Highly enantioselective synthesis of optically active ketones by iridium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.200803709

(Chemical Equation Presented) Close to perfect enantioselectivity (up to 99% ee, see scheme) is found for the formation of α-substituted ketones by the asymmetric hydrogenation of enones with an iridium-phosphinooxazoline catalyst. In an operationally simple process, both linear and cyclic substrates react well and afford the desired products in high yields. A wide variety of substituents are tolerated, thus making the method synthetically appealing.

Full text of DOI:10.1002/anie.200803709

Communications
DOI: 10.1002/anie.200803709
Asymmetric Synthesis
Highly Enantioselective Synthesis of Optically Active Ketones by
Iridium-Catalyzed Asymmetric Hydrogenation**
Sheng-Mei Lu and Carsten Bolm*
Table 1: Optimization of the reaction conditions.[a]
Strategies for controlling the absolute configuration at the
a position of a ketonic carbonyl compound usually rely on
enantioselective protonations of achiral enolates or enol
equivalents,[1] asymmetric a alkylations using chiral auxilia-
ries,[2] or enantioselective reductions of enones.[3] However,
most of the reported methods are limited in substrate scope,
only a few are catalytic, and overall they do not provide a
general solution for the preparation of optically active
ketones. A highly enantioselective catalytic method for
achieving this goal is most desirable, but has remained
undiscovered to date.
As a consequence of their high efficiency, atom economy,
EntryComplex
Solvent
H
2 [bar]
t [h]
ee of 2a [%][b]
and operational simplicity, asymmetric hydrogenations of
properly selected prochiral starting materials provide highly
practical and powerful routes to enantiomerically enriched
compounds.[4] Bearing this in mind, we realized that the
hydrogenation of readily accessible a-substituted enones
would be one of the most straightforward and simplest ways
to prepare a-substituted chiral ketones. While there has been
significant progress in the asymmetric hydrogenation of cyclic
compounds of this type,[5,6] to the best of our knowledge, there
is no example of such a reduction with acyclic compounds.[7,8]
Herein, we report the first general method for the asymmetric
synthesis of a-substituted ketones by the hydrogenation of
enones which is applicable for both cyclic and acyclic
substrates.[9,10]
Initially, we examined the hydrogenation reaction of (E)-
3-methyl-4-phenyl-3-buten-2-one ((E)-1a) in the presence of
iridium complexes bearing chiral sulfoximine-type ligands,
which had proven to be highly efficient for the asymmetric
hydrogenation of b,b-disubstituted linear enones.[11,12] The
reduction proceeded well with 1a as substrate and complex 3
as catalyst (under a hydrogen pressure of 2 bar at room
temperature for 2 h), but the resulting ketone 2a had only
55% ee (Table 1, entry 1). When the iridium–phosphinoox-
azoline (phox) complex[13,14] 4a was applied under the same
conditions, the hydrogenation gave 2a with 84% ee (Table 1,
entry 2). To our surprise, in both cases the major product (ꢀ
1
2
3
4
5
6
7
8
9
3
toluene
2
2
10
10
5
2
2
2
2
12
12
1
1
1
3
3
3
3
55
84
83
78
84
85
98
69
25
99[c]
4a
4a
4a
4a
4a
4b
4c
4d
4b
toluene
toluene
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
10
10
16
[a] Reactions conditions: 1a (0.25 mmol), catalyst (1 mol%), solvent
(1.0 mL). All the reactions were carried out under argon at room
temperature. The conversion was greater than 95% in all cases (as
determined by 1H NMR spectroscopy). [b] ee values were determined by
HPLC on a Chiralcel OJ column. The S enantiomer of the product was
formed in excess. [c] A catalyst loading of 0.1 mol% was used, and the
yield was 98% on a 2.5 mmol scale of 1a. Bn=benzyl.
98%) was the saturated ketone 3-methyl-4-phenyl-2-buta-
none (2a), thus indicating that complex 4a induced a much
better chemoselectivity than in the hydrogenation of b,b-
disubstituted linear enones.[11] At this point, we focused our
attention on the effect of the solvent, the hydrogen pressure,
and the reaction time on the reduction of 1a, with 4a used as
the catalyst. The results revealed that the reaction was slightly
more enantioselective in toluene than in dichloromethane
(Table 1, entries 3and 4). The hydrogenation pressure and the
reaction time had no clear effect on the conversion and
enantioselectivity: almost the same results (83–85% ee) were
obtained when the hydrogen pressure was varied from 2 to
10 bar and the reaction time was changed from 1 to 12 h
(Table 1, entries 2, 3, 5, and 6). On the basis of these
observations, the conditions described in Table 1, entry 6
(2 bar H2, 3h reaction time) were selected for the following
reactions.
[*] Dr. S.-M. Lu, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax: (+49)241-8092-391
E-mail: Carsten.Bolm@oc.rwth-aachen.de
[**] We are grateful to the Fonds der Chemischen Industrie for financial
support, and S.-M.L. thanks the Alexander von Humboldt Founda-
tion for a postdoctoral fellowship. We also acknowledge Dr. C. Jaekel
(BASF AG) for pointing out Refs. [5h] and [6].
Three other Ir complexes with phox-type ligands were
next tested. The results indicated that the enantioselectivity in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803709.
8920
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 8920 –8923

Angewandte
Chemie
Table 2: Hydrogenation of a-substituted acyclic enones using complex
the asymmetric reduction of enone 1a was greatly affected by
the properties of the substituents on the oxazoline moiety.
Although the conversions were complete in all cases, the
reaction with tert-butyl-substituted complex 4b (Table 1,
entry 7) gave a much higher enantioselectivity (98% ee)
than 4a (R = iPr, 85% ee; Table 1, entry 6), 4c (R = Bn,
69% ee; Table 1, entry 8), and 4d (R = Ph, 25% ee; Table 1,
entry 9). The reaction was also performed with 2.5 mmol 1a
and a catalyst loading of 0.1 mol% (Table 1, entry 10), using
4b as the catalyst. The high yield (98%) and excellent
enantioselectivity (99% ee) were maintained despite the
higher pressure and longer reaction time.
4b.[a]
[b]
EntrySubstrate
Yield [%]
ee [%][c]
Config.[d]
1
2
3
1a, R=Me
1b, R=Et
1c, R=Ph
91
90
96
98 (S)
99 (S)
99 (S)
4
5
6
1d, R=Et
1e, R=Pr
1 f, R=Ph
86
88
94
98 (S)
99 (S)
98 (R)
With the optimized reaction conditions in hand, the scope
and limitations of the hydrogenations were investigated. The
results are summarized in Table 2. The reductions of enones
1a–c revealed that changing the substitution pattern of the
ketonic moiety has no apparent effect on the conversion and
enantioselectivity. The hydrogenation of both the ethyl- and
the phenyl-substituted analogues of 1a (enones 1b and 1c,
respectively) gave full conversion and excellent enantiose-
lectivities (99% ee) after 3h under a H 2 pressure of 2 bar
(Table 2, entries 2 and 3). Replacing the methyl group at the
a position of the enone by ethyl, propyl, or phenyl (to give
substrates 1d, 1e, and 1 f, respectively) affected neither the
conversion nor the enantioselectivity of the reaction, and gave
the corresponding products with similar selectivity (Table 2,
entries 4–6; full conversion and 98–99% ee).
7
8
9
1g
1h
1i
89
87 (S)
99 (R)
86 (R)
93
84[e]
10
1j
91[f]
98 (S)
Substrate 1g, in which the phenyl group at the b position
of 1c has been replaced with an ethyl group, was reduced with
lower enantioselectivity (87% ee) under the same conditions
(Table 2, entry 7 versus 3). In contrast, enone 1h, with phenyl
groups at both the a and the b positions, showed excellent
activity and enantioselectivity (full conversion, 99% ee;
Table 2, entry 8). For substrate 1i, with no substituent other
than hydrogen at the b position, a higher pressure (10 bar)
was needed to obtain full conversion, and the enantioselec-
tivity was lower (86% ee; Table 2, entry 9). The reduction of
(E,E)-5-(4-methoxy-phenyl)-2-methyl-1-phenyl-1,4-penta-
11
12
1k, R=2-Me 89
98 (S)
99 (S)
1l, R=2-
90
MeO
1m, R=2-Cl 89
13
14
98 (S)
99 (S)
1n, R=3-
MeO
93
15
16
1o, R=3-Cl
1p, R=3-
NO2
92
91
98 (S)
98 (S)
17
18
1q, R=4-Me 90
98 (S)
98 (S)
1r, R=4-
MeO
97
À
dien-3-one (1j; Table 2, entry 10), which possesses two C C
19
20
1s, R=4-Cl
92
99 (S)
99 (S)
double bonds, led to three different products after 3h under
2 bar H2 pressure. The major product (50%) was the
1t, R=4-NO2 88
[a] All reactions were carried out with 0.25 mmol substrates and 1 mol%
complex 4b in toluene (1 mL) for 3 h under argon at room temperature,
unless otherwise specified. [b] All reactions gave complete conversion
unless otherwise specified. The yields are based on enone conversions.
The yields refer to the amount of isolated product. [c] Determined by
HPLC analysis, see the Supporting Information. [d] The absolute
configurations were assigned bycomparison of the optical rotations
with literature values or assuming analogous reaction pathways.
[e] Reaction was carried out at a H2 pressure of 10 bar for 18 h.
[f] Reaction was carried out at a H2 pressure of 10 bar for 3 h. The
product was the fullysaturated ketone.
=
unsaturated ketone with the C C bond at the 1,2-position
reduced, along with 23% of the fully saturated ketone (2j)
=
and 27% of the other enone with the 4,5-C C bond reduced.
À
When the H2 pressure was raised to 10 bar, both C C double
bonds were reduced and saturated ketone 2j with 98% ee was
produced.
b-Aryl-substituted enones bearing electron-donating and
electron-withdrawing groups at the ortho, meta, or para
positions of the arene were equally reactive and were
hydrogenated with similar results (full conversion, 98–
99% ee, Table 2, entries 11–20). All these results support
the conclusion that this catalyst system has a high tolerance to
the substitution pattern and electronic properties of the
substrates.
To demonstrate the potential of the catalyst system in the
asymmetric synthesis of a-substituted chiral ketones, the
hydrogenation of 3-ethyl-4-(3-nitrophenyl)-3-buten-2-one (5)
was carried out on a gram scale (1.480 g, 6.7 mmol) with 4b
(substrate/catalyst = 870:1) under 10 bar H2 pressure for 24 h
(Scheme 1). Product 6 was isolated in 98% yield and 98% ee.
Encouraged by the results obtained with the linear
enones, we also tested complex 4b in the asymmetric
hydrogenation of cyclic substrates. Pleasingly, all aryl-sub-
stituted exo-cyclic enones, regardless of the ring size (Table 3,
entries 1–4) or the substitution pattern of the aryl ring
Angew. Chem. Int. Ed. 2008, 47, 8920 –8923
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8921

Communications
spectroscopic analysis of the crude reaction mixture, and the product
was purified by chromatography using a pentane/ethyl acetate
mixture (10:1) as eluent. Enantiomeric ratios were determined by
HPLC on a Chiralcel column. The HPLC conditions and the spectral
data of all compounds are provided in the Supporting Information.
Scheme 1.
Received: July 29, 2008
Published online: October 15, 2008
Table 3: Hydrogenation of a-substituted cyclic enones using complex
Keywords: asymmetric synthesis · enantioselectivity · enones ·
hydrogenation · iridium
4b.[a]
.
[1] For reviews covering enantioselective protonations, see: a) H.
Zimmerman, Acc. Chem. Res. 1987, 20, 263– 268; b) C. Fehr,
Angew. Chem. 1996, 108, 2726 – 2748; Angew. Chem. Int. Ed.
Engl. 1996, 35, 2566 – 2587; c) A. Yanagisawa, K. Ishihara, H.
Yamamoto, Synlett 1997, 411 – 420; d) J. Eames, N. Weerasoor-
iya, Tetrahedron: Asymmetry 2001, 12, 1 – 24; e) L. Duhamel, P.
Duhamel, J. C. Plaquevent, Tetrahedron: Asymmetry 2004, 15,
3653 – 3691; f) M. Naodovice, H. Yamamoto, Chem. Rev. 2008,
108, 3132 – 3148.
EntrySubstrate
Yield [%]
ee [%] Config.
1
2
3
4
7a, n=0
7b, n=1
7c, n=2
7d, n=3
91
93
91
94
92
94
99
97
S
S
S
S
[2] a) D. Caine in Comprehensive Organic Synthesis, Vol. 3 (Eds.:
B. M. Trost, I. Pleming), Pergamon, Oxford, 1991, pp. 1 – 63;
b) A. Job, C. F. Janeck, W. Bettray, R. Peters, D. Enders,
Tetrahedron 2002, 58, 2253– 2329.
5
6
7
7e, Ar=4-ClC6H4
7 f, Ar=4-MeOC6H4 97
7g, Ar=3-NO2C6H4 96
94
97
98
99
S
S
S
[3] For examples, see: M. Zagozda, J. Plenkiewicz, Tetrahedron:
Asymmetry 2006, 17, 1958 – 1962, and references therein.
[4] For recent comprehensive overviews, see: a) The Handbook of
Homogeneous Hydrogenation (Eds.: J. G. de Vries, C. Elsevier),
Wiley-VCH, Weinheim, 2006; b) special issue: Acc. Chem. Res.
2007, 41(12).
[5] For homogeneous hydrogenations of exo-cyclic enones, see: a) T.
Ohta, T. Miyake, N. Seido, H. Kumobayashi, H. Takaya, J. Org.
Chem. 1995, 60, 357 – 363; for heterogeneous hydrogenations of
cyclic enones, see: b) G. Fogassy, A. Tungler, A. Levai, J. Mol.
Catal. A. 2003, 192, 189 – 194; c) C. Thorey, S. Bouquillon, A.
Helimi, F. Henin, J. Muzart, Eur. J. Org. Chem. 2002, 2151 – 2159;
d) C. Thorey, F. Henin, J. Muzart, Tetrahedron: Asymmetry 1996,
7, 975 – 976; e) A. Tungler, M. Kajtar, T. Mathe, G. Toth, E.
Fogassy, J. Petro, Catal. Today 1989, 5, 159 – 171; f) A. Tungler, T.
MµthØ, T. Tarnai, K. Fodor, G. Tóth, J. Kajtµr, I. Kolossvµry, B.
HerØnyi, R. A. Sheldon, Tetrahedron: Asymmetry 1995, 6, 2395 –
2402; g) A. Tungler, Y. Nitta, K. Fodor, G. Farkas, T. Mathe, J.
Mol. Catal. A. 1999, 149, 135 – 140; h) C. Jaekel, R. Pachello
(BASF AG), WO 2006/040096A1, 2006.
[6] For early studies on the metal-catalyzed asymmetric hydro-
genation of the double bonds of enals, see: a) P. Avircin-Violet,
T.-P. Dang (Rhone-Poulenc Industries), EU 78420001.6, 1978;
b) P. Aviron-Violet, T.-P. Dang (Rhone-Poulenc Industries), US
42707, 1980; c) T.-P. Dang, P. Aviron-Violet, Y. Colleuille, J.
Varagnat, J. Mol. Catal. 1982, 16, 51 – 59.
[7] Alternatively, catalytic asymmetric hydrosilylations of a,b-
unsaturated ketones lead to chiral ketones. Those products,
however, have the stereogenic centers at the b position. For
recent examples, see: a) B. H. Lipshutz, J. M. Servesko, Angew.
Chem. 2003, 115, 4937 – 4940; Angew. Chem. Int. Ed. 2003, 42,
4789 – 4792; b) B. H. Lipshutz, B. A. Frieman, A. E. Tomaso, Jr.,
Angew. Chem. 2006, 118, 1281 – 1286; Angew. Chem. Int. Ed.
2006, 45, 1259 – 1264; c) Y. Kanazawa, Y. Tshchiya, K. Kobaya-
shi, T. Shiomi, J.-I. Itoh, M. Kikuchi, Y. Yamamoto, H.
Nishiyama, Chem. Eur. J. 2006, 12, 63– 71.
8
9
10
7h, R=Ph
7i, R=nPr
7j, R=iPr
96
89
94
99
S
S
R
91[b]
89[c]
[a] The reaction conditions and methods of analysis are the same as
those of Table 2 unless otherwise specified. [b] The reaction was carried
out at a H2 pressure of 5 bar for 24 h. [c] Using complex 3 as the catalyst
and a H2 pressure of 5 bar for 20 h. Complex 4b gave 56% conversion
and 70% ee under the same conditions.
(Table 3, entries 5–7), afforded the corresponding products
with full conversion and excellent enantioselectivity (92–
99% ee). Somewhat lower activities and ee values were
observed in the hydrogenation of alkyl-substituted tetralone
derivatives (Table 3, entries 9 and 10). In contrast, substrate
7h, with a phenyl group, underwent complete conversion with
excellent enantioselectivity (Table 3, entry 8, 99% ee).
In conclusion, we have discovered a simple and highly
efficient asymmetric synthesis of a-substituted ketones. Both
acyclic and cyclic enones undergo smooth catalytic enantio-
selective hydrogenations on application of an iridium com-
plex bearing a phox ligand. In contrast to other methods, the
protocol tolerates a wide variety of substituents[15] and
delivers products with excellent enantioselectivity in high
yields under mild reaction conditions.
Experimental Section
General procedure for the hydrogenation: Complex 4b (3.9 mg,
0.0025 mmol) and substrate 1 (0.25 mmol) were placed in a 5 mL vial
equipped with a stirrer bar. This vial was then put into an argon-filled
steel autoclave. Toluene (1.0 mL) was added to the mixture under an
argon atmosphere. The autoclave was then closed, purged three times
with hydrogen (less than the pressure needed), and finally pressurized
to the required value. The reaction mixture was stirred for the
indicated period of time, and then the hydrogen gas slowly released.
The conversion of the substrate was determined by 1H NMR
[8] For a non-asymmetric iridium-catalyzed reduction of an enone
by transfer hydrogenation, see: S. Sakaguchi, T. Yamaga, Y. Ishii,
J. Org. Chem. 2001, 66, 4710 – 4712.
[9] For recent contributions on iridium-catalyzed hydrogenations of
a,b-unsaturated acids and esters, see: a) S. Li, S.-F. Zhu, C.-M.
8922 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 8920 –8923

Angewandte
Chemie
Zhang, S. Song, Q.-L. Zhou, J. Am. Chem. Soc. 2008, 130, 8584 –
8585; b) Y. Zhu, K. Burgess, J. Am. Chem. Soc. 2008, 130, 8894 –
8895.
Synthesis (Eds.: T. Toru, C. Bolm), Wiley-VCH, Weinheim, 2008;
pp. 209 – 229.
[13] For the development of phosphinooxazolines and their use in
asymmetric catalysis, see a) J. M. J. Williams, Synlett 1996, 705 –
710; b) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 3 3 6 –
345; c) H. A. McManus, P. J. Guiry, Chem. Rev. 2004, 104, 4151 –
4202, and references therein.
[14] Related P,N ligands have also proven applicable in the asym-
metric reductions of (largely) unfunctionalized olefins; for key
reviews, see: a) X. Cui, K. Burgess, Chem. Rev. 2005, 105, 3272 –
3296; b) S. Bell, B. Wꢀstenberg, S. Kaiser, F. Menges, T.
Netscher, A. Pfaltz, Science 2006, 311, 642 – 644.
[10] For a rhodium-catalyzed asymmetric hyrdogenative aldol cou-
pling of vinl ketones, see: C. Bee, S. B. Han, A. Hassan, H. Iida,
M. J. Krische, J. Am. Chem. Soc. 2008, 130, 2746 – 2747.
[11] S.-M. Lu, C. Bolm, Chem. Eur. J. 2008, 14, 7513– 7516.
[12] For the application of sulfoximine-derived P,N ligands, see a) C.
Moessner, C. Bolm, Angew. Chem. 2005, 117, 7736 – 7739;
Angew. Chem. Int. Ed. 2005, 44, 7564 – 7567; b) S.-M. Lu, C.
Bolm, Adv. Synth. Catal. 2008, 350, 1101 – 1105; for recent
overviews on the use of sulfoximines in asymmetric synthesis and
metal catalysis, see: c) C. Bolm in Asymmetric Synthesis with
Chemical and Biological Methods (Eds.: D. Enders, K.-E.
Jaeger), Wiley-VCH, Weinheim, 2007; pp. 149 – 176; d) C.
Worch, A. Mayer, C. Bolm, in Sulfur Chemistry in Asymmetric
[15] Hydrogenations of tetrasubstituted olefins under these condi-
tions have not yet been studied. Results along this line will be
reported in due course.
Angew. Chem. Int. Ed. 2008, 47, 8920 –8923
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8923