Conformationally flexible biphenylphosphane ligands for Ru-catalyzed enantioselective hydrogenation

Article abstract of DOI:10.1002/(SICI)1521-3773(19990215)38:4<495::AID-ANIE495>3.0.CO;2-O

Stereomutation of a BIPHEP/RuCl₂/diamine complex (shown schematically) is possible because of the conformational flexibilty of BIPHEP ligands. The result is an asymmetric activation in the Ru-catalyzed hydrogenation of carbonyl compounds to optically active alcohols. Whereas a racemic BINAP/RuCl₂ complex with a chiral diamine activator gives a 1:1 mixture of two diastereomers, unequal amounts of the diastereomers can be produced from a BIPHEP/RuCl₂ complex and a chiral diamine. Ar = 3,5-dimethylphenyl, BINAP = 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl, BIPHEP = 2,2'- bis(diarylphosphanyl)biphenyl.

Full text of DOI:10.1002/(SICI)1521-3773(19990215)38:4<495::AID-ANIE495>3.0.CO;2-O

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Crystallographic Data Centre as supplementary publication nos.
CCDC-102586 and CCDC-102587 (1a and 1e, respectively). Copies
of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (Fax: (‡44)1223-336-033;
E-mail: deposit@ccdc.cam.ac.uk).
formed, in principle, in unequal amounts. Here, if the major
diastereomer shows higher chiral efficiency than does the
minor isomer, this strategy becomes more beneficial than the
use of structurally similar BINAP analogues.
[
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The hydrogenation of a carbonyl compound by the complex
formed from [RuCl (dm-biphep)(dmf) ] (1; DM-BIPHEP ˆ
2
n
2
,2'-[(3,5-dimethylphenyl)phosphanyl]biphenyl) and enantio-
pure (S,S)-1,2-diphenylethylenediamine ((S,S)-DPEN; (S,S)-
2)[ is shown in Scheme 1. Conformational flexibility of the
7]
[
[
1
664.
H2
N
H2
N
[
20] M. E. Brown, M. D. Hollingsworth, Nature 1995, 376, 323 ± 326.
21] M. Sakamoto, Chem. Eur. J. 1997, 3, 684 ± 689.
Ar2
P
Cl
Ph
H
H
Ar
P
2 Cl
Ph
?
[
H
H
Ru
Ru
P
N
P
N
Ar2 Cl
Ph
Ar Cl
H2
H2
Ph
2
(S)-1 / (S,S)-2
(R)-1 / (S,S)-2
1
O
OH
+
H2
Conformationally Flexible Biphenyl-
phosphane Ligands for Ru-Catalyzed
Enantioselective Hydrogenation**
∗
Ar'
Ph
H2N
Ph
Ar'
(S,S)-2
NH2
Scheme 1. Enantioselective hydrogenation of carbonyl compounds to
optically active alcohols catalyzed by Ru complexes containing conforma-
tionally flexible BIPHEP ligands. In each case, (S)-1 and (R)-1 (Arˆ 3,5-
dimethylphenyl) is fixed in the respective configuration. The chiral amine
Koichi Mikami,* Toshinobu Korenaga,
Masahiro Terada, Takeshi Ohkuma, Trang Pham,
and Ryoji Noyori*
(
S,S)-2 is added as activator to complex 1 prior to the hydrogenation.
In asymmetric catalytic reactions,[1] racemic catalysts in-
herently give only racemic products, whereas nonracemic
catalysts generate nonracemic products with or without a
nonlinear relationship. Conversely, we reported a concep-
tually new strategy for asymmetric catalysis using racemic
1
BIPHEP/RuCl
/diamine complexes was proven by H NMR
2
spectroscopic analysis. A mixture of 1 and 2 in CDCl
at room
3
[
2]
1
temperature showed a H NMR spectrum that is quite similar
to that of the racemic DM-BINAP/RuCl
/(S,S)-DPEN com-
This indicated the initial formation of an equimolar
2
[
3]
[8, 9]
catalysts wherein a chiral additive selectively activates,
plex.
rather than deactivates,[4] one enantiomer of the racemic
catalyst. We here describe an advanced strategy that uses
conformationally flexible bis(phosphanyl)biphenyl ligands
mixture of S- and R-fixed DM-BIPHEP/RuCl
diastereomers in this solvent ( H NMR (CDCl
/(S,S)-DPEN
): (S)-DM-
2
1
3
BIPHEP/RuCl
BIPHEP/RuCl
/(S,S)-DPEN: d ˆ 3.42, 3.43, 4.33; (R)-DM-
2
[
5]
(
BIPHEP) for a Ru catalyst which, following activation by
2
/(S,S)-DPEN: d ˆ 3.28, 4.06, 4.59). However,
[
3d, 6]
a chiral diamine,
achieves high enantioselectivity in the
when this mixture was diluted with [D ]2-propanol (CDCl /
8 3
hydrogenation of carbonyl compounds (see Scheme 1). Com-
(CD ) CDOD 1/2) and allowed to stand at room temperature
3 2
bination of a racemic BINAP/RuCl species (BINAP ˆ 2,2'-
for 3 h or at 808C for 30 min, a 3:1 mixture of the S/S,S and R/
S,S diastereomers was formed (Figure 1, Scheme 2; H NMR
2
1
bis(diphenylphosphanyl)-1,1'-binaphthyl) with an equimolar
amount of an enantiomerically pure diamine gives a 1:1
mixture of two diastereomeric diphosphane/diamine com-
[
3d]
plexes. When the BINAP ligand is replaced by the flexible
and proatropisomeric BIPHEP, diastereomeric complexes are
[
*] Prof. Dr. K. Mikami, T. Korenaga, Dr. M. Terada
Department of Chemical Technology
Tokyo Institute of Technology
Ookayama, Meguro-ku, Tokyo 152 ± 8552 (Japan)
Fax: (‡81)3-5734-2776
E-mail: kmikami@o.cc.titech.ac.jp
Prof. Dr. R. Noyori, Prof. Dr. T. Ohkuma, Dr. T. Pham
Department of Chemistry and Molecular Chirality
Research Unit, Nagoya University
Chikusa, Nagoya 464 ± 8602 (Japan)
Fax: (‡81)52-783-4177
E-mail: noyori@chem3.chem.nagoya-u.ac.jp
[
**] We are grateful to Dr. H. Kumobayashi and Dr. N. Sayo of Takasago
International Corp. for providing BINAP ligands. This work was
financially supported by the Ministry of Education, Science, Sports
and Culture of Japan (nos. 07CE2004, 09238209, and 10208204).
Figure 1. Stereomutation of DM-BIPHEP/RuCl
eomers in CDCl /(CD
/DPEN to (R)-DM-BIPHEP/RuCl
2
2
/(S,S)-DPEN diaster-
CDOD (1/2) at 258C. x ˆ ratio of (S)-DM-
/DPEN.
3
3 2
)
BIPHEP/RuCl
2
Angew. Chem. Int. Ed. 1999, 38, No. 4
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(
CDCl /(CD ) CDOD 1/2): (S)-DM-BIPHEP/RuCl /(S,S)-
so, a higher enantioselectivity with a 3:1 BIPHEP-chelate
equilibrium (run 3) clearly indicated the advantage of con-
formationally flexible BIPHEP compared with that of a 1:1
BINAP pair (run 4).
3
3
2
2
DPEN: d ˆ 3.37, 3.66, 4.34; (R)-DM-BIPHEP/RuCl /(S,S)-
2
DPEN: d ˆ 3.26, 4.07, 4.59). Stereomutation of the DM-
BIPHEP/RuCl /DPEN complex could occur through rupture
2
of a Ru�P bond, rotation about the C1�C1' bond to invert the
Further increase in enantioselectivity was attained at a
lower reaction temperature (� 358C, run 5). The enantiose-
lectivity by 1/(S,S)-2 was higher than that by the (Æ)-DM-
BINAP/RuCl /(S,S)-diamine complex at the same low tem-
H2
N
Ar2
P
H2
N
2
Ar2
P
Ph
H
H
Ph
H
H
Cl
Cl
perature and high pressure (run 6). Thus, (R)-1-(1-naph-
Ru
Ru
[12]
P
N
P
N
thyl)ethanol (4) was obtained with 92% ee in quantitative
Ar2 Cl
Ph
Ar2Cl
Ph
H2
H2
yield. DM-BIPHEP/RuCl /DPEN was also employable in the
2
4.34
4.59
reduction of o-methylacetophenone with H2 (8 atm). The
reaction was carried out with KOH and 2-propanol at 08C for
4 h to provide 1-o-methylphenylethanol quantitatively and
with 88% ee (for comparison, the analogous reaction with
3
.37
3.26
4.07
(S)
3.66
(R)
3
:
1
1
Scheme 2. Assignment of H NMR signals for DM-BIPHEP/RuCl
2
/(S,S)-
CDOD (1/2). In each case, the R and
S configuration is fixed. Arˆ 3,5-dimethylphenyl.
3 3 2
DPEN diastereomers in CDCl /(CD )
(
Æ)-DM-BINAP/RuCl /(S,S)-DPEN proceeds with 86% ee).
2
In summary, we have presented an enantioselective hydro-
genation by a conformationally flexible BIPHEP-Ru catalyst
containing a chiral diamine ligand. The asymmetric activation
will provide a general strategy for the use of not only racemic
but also conformationally flexible ligands.
[
5a]
configuration of the diphosphane, and recoordination of P
[
10]
to Ru. Alternatively, the configuration of the diphosphane-
chelated seven-membered ring might be directly inverted.
The dichloro complexes may further be converted into active
mono- or dihydrido Ru species under hydrogenation con-
Experimental Section
[
11]
ditions.
4
2
: A 100-mL autoclave was charged with solid 1 (11.4 mg, 0.012 mmol) and
(2.6 mg, 0.012 mmol). 2-Propanol (3.3 mL) was added to the autoclave
The enantioselective hydrogenation was performed after
addition of KOH and a ketone (e.g. 3) to a mixture of 1 and 2
with or without preheating at 808C for 30 min [Eq. (1),
Table 1]. The advantage of the conformationally flexible
under a stream of argon. The solution was preheated at 808C for 30 min,
and KOH/2-propanol (0.5m, 48 mL, 0.024 mmol) was added with stirring at
room temperature over 30 min. 1'-Acetonaphthone (3; 0.46 mL,
3
.00 mmol) was added to the autoclave at room temperature under a
stream of argon, and then hydrogen (40 atm) was introduced. After the
mixture was vigorously stirred for 12 h at � 358C, the solution was
concentrated under reduced pressure. The resulting residue was filtered
through a short column of silica gel. The chemical yield and enantiomeric
ratio of 4 were calculated by chiral GC (>99%, (R)-4:(S)-4 ˆ 96.0:4.0).
Product 4 can also be isolated (510 mg, 99%) by column chromatography
O
OH
1
(0.4 mol%)
+
H2
(1)
(
S,S)-2 (0.4 mol%)
KOH (0.8 mol%)
2-propanol
28
3
(R)-4
on silica gel (eluent: hexane/EtOAc 5/1). [a]
D
ˆ ‡69.0 (c ˆ 1.0, CHCl
3
; lit.
[
12]
25
D
value:
[a]
ˆ ‡78.9 (c ˆ 1, CHCl
3
), R isomer); GC (column: CP-
Table 1. Results of the enantioselective hydrogenation of ketone 3 to
alcohol 4. Equation (1) shows the reaction catalyzed by the complex
Cyclodextrin-b-2,3,6-M-19, inner diameter: 0.25 mm  25 m, CHROM-
PACK, carrier gas: nitrogen (75 kPa), column temperature: 1608C,
formed from [RuCl
2
(dm-biphep)(dmf)
n
]
(1) and (S,S)-1,2-diphenyl-
injection temperature: 1908C, split ratio: 100:1), retention time t
32.7 min ((R)-(‡)-4, 96.0%), 31.6 min ((S)-(� )-4, 4.0%), 21.3 min (3, 0%).
ˆ
R
ethylenediamine ((S,S)-2).[
a]
Run Phosphane
S/S,S:R/S,S[b] p(H
atm] [8C]
2
)
T
t
ee
[h] [%] [%]
Yield
Received: July 8, 1998
Revised version: November 3, 1998 [Z12118IE]
German version: Angew. Chem. 1999, 111, 517 ± 519
[
1
2
3
4
5
6
DM-BIPHEP
DM-BIPHEP
DM-BIPHEP
(Æ)-DM-BINAP
DM-BIPHEP
(Æ)-DM-BINAP
1:1
2:1
3:1
8
8
8
8
28
28
28
28
4
4
4
4
63
73
84
80
92
89
> 99
> 99
> 99
> 99
> 99
> 99
[
[
c]
c]
Keywords: activation ´ asymmetric catalysis ´ atropisomer-
ism ´ P ligands ´ ruthenium
3:1
40
40
� 35 12
� 35
7
[
a] Hydrogenation performed as described in the text without preheating,
[
1] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
York, 1994; b) H. Brunner, W. Zettlmeier, Handbook of Enantiose-
lective Catalysis, VCH, Weinheim, 1993; c) Catalytic Asymmetric
Synthesis (Ed.: I. Ojima), VCH, New York, 1993; d) H. B. Kagan,
Comprehensive Organic Chemistry, Vol. 8,, Pergamon, Oxford, 1992.
2] Reviews: R. Noyori, M. Kitamura, Angew. Chem. 1991, 103, 34 ± 55;
Angew. Chem. Int. Ed. Engl. 1991, 30, 49 ± 69; H. B. Kagan, D.
Guillaneux, D. Rainford, O. Samuel, S.-H. Zhao, Acta Chem. Scand.
1996, 50, 345 ± 352; M. Avalos, R. Babiano, P. Cintas, J. L. Jim e nez,
J. C. Palacios, Tetrahedron Asymm. 1997, 8, 2997 ± 3017; C. Girard,
H. B. Kagen, Angew. Chem. 1998, 110, 3088 ± 3127; Angew. Chem. Int.
Ed. 1998, 37, 2922 ± 2959; examples: a) D. Guillaneux, S.-H. Zhao, O.
Samuel, D. Rainford, H. B. Kagan, J. Am. Chem. Soc. 1994, 116,
unless otherwise noted. [b] The ratio of (S)-1/(S,S)-2 to (R)-1/(S,S)-2 was
determined by 1H NMR spectroscopy. [c] 1/(S,S)-2 in 2-propanol was
preheated at 808C for 30 min.
[
BIPHEP/RuCl /diamine complexes is clear in the ratio-
dependent enantioselectivity of hydrogenation of 1'-aceto-
naphthone (3) in comparison with the enantioselectivity
2
obtained using the (Æ)-DM-BINAP/RuCl /(S,S)-diamine pair
2
(
Table 1, runs 1 ± 3 versus run 4). The lower enantioselectivity
of the 1:1 BIPHEP chelate complex pair compared with the
:1 BINAP chelate pair (runs 1 versus 4) indicates the
differences in steric demand of the two types of ligands. Even
1
9
430 ± 9439; C. Puchot, O. Samuel, E. Dunach, S. Zhao, C. Agami,
H. B. Kagan, J. Am. Chem. Soc. 1986, 108, 2353 ± 2357; b) M.
4
96
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1433-7851/99/3804-0496 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 4

COMMUNICATIONS
Kitamura, S. Suga, M. Niwa, R. Noyori, J. Am. Chem. Soc. 1995, 117,
Super High Throughput Screening (SHTS) of
Chiral Ligands and Activators: Asymmetric
Activation of Chiral Diol ± Zinc Catalysts by
Chiral Nitrogen Activators for the
Enantioselective Addition of Diethylzinc
to Aldehydes**
4832 ± 4842; c) N. Oguni, Y. Matsuda, T. Kaneko, J. Am. Chem. Soc.
1988, 110, 7877 ± 7877; d) K. Mikami, Y. Motoyama, M. Terada, J. Am.
Chem. Soc. 1994, 116, 2812 ± 2820; K. Mikami, M. Terada, Tetrahedron
992, 48, 5671 ± 5680; M. Terada, K. Mikami, T. Nakai, J. Chem. Soc.
1
Chem. Commun. 1990, 1623 ± 1624.
[
[
[
3] a) K. Mikami, S. Matsukawa, Nature 1997, 385, 613 ± 615; b) S.
Matsukawa, K. Mikami, Tetrahedron Asymm. 1997, 8, 815 ± 816;
c) Enantiomer 1996, 1, 69 ± 73; d) T. Ohkuma, H. Doucet, T. Pham, K.
Mikami, T. Korenaga, M. Terada, R. Noyori, J. Am. Chem. Soc. 1998,
Kuiling Ding, Akihiro Ishii, and Koichi Mikami*
1
20, 1086 ± 1087.
4] For an opposite strategy of deactivation, see N. W. Alcock, J. M.
Brown, P. J. Maddox, J. Chem. Soc. Chem. Commun. 1986, 1532 ±
Combinatorial chemistry has been well recognized as a
useful strategy for the discovery and optimization of bioactive
drugs, coordination complexes, and solid-state materials.[ Of
the split-and-mix and parallel-matrix strategies, the latter is
more employable for lead optimization, and high-throughput
screening (HTS) is essential for tuning a variety of modifica-
1534; J. M. Brown, P. J. Maddox, Chirality 1991, 3, 345 ± 354; K.
1]
Maruoka, H. Yamamoto, J. Am. Chem. Soc. 1989, 111, 789 ± 790; J. W.
Faller, J. Parr, J. Am. Chem. Soc. 1993, 115, 804 ± 805.
5] a) The activation barrier to axial torsion in selectively deuterated
BIPHEP is measured to be only (22 Æ 1) kcal, which suggests that
axial rotation takes place at room temperature or above: O. Desponds,
M. Schlosser, Tetrahedron Lett. 1996, 37, 47 ± 48, and references
therein; b) see also 6,6'-substituted analogues: G. Trabesinger, A.
Albinati, N. Feiken, R. W. Kunz, P. S. Pregosin, M. Tschoerner, J. Am.
Chem. Soc. 1997, 119, 6315 ± 6323, and references therein.
[2]
tions. However, only a limited number of investigations has
so far been reported on the optimization of chiral ligands for
metal complexes.[ With HPLC or gas chromatography (GC)
on chiral columns, it takes a tediously long time to separate
enantiomeric products and then to determine the enantiose-
lectivity of the reactions. The application of a detection
system based on circular dichroism (CD) to HPLC on
nonchiral stationary phases allows the simultaneous monitor-
ing of the CD signal De, the absorption e, and their ratio g ˆ
De/e. The dissymmetry factor g is independent of concen-
tration and is linearly related to the enantiomeric excess.[
With this technique, the enantiomeric excess of the product
could be determined within minutes without separation of the
enantiomeric products. Therefore, combined application of
the combinatorial chemistry (CC) factory (Dainippon Seiki,
DNC) for reactions and HPLC-CD provide a highly efficient
screening system, which we refer to as the super high
throughput screening (SHTS) system, for finding the most
effective catalyst through asymmetric activation.
3]
[
6] a) T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1995, 117, 2675 ± 2676; b) T. Ohkuma, H. Ooka, T. Ikariya,
R. Noyori, J. Am. Chem. Soc. 1995, 117, 10417 ± 10418; c) H. Doucet,
T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, E. Katayama, A. F.
England, T. Ikariya, R. Noyori, Angew. Chem. 1998, 110, 1792 ± 1796;
Angew. Chem. Int. Ed. 1998, 37, 1703 ± 1707.
[
[
7] a) P. Mangeney, T. Tejero, A. Alexakis, F. Grosjean, J. Normant,
Synthesis 1988, 255 ± 257; b) S. Pikul, E. J. Corey, Org. Synth. 1993, 71,
4]
22 ± 29.
8] 3,5-Dimethylphenyl-BINAP: K. Mashima, Y. Matsumura, K. Kusano,
H. Kumobayashi, N. Sayo, Y. Hori, T. Ishizaki, S. Akutagawa, H.
Takaya, J. Chem. Soc. Chem. Commun. 1991, 609 ± 610.
[
9] 1
H
3
NMR (CDCl
.16, 4.19; (R)-DM-BINAP/RuCl
3
): (S)-DM-BINAP/RuCl
/(S,S)-DPEN: d ˆ 2.62, 3.86, 4.43.
CDOD 1/2): (S)-DM-BINAP/RuCl /(S,S)-
DPEN: d ˆ 2.98, 3.36, 4.21; (R)-DM-BINAP/RuCl /(S,S)-DPEN: d ˆ
.60, 3.87, 4.42.
10] Although the DM-BIPHEP/RuCl
2
/(S,S)-DPEN: d ˆ 3.02,
2
1
H NMR (CDCl
3
/(CD
3
)
2
2
2
2
[
2
/DPEN complex was treated with
1
DM-BINAP in 2-propanol, it was not observed by H NMR spectro-
scopy.
Asymmetric activation of a chiral catalyst with a chiral
additive may enhance the levels of catalyst efficiency and
enantioselectivity.[ The advantage of this approach over the
[
11] R. L. Chowdhury, J.-E. Bäckvall, J. Chem. Soc. Chem. Commun. 1991,
5]
1
063 ± 1064; K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori,
Angew. Chem. 1997, 109, 297 ± 300; Angew. Chem. Int. Ed. Engl. 1997,
3
[6]
deactivation strategy is that the activated catalyst can
6, 285 ± 288; R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97 ±
produce a greater enantiomeric excess in the products than
can the enantiomerically pure catalyst on its own. Sharpless
et al. emphasized the importance of ªchiral ligand accelationº
through the construction of an asymmetric catalyst from an
achiral precatalyst by ligand exchange with a chiral ligand.[
Chiral catalysts thus obtained with chiral ligands (L1*, L2*,...)
may be further evolved with chiral activators (A1*, A2*,...)
into the most catalytically active and enantioselective chiral
catalysts (Scheme 1).
1
02.
[
12] P. D. Theisen, C. H. Heathcock, J. Org. Chem. 1988, 53, 2374 ± 2378;
W. H. Pirkle, S. D. Beare, J. Am. Chem. Soc. 1967, 89, 5485 ± 5487.
7]
[
*] Prof. Dr. K. Mikami, Prof. Dr. K. Ding, A. Ishii
Department of Chemical Technology, Faculty of Engineering
Tokyo Institute of Technology
2
-12-1 Ookayama, Meguro-ku, Tokyo 152 (Japan)
Fax: (‡81)3-5734-2776
E-mail: kmikami@o.cc.titech.ac.jp
[
**] This work was aided by the Ministry of Education, Science, Sports and
Culture of Japan (nos. 09238209 and 10208204). A UNESCO research
fellowship for K. D. is gratefully acknowledged. We are grateful to Mr.
Naotaka Sawada of Dainippon Seiki Co., Ltd., Dr. Akito Tanaka of
Fujisawa Pharmaceutical Co., Ltd., and Mr. Kenichi Kudo of JASCO
Corp. for their technical assistance.
Angew. Chem. Int. Ed. 1999, 38, No. 4
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3804-0497 $ 17.50+.50/0
497