa,
M. Hatano, Org. Lett. 2002, 4, 91; for an insightful contextualization of
the concept behind the findings of reference [20a]—which is very dif-
ferent from ours—see: b) K. Mikami, K. Aikawa, Y. Yusa, J. J. Jodry, M. Ya-
manaka, Synlett 2002, 1561.
[37] Detailed representations of all minimum and transition structures,
atomic coordinates, bond angles, dihedral angles, distortion parame-
ters, and paralleling results obtained with other functional/basis set
combinations: Supporting Information.
[38] a) C. Wang, G. Yang, J. Zhuang, W. Zhang, Tetrahedron Lett. 2010, 51,
2044; corrigendum: C. Wang, G. Yang, J. Zhuang, W. Zhang, Tetrahedron
ꢀ
1
[
21] Potential energy differences of ꢀ3.7 to +6.8 kcalmol between the
P)- vs. (M)-atropisomer were calculated (B3LYP/6-31G*) for biaryls in
which a homochiral tetralactame links C-5 to C-5’ and the C-2- and C-
’-substituents are H, OH, OMe, Me or Br: G. Haberhauer, C. Tepper, C.
(
n
Lett. 2011, 52, 5196; these ligands were named “C -BridgePHOSs” by
2
b) J. Chen, D. Liu, D. Fan, Y. Liu, W. Zhang, Tetrahedron 2013, 69, 8161.
[39] a) W. Zhang, J. Shen, D. Liu, Faming Zhuanli Shenqing, CN 105481684 A
20160413, 2016; b) W. Zhang, J. Li, J. Shen, D. Liu, Faming Zhuanli
Shenqing, CN 105384623 A 20160309, 2016; c) W. Zhang, Z. Zhang, J.
Chen, Y. Bao, J. Dong, Y. Jing, Y. Li, Faming Zhuanli Shenqing, CN
105254474 A 20160120, 2016; d) W. Zhang, Z. Zhang, J. Chen, Y. Bao, Y.
Zhang, Y. Li, Faming Zhuanli Shenqing, CN 105218335 A 20160106,
2016.
Wçlper, D. Blꢃser, Eur. J. Org. Chem. 2013, 2325. It was assumed but not
proved that these biaryls are atropisomerically labile.
[
[
22] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.
23] Analytical data: M. S. Nery, N. S. Azevedo, J. N. Cardoso, G. B. C. Slana,
R. S. C. Lopes, C. C. Lopes, Synthesis 2007, 1471.
24] A different synthesis of compound 12 appeared after our studies were
underway: K. Gedrich, M. Heitbaum, A. Notzon, I. Senkovska, R. Frçhlich,
J. Getzschmann, U. Mueller, F. Glorius, S. Kaskel, Chem. Eur. J. 2011, 17,
[
[40] The diphosphanes (M)-17a–e or ꢀ19a–g and their (P)-atropisomers are
2099.
pairs of enantiomers. Thus, accessing them atropisomerically pure re-
[
38,39]
[
25] a) S. Itsuno, K. Ito, A. Hirao, S. Nakahama, J. Chem. Soc. Chem. Commun.
quired resolving racemic specimens by chiral HPLC.
These proper-
1
1
983, 469; b) S. Itsuno, K. Ito, A. Hirao, S. Nakahama, J. Org. Chem.
984, 49, 555; c) S. Itsuno, M. Nakano, K. Miyazaki, H. Masuda, K. Ito, A.
ties liken 17 and 19 to the diphosphanes 1–6 (Figure 1), but differenti-
ate them from (M)- vs. (P)-16 which are a pair of diastereomers.
Chem. Eur. J. 2017, 23, 1 – 7
www.chemeurj.org
5
ꢁ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
2
D
0
[
[
41] Recent reviews: a) R. Ferraccioli, L. Pignataro, Curr. Med. Chem. 2015, 19,
06; b) B. M. Trost, D. R. Fandrick, Aldrichimica Acta 2007, 40, 59;
[47] a) (+)-25 exhibited ½aꢃ = +18.3 (c=1.13, CHCl
3
); b) (+)-25 is (R)-con-
1
figured according to A. G. Schultz, R. E. Harrington, J. Am. Chem. Soc.
2
D
2
c) B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem. Res. 2006, 39, 747;
d) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921.
42] Diphosphane (R,R)-16 need not assume the same (M):(P) equilibrium
ratio in a Pd-, Rh- or Rh-complex as if unbound (cf. reference [18]).
43] Calculation: see the Supporting Information, Section 10.3.
1991, 113, 4926 {½aꢃ = +20.5 (c=0.58, CHCl
3
)}.
[48] T. Hayashi, M. Takahashi, Y. Takaya, M. Ogasawara, Org. Synth. 2002, 79,
84.
[49] Reviews: a) M. Kitamura, R. Noyori in Ruthenium in Organic Synthesis
(
Ed.: S.-I. Murahashi,) Wiley-VCH, Weinheim, 2004, pp. 3–52; b) T.
Ohkuma, M. Kitamura, R. Noyori in Catalytic Asymmetric Synthesis,
nd ed. (Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, p. 1.
[
[
2
D
0
44] a) (ꢀ)-23 exhibited ½aꢃ =ꢀ9.0 (c=0.85, CHCl
3
); b) (ꢀ)-23 is (S)-config-
2
ured according to V. G. Albano, M. Bandini, M. Monari, E. Marcucci, F.
2
0
2
0
[50] a) (ꢀ)-27 exhibited ½aꢃ =ꢀ41.2 (c=0.98, CHCl ); b) (ꢀ)-27 is (R)-config-
Piccinelli, A. Umani-Ronchi, J. Org. Chem. 2006, 71, 6451 {½aꢃ =ꢀ8.8
D
3
D
ured according to D. A. Evans, J. Bartroli, T. L. Shi, J. Am. Chem. Soc.
981, 103, 2127 {[a] )}.
(
3
c=0.6, CHCl )}.
1
D
=ꢀ45.8 (c=1.7, CHCl
3
[
[
45] a) T. Baumann, R. Brꢀckner, unpublished results; b) N. Kinoshita, T. Kawa-
bata, K. Tsubaki, M. Bando, K. Fuji, Tetrahedron 2006, 62, 1756.
[
51] a) T. P. Yoon, E. N. Jacobsen, Science 2003, 299, 1691; b) Privileged Chiral
Ligands and Catalysts (Ed.: Q.-L. Zhou), Wiley-VCH, Weinheim, 2011.
46] Reviews: a) G. Berthon-Gelloz, T. Hayashi in Boronic Acids: Preparation
and Applications in Organic Synthesis Medicine and Materials, 2nd ed.
(
Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2011, pp. 263; b) T. Hayashi, K.
Manuscript received: June 15, 2017
Yamasaki, Chem. Rev. 2003, 103, 2829.
Revised manuscript received: October 11, 2017
Version of record online: && &&, 0000
&
&
Chem. Eur. J. 2017, 23, 1 – 7
www.chemeurj.org
6
ꢁ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
Diphosphane Chemistry
F. Sartorius, M. Trebing, C. Brꢀckner,
R. Brꢀckner*
&& – &&
Atropconvergence: A 1,1’-biaryl-2,2’-di-
phosphane with a “homochiral bridge”
between C-5 and C-5’ defines a pair of
atropisomers that are diastereomers.
This suggests that the synthesis of such
a compound as a pure atropisomer may
be achieved by a unilaterally biased
atropisomerization. The first diphos-
phane synthesis of this kind is report-
ed—the reduction of a 60:40 mixture of
atropisomeric bis(phosphane oxides) at
110 8C provided 67% of a single diphos-
phane atropisomer.
Reducing Diastereomorphous
Bis(phosphane oxide) Atropisomers to
One Atropisomerically Pure
Diphosphane: A New Ligand and a
Novel Ligand-Preparation Design
Chem. Eur. J. 2017, 23, 1 – 7
www.chemeurj.org
7
ꢁ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ