Chiral diphosphine ligands based on camphor: Synthesis and applications in asymmetric hydrogenations

Article abstract of DOI:10.1016/j.tetlet.2005.08.103

The synthesis of a novel class of atropisomer chiral diphosphine ligands with a bornene framework is described. The new ligands showed in Rh catalyzed asymmetric hydrogenation of α- and β-enamides very high ee's (more than 99%).

Full text of DOI:10.1016/j.tetlet.2005.08.103

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7397–7400
Chiral diphosphine ligands based on camphor: synthesis
and applications in asymmetric hydrogenations
Renat Kadyrov,a,* Ilyas Z. Ilaldinov,b Juan Almena,a
Axel Monseesa and Thomas H. Riermeiera
aDegussa AG, Degussa Homogeneous Catalysts, Rodenbacher, Chaussee 4, 63457 Hanau, Germany
bTatchemicals Ltd, Pravobulachnaj Street, 13, 420111 Kazan, Russia
Received 1 July 2005; revised 9 August 2005; accepted 22 August 2005
Available online 9 September 2005
Abstract—The synthesis of a novel class of atropisomer chiral diphosphine ligands with a bornene framework is described. The new
ligands showed in Rh catalyzed asymmetric hydrogenation of a- and b-enamides very high eeÕs (more than 99%).
Ó 2005 Elsevier Ltd. All rights reserved.
The development of highly efficient chiral ligands plays a
crucial role in expanding the utility of transition metal
catalyzed asymmetric reactions. Considerable efforts
have been taken in the design and synthesis of axially
chiral biaryl ligands.1 Most of them are readily avail-
able, easily modified to obtain various structural futures,
and air stable. These advantages make this type of
diphosphines very attractive for practical applications.
Albeit, racemic resolution is required in most cases to
obtain enantiomerically pure atropisomers. Knochel
introduced a new type of planar chiral ligand by replac-
ing one of the aryl moiety with a ferrocene unit using
chiral ferrocenyl sulfoxide as starting compound.2 By
complexation to the metal, the conformation of the aryl
group is locked generating axial chirality. We expanded
this concept by replacing the ferrocenyl group with
cycloolefinic unit having central chirality. The use of
chiral, nonracemic components derived from readily
available naturally occurring materials is obviously the
most effective strategy to access the ligand in commercial
scale. In this respect, terpenes routinely serve the
desired chiral cycloolefinic scaffolds by applying sophi-
sticated synthetic methods. Described herein are the first
examples of this novel class of ligands containing a
bornene backbone, which is combined with axial
chirality.3
The general route for synthesis of the ligands is illus-
trated in Scheme 1. Commercially available 3-bromo-
camphor was converted to the corresponding vinyl
triflate 1. The key intermediate 2 was prepared by means
of cross-coupling with a Grignard reagent. Applying the
reaction conditions we optimized gave chemoselectively
the desired product 2 in 78% isolated yield as a mixture
of two atropisomers in 9:1 ratio. These atropisomers did
not racemize even in boiling DMSO that is consistent
with an activation barrier of 36 kcal/mol calculated
using MMFF force field.4 Assignment of the NMR sig-
nals was established by applying multidimensional
Br
O
Br
b
BrMg
Br
Br
a
OTf
S
S
Br
1
2
d
c
R2P
R2P
Br
PR'2
S
S
3 R = Ph, 74%
4 R = 3,5-Me2C6H3, 71%
5 R = Ph, R' = Ph, 49%
6 R = Ph, R' = 3,5-Me2C6H3, 72%
7 R = 3,5-Me2C6H3, R' = Ph, 72%
Scheme 1. Reagents and conditions: (a) (i) LDA, THF, ꢀ30 °C, (ii) o-
PyNTf2, 88%, (b) 3-bromo-2,5-dimethylthienyl-4-magnesium bromide,
Pd(PPh3)2Cl2, 50 °C, THF, 78%, (c) (i) n-BuLi, THF, ꢀ78 °C, (ii)
Keywords: Asymmetric synthesis; Homogeneous catalysis; Phosphane
ligands; Rhodium; Terpenes.
*
Corresponding author. Tel.: +49 6182 59 8710; fax: +49 6182 59
ClPR2, (d) (i) t-BuLi, THF, ꢀ90 °C, (ii) ClPR0 .
2117; e-mail: renat.kadyrov@degussa.com
2
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.103

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R. Kadyrov et al. / Tetrahedron Letters 46 (2005) 7397–7400
Figure 1. Optimized at pBP/DN* level geometry of major atropisomer
of 2.
Figure 2. Optimized at pBP/DN* level geometry of the complex 8. The
cod-ligand at Rh and three P-phenyl groups are omitted for clarity.
NMR experiments. The (Ra)-configuration for the
major isomer was deduced from NOE correlations
observed between 60-H, 8-H and 10-H as shown in com-
puter-generated three-dimensional drawing (Fig. 1). It is
not necessary to resolve the atropisomers for the large
scale synthesis. The intermediary monophosphine deriv-
atives 3 and 4 crystallize from the reaction mixture as a
single isomer in 71% and 74% yields. This is achieved
after bromine–lithium interconversion at the thienyl
group followed by a reaction with the corresponding
chlorophosphine. Next metalation with t-BuLi5 and
subsequent electrophilic phosphinylation with chlorodi-
arylphosphine delivered the desired diphosphine ligands
5–7 in satisfactory yields. The new compounds have a
remarkable large coupling constants5 J(P,P) (= 20–
24 Hz).
Table 1. Enantioselective hydrogenation of (Z)-a-(N-acetamido)-
cinnamates using Rh(I)-complexes with new ligandsa
Ph
Ph
Rh(COD)2BF4(1mol%)
Ligand (1.1mol%)
(R)
ROOC
NHAc
ROOC
NHAc
H2 (8bar), 16 h, rt
R
Ligand
Solvent
eeb (%)
H
H
H
Me
Me
Me
5
6
7
5
6
7
MeOH
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
99.4
96
99.6
99.2
97
76
a Conditions: 0.2 mmol substrate, 2 lmol [Rh(COD)2]BF4, 2.2 lmol
ligand, 1 mL solvent, 20 °C, 8 bar, 16 h. The reaction proceeds
quantitatively.
b Enantiomeric excesses were determined by chiral HPLC on Chir-
alPak AD (hexane–2-PrOH, 75:25).
The Rh(I) complex 8 ([Rh(6)(cod)]BF4) was prepared
from [Rh(cod)(acac)] and ligand 6 according to the
known procedure.6 The stereochemistry of the obtained
products 6 and 8 was confirmed by multidimensional
NMR experiments and has the same configuration
around of the chiral axis as the starting dibromide 2.7
Noteworthy is the abnormally high field position
To explore the performance of new ligands, a variety of
a-enamides were prepared according to the literature
procedures.8 The best results from screening various sol-
vents are summarized in Table 2. In all cases the reac-
tion proceeded smoothly with a substrate to catalyst
ratio of S/C = 100 at ambient temperature to give the
hydrogenation product in almost quantitative yield after
4 h. An enantiomeric excess of 84–99% was reached by
employing ligands 5 and 6. While the catalyst derived
from 7 surprisingly gave lower asymmetric induction.
The highest enantioselectivity of 99.7% was observed
with ligand 6 in the hydrogenation of the N-acetyl-1-
(3-nitrophenyl)-ethenamine. There are several electro-
nically more rich alkylphosphine ligands8,9 that are
effective in hydrogenations of electron-rich enamides.
However, in general, lower enantioselectivities are
observed with ligands in the hydrogenation of a-aryl-
enamides with electron-withdrawing substituents.9b,10
When the isolated complex 8 was employed at S/C =
1
(ꢀ0.30 ppm) in the H NMR spectrum of 8 assigned
to 6-Hax. According to DFT-calculations, 6-Hax is
located at close-contact perpendicular distances of
˚
2.7 A above the face of one of the P-phenyl ring and
thus experiences ring current shielding. A three-dimen-
sional model of the optimized structure of complex 8
depicted in Figure 2 is consistent with the NOESY
experiment.
We examined the performance of the novel ligands in
asymmetric hydrogenation model substrates at standard
conditions. Particularly promising results were achieved
in the Rh-catalyzed hydrogenation of (Z)-a-(N-acetam-
ido)cinnamates. All three ligands produced (R)-N-acyl-
aminoacids and their esters with good to excellent
enantioselectivities (Table 1).

R. Kadyrov et al. / Tetrahedron Letters 46 (2005) 7397–7400
7399
Table 2. Enantioselective hydrogenation of enamides using Rh(I)-complexes with new ligandsa
Rh-Ligand
H2
NHAc
NHAc
(R)
R
R
Rd
Ligand
Solvent
H2, bar
Time (h)
eeb (%)
t-Bu
t-Bu
t-Bu
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-C10H7
2-C10H7
2-C10H7
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
5
6
7
5
6
7
5
6
7
5
6
7
5
8
8
7
CH2Cl2
CH2Cl2
Toluene
Toluene
MeOH
MeOH
MeOH
MeOH
MeOH
Toluene
Toluene
Toluene
MeOH
Toluene
MeOH
MeOH
50
50
50
50
8
3
3
3
87 (S)
84 (S)
66 (S)
88 (R)
92 (R)
46 (R)
84 (R)
85 (R)
56 (R)
94 (R)
98 (R)
44 (R)
97 (+)
99.7 (+)
99 (+)
76 (+)
4
16
16
3
3
3
4
4
4
3
8
50
50
50
50
50
50
50
5
1
60
50
1c
3
a Conditions: 0.2 mmol substrate, 2 lmol [Rh(COD)2]BF4, 2.2 lmol ligand, 1 mL solvent, 20 °C. The reaction proceeds quantitatively.
b Enantiomeric excesses were determined by chiral GC on CP Chirasil Dex-CB.
c The reaction was carried out in 2 mmol scale with S/C = 1000. Conversion 95% after 1 h.
d 2-C10H7 is naphthyl-2.
1000, 95% conversion was obtained within 1 h to afford
the desired product in 99% ee. To the best of our knowl-
edge, these results represent the highest enantioselectiv-
ity and activity achieved in Rh-catalyzed hydrogenation
of this challenging substrate. The nitro-substituted
phenylethylamines are important intermediates for phar-
maceuticals,11 particularly, the 3-nitro derivative is used
in the synthesis of inhibitors of IMPDH enzyme.11a
suitable asymmetric environment around the metal,
resulting in high asymmetric induction.
In conclusion, we have developed a new class of diphos-
phine ligands possessing a bornene backbone in combi-
nation with the axial chirality. Their catalytic potential
has been demonstrated in the highly enantioselective
Rh-catalyzed hydrogenation of a- and b-enamides. Full
details of this survey along with further applications in
new asymmetric reactions and the successful upscaling
of the new ligands will be published shortly.12
In order to examine further the synthetic utility of the
new ligands, b-dehydroaminoacids were used as test
substrates. The hydrogenation results of (Z)- and (E)-
methyl 3-acetylamino-but-2-enoates are summarized in
Table 3. Excellent enantiomeric excesses of >99% were
reached by the hydrogenation of E-isomer. With the
more challenging Z-substrate, the catalysts based on
ligand 6 provided high ee of 94%. The encouraging
results of enantioselective hydrogenation presented
herein indicate that the new ligands are able to form a
Acknowledgements
We thank Mrs. N. Solovjeva for the technical assistance
and Professor S. V. Bukharov, for helpful suggestions.
I.Z.I. thanks Degussa AG, for financial support.
References and notes
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acetylamino-but-2-enoates using Rh(I)-complexes with new ligands
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