Asymmetric hydrogenation of α,β-unsaturated carboxylic esters with chiral iridium N,P ligand complexes

Article abstract of DOI:10.1002/chem.201202397

Enantioselective conjugate reduction of a wide range of α,β-unsaturated carboxylic esters was achieved using chiral Ir N,P complexes as hydrogenation catalysts. Depending on the substitution pattern of the substrate, different ligands perform best. α,β-Unsaturated carboxylic esters substituted at the α position are less problematic substrates than originally anticipated and in some cases α-substituted substrates actually reacted with higher enantioselectivity than their β-substituted analogues. The resulting saturated esters with a stereogenic center in the α or β position were obtained in high enantiomeric purity. Copyright

Full text of DOI:10.1002/chem.201202397

FULL PAPER
DOI: 10.1002/chem.201202397
Asymmetric Hydrogenation of a,b-Unsaturated Carboxylic Esters with
Chiral Iridium N,P Ligand Complexes
David H. Woodmansee, Marc-Andrꢀ Mꢁller, Lars Trçndlin, Esther Hçrmann, and
Andreas Pfaltz*[a]
Abstract: Enantioselective conjugate
reduction of a wide range of a,b-unsa-
turated carboxylic esters was achieved
using chiral Ir N,P complexes as hydro-
genation catalysts. Depending on the
substitution pattern of the substrate,
different ligands perform best. a,b-Un-
saturated carboxylic esters substituted
at the a position are less problematic
substrates than originally anticipated
and in some cases a-substituted sub-
strates actually reacted with higher
enantioselectivity than their b-substi-
tuted analogues. The resulting saturat-
ed esters with a stereogenic center in
the a or b position were obtained in
high enantiomeric purity.
Keywords: asymmetric catalysis
hydrogenation iridium N,P
ligands · unsaturated esters
·
·
·
Introduction
line pincer complexes as catalysts.[6] For catalytic hydrogena-
tion using dihydrogen as the reductant, Ir complexes with
chiral N,P ligands have emerged as catalysts of choice for
this substrate class.[7] Rh– and Ru–diphosphine catalysts
have been used as well, but in general their application
range is restricted to additionally functionalized esters such
as dehydroamino acid derivatives.[7d] Although high enantio-
selectivities have been reported for a diverse array of Ir cat-
alysts based on N,P and C,N ligands, only a limited number
of substrates has been investigated so far, with most studies
focusing on simple a- or b-substituted cinnamic esters.
Here, we report the results of a systematic evaluation of
Ir complexes with chiral N,P ligands in the asymmetric hy-
drogenation of a wide range of a,b-unsaturated carboxylic
esters, which demonstrates the scope of Ir catalysts for this
transformation. Our study focused on pyridine-derived
ligand complexes 1–7, based on promising results that we
had recently obtained with catalysts of this type (Figure 1).[8]
In previous work, which featured a modular approach to
iridium pyridyl–phosphinite catalysts,[8,9] we demonstrated
that small changes made to the catalyst led to large differen-
ces in enantioselectivity.[8] Replacing the ortho-phenyl group
in ligand 1 by sterically more demanding aryl groups, such
as mesityl or 3,5-di-tert-butyl-4-methoxyphenyl (ligands 2
Enantioselective conjugate reduction of a,b-unsaturated car-
boxylic acids and esters is an important transformation lead-
ing to synthetically useful products, which can be further
elaborated by reactions at the carboxyl or ester group.
Moreover, many natural and synthetic bioactive carboxylic
acid derivatives are known that possess a tertiary stereogen-
ic center in the a or b position.[1] A variety of chiral metal
catalysts and reducing agents such as hydrosilanes, sodium
borohydride, or dihydrogen have been used for conjugate
reductions. For the asymmetric hydrogenation of a,b-unsatu-
rated carboxylic acids ruthenium–binap complexes have es-
tablished themselves as efficient, widely applicable cata-
lysts,[2] but they do not react with the corresponding esters.
More recently, very high enantioselectivities and turnover
numbers have been achieved in the hydrogenation of a-sub-
stituted unsaturated carboxylic acids with iridium catalysts
based on spirocyclic phosphine–oxazoline ligands.[3]
In many synthetic applications the use of esters rather
than carboxylic acids is preferred because polar free acids
are in general more difficult to handle. High enantioselectiv-
ities in the conjugate reduction of a,b-unsaturated carboxyl-
ic esters have been achieved with cobalt catalysts using
sodium borohydride as a reductant[4] and in hydrosilane-
based reductions using Cu–diphosphine[5] or Rh–bisoxazo-
[a] Dr. D. H. Woodmansee,+ M.-A. Mꢀller,+ Dr. L. Trçndlin,+
E. Hçrmann, Prof. A. Pfaltz
Department of Chemistry
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
[+] These authors contributed equally to this publication.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202397.
Figure 1. Chiral iridium N,P precatalysts 1–7.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Table 1. Enantioselective hydrogenation of (E)-b-methylcinnamic acid
ethyl ester S1.
and 3), gave appreciable increases in enantioselectivity for
difficult substrates. The importance of the substituent at the
ortho position of the pyridine ring is in accordance with An-
derssonꢂs model for the enantioselectivity-determining step
(Figure 2)[10] because it is this substituent that is closest to
Entry
Catalyst
DDG° [kcalmolÀ1
]
ee [%] P1
1
2
3
4
5
6
7
1 (S)
2 (S)
3 (R)
4 (1R,2R,2’R)
5 (1S,2R,2’R)
6 (1R,2R,2’R)
7 (1S,2R,2’R)
>3.09
2.68
1.94
1.94
2.14
1.86
1.43
>99 (S)[a]
98 (S)
93 (R)
93 (R)
95 (S)
92 (R) (94)[b]
84 (S) (95)[b]
[a] Catalyst (S)-1 produced P1 in >99% ee with [a]2D0 (c=0.91, CHCl3),
consistent with the values in the literature for the S enantiomer. [b] Con-
versions less than complete are listed next to the ee value in brackets.
Figure 2. Anderssonꢂs model for the enantioselectivity-determining
step.[10]
longer reaction times. Initial hydrogenation studies indicated
a complicated selectivity trend (Table 2). Complexes derived
from ligands 2 and 3 with sterically more demanding ortho-
aryl substituents induced distinctly higher enantioselectivi-
ties than the parent complex 1. Complex 2 provided by far
the best results with ee values of 97 to >99% (Table 2,
entry 2). Among the bis(N-arylamino)phosphine derivatives
4–7 the (1R,2R,2’R)-isomer 4 was the most selective catalyst
across the range of esters S2–4, with a marked improvement
over the parent complex 1, whereas catalysts 5–7 gave unsat-
isfactory results in terms of ee value and conversion.
the coordinated substrate. Although the substituents at the
phosphorus atom are too remote for direct steric interaction
with the substrate, they too can influence the enantioselec-
tivity through electronic effects as well as steric effects by
interaction with axial ligands and the carbocyclic ring. Such
effects are expected to be most pronounced for sterically de-
manding phosphine units such as bis(N-arylamino)phos-
phine, which we had used before as a phosphinite replace-
ment for oxazoline-based N,P ligands.[11] This led us to use
this modification with the pyridyl alcohol scaffold of 1 to
create a set of diastereomeric complexes 4–7, which we then
evaluated as catalysts for the asymmetric hydrogenation of
a,b-unsaturated carboxylic esters. A first successful applica-
tion of these complexes was recently reported for two hy-
drogenation steps in the synthesis of platensimycin.[12]
Table 2. Enantioselective hydrogenation of (E)-a-methylcinnamic acid
esters S2–4.
Results and Discussion
Entry
Catalyst
ee [%] P2[a]
ee [%] P3[a]
ee [%] P4[a]
Hydrogenation of the b-methyl-substituted ester S1 indicat-
ed that replacement of the phenyl group in the parent com-
plex 1 by more sterically demanding aryl groups resulted in
a loss of enantioselectivity. However, with the exception of
7, all other catalysts still gave enantioselectivities above
90% enantiomeric excess (ee; Table 1). The configuration of
the product P1 produced by catalysts 4–7 was found to
depend on the configuration of the stereogenic center next
to the pyridine ring. Only a small difference in enantioselec-
tivity was observed between the diastereomeric complexes 4
and 5, indicating that the additional chiral diaminophos-
phine unit makes little contribution to the enantioselectivity.
However, a more pronounced contribution to the enantiose-
lectivity was observed with the less reactive diastereomeric
iridium complexes 6 and 7, amounting to a 0.4 kcalmolÀ1
lower activation energy of the enantioselectivity-determin-
ing step for the (1S,2R,2’R) catalyst 7 at 298 K.
1
2
3
4
5
6
7
1 (S)
2 (S)
3 (R)
4 (1R,2R,2’R)
5 (1S,2R,2’R)
6 (1R,2R,2’R)
7 (1S,2R,2’R)
46 (R)
97 (R)
76 (S)
87 (R)
76 (S) (93)
76 (R) (23)
43 (S) (13)
69 (R)
70 (R)
>99 (R)
93 (S)
97 (R)[b]
95 (S)
77 (R)
75 (R)
60 (S) (92)
70 (R) (20)
47 (S) (14)
48 (S) (90)
58 (R) (10)
39 (S) (9)
[a] All conversions less than complete are listed next to the ee value in
brackets. [b] Catalyst (S)-2 produced P2 in 97% ee with [a]2D0 (c=0.17,
CHCl3), consistent with the values in literature for the R enantiomer.
Although the configuration induced by complexes 4–7 is
controlled by the stereogenic center next to the pyridine
ring, as in the hydrogenation of the b-methyl cinnamic ester
S1, the sense of chiral induction is opposite to that observed
for catalysts 1–3. This discrepancy in product configuration
indicates a divergence in coordination modes of the alkene
in the active catalysts between pyridyl phosphinites 1–3 and
the diazaphospholane analogues 4–7.
A completely different selectivity order of catalysts 1–7
was observed for the a-methyl cinnamic esters S2–4. These
substrates are less reactive than S1 and, in general, require
&
2
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Hydrogenation of a,b-Unsaturated Carboxylic Esters
FULL PAPER
The configuration induced by catalysts 1–3 is opposite to
that predicted by Anderssonꢂs model[10] considering only
steric interactions (Figure 2). However, based on their com-
putational studies Andersson et al. noted that a-substituted
esters are special substrates, because the sterically favored
transition state involves hydride transfer to the a-C atom of
the ester, which is electronically disfavored. So they con-
cluded that the a-methylcinnamic ester S2 reacts through a
sterically favored but electronically disfavored alignment
and that the lower enantioselectivity they observed for this
substrate compared with the b-methyl isomer is due to this
steric–electronic mismatch. In our case, catalysts 1–3 seem
to prefer a sterically disfavored but electronically favored
orientation, whereas catalysts 4–7 show the same behavior
as Anderssonꢂs catalysts. What is surprising is that catalysts
2 and 3 induce such high enantioselectivities that are almost
the same or, in the case of 3, even higher compared with
those recorded for the b-methyl-substituted ester S1. The
perception that a-substituted a,b-unsaturated esters are
more difficult substrates than the b-methyl-substituted ana-
logues apparently does not apply to all catalysts.
Ester S7 was efficiently reduced by iridium catalysts 1–5
but conversion was incomplete with the less reactive six-
membered ring analogues 6 and 7 (Table 4). Excellent enan-
Table 4. Enantioselective hydrogenation of (E)-ethyl b-methyl-5-phenyl-
pent-2-enoate S7.
Entry
Catalyst
ee [%] P7[a]
1
2
3
4
5
6
7
1 (S)
2 (S)
3 (R)
4 (1R,2R,2’R)
5 (1S,2R,2’R)
6 (1R,2R,2’R)
7 (1S,2R,2’R)
86 (R)
94 (R)[b]
40 (S)
93 (S)
88 (R)
86 (S) (95)
67 (R) (95)
[a] All conversions less than complete are listed next to the ee value in
brackets. [b] Catalyst (S)-2 produced P7 in 94% ee with [a]2D0 (c=0.71,
CHCl3), consistent with the values in literature for the R enantiomer.
For catalyst 2 a positive effect on the enantioselectivity
with increasing steric demand of the ester group was evi-
dent. Consequently, substrates S5 and S6 were evaluated to
further investigate the influence of the ester group
(Table 3). The products P5 and P6 were formed with excel-
tioselectivity was obtained with catalyst (S)-2 producing
(R)-P7 in 94% ee. Iridium complex (1R,2R,2’R)-4 was also
highly selective to give (S)-P7 in 93% ee, whereas the dia-
stereomer (1S,2R,2’R)-5 led to the R isomer with 88% ee, in-
dicating that the product configuration is controlled by the
stereogenic center in the carbocyclic ring, as observed
before for cinnamic acid esters.
For the a-substituted esters, complexes 2 and 4 were
again the most enantioselective catalysts (Table 5). The
highest ee value of 96% was obtained in the hydrogenation
Table 3. Enantioselective hydrogenation of (E)-a-methylcinnamic esters
S5 and S6.
Table 5. Enantioselective hydrogenation of (E)-a-methyl-5-phenylpent-2-
enoic esters S8 and S9.
Entry
Catalyst
ee [%] P5[a]
ee [%] P6[a]
1
2
3
1 (S)
2 (S)
3 (R)
78 (R)
96 (R)
74 (S)
75 (R)
97 (R)
89 (S)
[a] Full conversion was obtained for all entries.
Entry
Catalyst
ee [%] P8[a]
ee [%] P9[a]
1
2
3
4
5
6
7
1 (S)
2 (S)
3 (R)
4 (1R,2R,2’R)
5 (1S,2R,2’R)
6 (1R,2R,2’R)
7 (1S,2R,2’R)
11 (+)
16 (À)
96 (À)
93 (À)
lent selectivity with (S)-2 giving the R-configured products
S5 in 96% ee and S6 in 97% ee. Evidently, primary and sec-
ondary alkyl ester groups are well tolerated. However, as
found later for a different carboxylic acid derivative S12
(Table 6), a tert-butyl ester group slows down the reaction
considerably resulting in incomplete conversion for catalysts
2–4. Apparently, there is a limit to the size of the functional
groups that can be accommodated by these sterically en-
cumbered catalysts.
Many catalysts that perform well with substrates that
have aromatic substituents on the C=C bond fail to give ap-
preciable levels of enantioselectivity when the aryl group is
replaced with an alkyl group. Therefore, we extended our
study to the b-alkyl substituted 1,4-unsaturated ester S7 and
a-substituted analogues S8 and S9 to identify the most suita-
ble catalysts for these more demanding substrates.
64 (+)
51 (+)
91 (À)
93 (À)
68 (+) (86)
89 (À)
81 (+)
79 (À) (96)
33 (+) (67)
60 (+) (89)
[a] Conversions less than complete are listed next to the ee value in
brackets.
of ethyl ester S8 with catalyst 2. In line with the results re-
corded for a- and b-methyl cinnamates S1 and S3, the enan-
tioselectivity was higher than for the corresponding b-
methyl analogue (96 vs. 94% ee). Catalysts 1 and 3 were
poorly suited for this type of substrate giving low enantiose-
lectivities for substrates S8 and S9.
Hydrogenation of purely aliphatic esters S10–12 proved to
be more difficult (Table 6). With the ethyl ester S10, only
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

A. Pfaltz et al.
Table 6. Enantioselective hydrogenation of (E)-a-methylpent-2-enoic
esters S10–12.
Table 8. Enantioselective hydrogenation of (E)-ethyl 3-(4-tert-butylphen-
yl)-2-methylacrylate S14.
Entry
Catalyst
Conv. [%] P14
ee [%] P14
Entry
Catalyst
ee [%] P10[a]
ee [%] P11[a]
ee [%] P12[a]
1
2
3
4
1 (S)
2 (S)
3 (R)
4 (1R,2R,2’R)
90
91
63
23
71 (R)
94 (R)
64 (S)
22 (R)
1
2
3
4
5
1 (S)
2 (S)
3 (R)
4 (1R,2R,2’R)
5 (1S,2R,2’R)
3 (À)
71 (À)
42 (+)
84 (À)
76 (+)
27 (À)
91 (À)
82 (+)
88 (À)
–
–
87 (À) (34)
n.d. (1)
74 (À) (70)
–
[a] Conversions less than complete are listed next to the ee value in
brackets.
proved very difficult to reduce at 1 mol% catalyst loading
and full conversion was not achieved for any of the attempt-
ed hydrogenations (Table 9). However, useful levels of con-
catalyst
4
reacted with appreciable enantioselectivity
(84% ee). Catalyst 2 that gave 96% ee in the hydrogenation
of the 4-phenyl-substituted analogue S8, induced only
71% ee. Obviously, the remote phenyl group in substrates
S8 and S9 has a surprisingly strong effect, possibly by inter-
action of the p-system with the catalyst.
Table 9. Enantioselective hydrogenation of (E)-2,3-diphenylacrylate
esters S15 and16.
Complex (S)-2 hydrogenated the isopropyl ester S11 to
produce (À)-P11 with 91% ee, in close agreement with the
selectivity for the analogous distal phenyl-substituted S9.
Catalyst 4 was similarly selective yielding P11 with 88% ee.
The tert-butyl ester S12 was much less reactive than the cor-
responding ethyl and isopropyl esters, resulting in incom-
plete conversion. In the hydrogenation of substrate S13
these catalysts showed very low enantioselectivity, with the
exception of complex 6 that led to product P13 with 68% ee
but incomplete conversion (Table 7).
Entry
Catalyst
Conv. [%]
P15
ee [%]
P15
Conv. [%]
P16
ee [%]
P16
1
2
3
4
1 (S)
2 (S)
3 (R)
4 (1R,2R,2’R)
41
8
90
2
89 (S)
67 (R)
57 (R)
n.d.
80
7
86
–
97 (+)
42 (À)
82 (À)
–
version and enantioselectivity were obtained with catalyst
(S)-1, which gave the R-configured product P16 in 97% ee
and 80% conversion. The more sterically encumbered com-
plexes 2 and 4 showed almost no reaction, which is not sur-
prising considering the severe steric shielding of the C=C
bond by the two phenyl groups.
Table 7. Enantioselective hydrogenation of (E)-ethyl 3-cyclohexyl-2-
methylacrylate S13.
The a-ethyl-substituted ester S17 proved to be a more
problematic substrate than the a-methyl analogue S4
(Table 10). Catalyst 3 performed best in this case with the R
complex giving product (+)-P17 in 88% ee and full conver-
sion.
Hydrogenation of the lactone S18 was very sensitive to
the reaction conditions (Table 11). Hydrogenations stopped
at conversions of less than 10% and indicated higher enan-
Entry
Catalyst
Conv. [%] P13
ee [%] P13
1
2
3
4
5
6
2 (S)
3 (R)
4 (1R,2R,2’R)
5 (1S,2R,2’R)
6 (1R,2R,2’R)
7 (1S,2R,2’R)
100
100
100
100
80
45 (+)
13 (À)
32 (+)
16 (À)
68 (+)
9 (+)
42
Table 10. Enantioselective hydrogenation of (E)-isopropyl 2-benzylide-
nebutanoate S17.
Substrate S14 proved to be unexpectedly difficult to
reduce and full conversion could not be reached with
1 mol% catalyst loading using standard conditions (Table 8).
Why the remote tert-butyl group has such a pronounced
effect is unclear. Nevertheless, catalyst 2 produced P14 in an
excellent 94% ee and 91% conversion.
Entry
Catalyst
Conv. [%] P17
ee [%] P17
1
2
3
1 (S)
2 (S)
3 (R)
36
89
100
n.d.
Next, the substituent at the a position next to the ester
group was varied. Incorporation of a phenyl group at this
position gave substrates S15 and S16. These bulky esters
78 (À)
88 (+)
&
4
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Hydrogenation of a,b-Unsaturated Carboxylic Esters
Table 11. Enantioselective hydrogenation of (E)-3-benzylidenedihydro-
FULL PAPER
gous esters had not been reported yet, we decided to investi-
gate the hydrogenation of substrates S20–25, which would
allow for alternative synthetic approaches to aliskiren.
furan-2ACHTUNGTRENNUNG(3H)-one S18.
Unfortunately, complexes 1–7 reacted with poor enantio-
selectivity and conversion with esters S20–25. However, in
an extensive screening of different N,P complexes, the phos-
phino–oxazoline (PHOX) as well as phosphino–imidazoline
(PHIM) complexes emerged as more promising catalysts.
The best results were obtained with catalysts 8–11
(Table 12). Increasing the steric hindrance of the ester group
Entry Catalyst
Catalyst
loading
T
[8C]
P
Conv. P19 ee [%]
A
iso
[%]
A
1
1 (S)
1
1
2
3
1
1
1
1
2
1
2
RT
RT
RT
RT
RT
RT
80
100
3
80
0
5
0
84 (À)
0
2
1 (S)
3
1 (S)
3
3
0
0
0
4
1 (S)
15
26
98
100
2
0
1
1
0
70 (À)
23 (+)
86 (+)
70 (+)
n. d.
5
2 (S)
100
100
55
90
90
100
100
Table 12. Asymmetric hydrogenation of aliskiren intermediate esters
S20–25.[a]
6
3 (R)
7
3 (R)
8
3 (R)
0
0
0
9
3 (R)
94
26
93
0
23
6
89 (+)
70 (+)
70 (+)
10
11
4 (1R,2R,2’R)
4 (1R,2R,2’R)
RT
RT
tioselectivity with catalyst 1, however, as the reaction pro-
ceeded a steady loss of ee value was observed. Isomerized
1
lactone P19 was detected by GC-MS and H NMR spectro-
scopy and quantified by GC, indicating that the observed
decrease in ee value could be due a competing isomeriza-
tion–hydrogenation sequence via P19. Lower temperature
and 2 mol% catalyst loading of iridium complex 3 gave P18
in 89% ee and 94% conversion at 90 bar of hydrogen pres-
sure; higher temperature gave better conversion but at a
loss of enantioselectivity.
An important a,b-unsaturated acid intermediate used in
the synthesis of the renin inhibitor aliskiren was reduced
with high efficiency and enantioselectivity by the group of
Zhou with an Ir-SiPHOX catalyst, a rigid large ring chelate
complex incorporating the coordinating units of PHOX
(Scheme 1).[3] Since the enantioselective reduction of analo-
Entry Substrate
R
8 ee [%] 9 ee [%] 10 ee [%] 11 ee [%]
1
2
3
4
5
6
S20
S21
S22
S23
S24
S25
Me
Et
iPr
65 (+)
83 (+)
92 (+)
70 (+)
87 (+)
92 (+)
80 (+)[b]
90 (+)
60 (+)[c]
74 (+)
92 (+)
95 (+)[f]
77 (+)
88 (+)
97 (+)
tBu 99 (+)[d] 99 (+)[e]
99 (+)[f]
90 (+)
Bn
Ph
81 (+)
78 (+)
85 (+)
72 (+)[g]
91 (+)[h]
[a] Full conversion was obtained unless otherwise noted. [b] 67% conver-
sion. [c] 96% conversion. [d] 24% sat. carboxylic acid was formed.
[e] 31% sat. carboxylic acid was formed. [f] 13% sat. carboxylic acid was
formed. [g] 93% conversion. [h] 81% conversion.
clearly had a beneficial effect on the overall enantioselectiv-
ity for complexes 8–11 with the exception of the phenyl
ester S25. The sterically demanding PHIM complex 10 per-
formed consistently in the good to excellent enantioselectiv-
ity range for the different esters. Clearly the highest enantio-
selectivities were achieved with this catalyst in the hydroge-
nation of the isopropyl and tert-butyl ester. Complexes 8, 9,
and 11 also gave very high levels of ee value with the tert-
butyl ester S23, however, formation of variable amounts of
the corresponding saturated carboxylic acid as a side prod-
uct was a recurrent problem, which we attribute to the
Brønsted acidity of Ir hydrides formed as intermediates in
the catalytic cycle.[14]
Conclusion
The high enantioselectivities obtained in the hydrogenation
of various a,b-unsaturated carboxylic esters with aryl or
alkyl substituents at the C=C bond show that iridium com-
Scheme 1. Ir–SiPHOX-catalyzed asymmetric hydrogenation of an aliski-
ren precursor developed by Zhou et al.[3]
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

A. Pfaltz et al.
plexes derived from chiral N,P ligands are efficient catalysts
for this transformation. As expected none of the complexes
that we evaluated emerged as a universal catalyst. Depend-
ing on the substitution pattern of the substrate, different li-
gands perform best. For instance, iridium complex 2 outper-
forms the less sterically demanding complex 1 by a consider-
able degree of enantioselectivity for a variety of substrates
but not all, which highlights the advantage of a modular ap-
proach to the synthesis of catalysts and the need for screen-
ing groups of catalysts with tuneable steric and electronic
properties. Our results also show that a,b-unsaturated car-
boxylic esters substituted at the a position are less problem-
atic substrates than originally anticipated based on previous
studies. In some cases a-substituted substrates actually re-
acted with higher enantioselectivity than their b-substituted
analogues. Pyridine-based N,P complexes proved to be ex-
cellent catalysts for sterically accessible unsaturated esters,
whereas for the sterically more demanding aliskiren precur-
sors S20–S22 with an isopropyl substituent in the a position,
phosphinooxazoline and phosphinoimidazoline complexes
emerged as superior catalysts.
Acknowledgements
Support of this work by the Swiss National Science Foundation and the
Federal Commission for Technology and Innovation (KTI) is gratefully
acknowledged.
[1] a) R. B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan, D. E.
Ward, B. W. Au-Yeung, P. Balaram, L. J. Browne, P. J. Card, C. H.
Chen, J. Am. Chem. Soc. 1981, 103, 3210–3213; b) K. Mashima, K.-
H. Kusano, T. Ohta, R. Noyori, H. Takaya, J. Chem. Soc. Chem.
Commun. 1989, 1208–1210; c) P. J. Harrington, E. Lodewijk, Org.
Process Res. Dev. 1997, 1, 72–76; d) A. W. Alberts, J. Chen, G.
Kuron, V. Hunt, J. Huff, C. Hoffman, J. Rothrock, M. Lopez, H.
Joshua, E. Harris, A. Patchett, R. Monaghan, S. Currie, E. Stapley,
G. Albers-Schonberg, O. Hensens, J. Hirshfield, K. Hoogsteen, J.
Liesch, J. Springer, Proc. Natl. Acad. Sci. USA 1980, 77, 3957–3961;
e) G. H. Posner, C. H. Oh, D. Wang, L. Gerena, W. K. Milhous, S. R.
Meshnick, W. Asawamahasadka, J. Med. Chem. 1994, 37, 1256–
1258; f) K. T. Nguyen, D. Ritz, J.-Q. Gu, D. Alexander, M. Chu, V.
Miao, P. Brian, R. H. Baltz, Proc. Natl. Acad. Sci. USA 2006, 103,
17462–17467.
[2] T. Ohta, H. Takaya, M. Kitamura, K. Nagai, R. Noyori, J. Org.
Chem. 1987, 52, 3174–3176.
[3] S. Li, S.-F. Zhu, C.-M. Zhang, S. Song, Q.-L. Zhou, J. Am. Chem.
Soc. 2008, 130, 8584–8585.
[4] a) U. Leutenegger, A. Madin, A. Pfaltz, Angew. Chem. 1989, 101,
61–62; Angew. Chem. Int. Ed. Engl. 1989, 28, 60–61; b) C. Geiger,
P. Kreitmeier, O. Reiser, Adv. Synth. Catal. 2005, 347, 249–254.
[5] a) D. H. Appella, Y. Moritani, R. Shintani, E. M. Ferreira, S. L.
Buchwald, J. Am. Chem. Soc. 1999, 121, 9473–9474; b) G. Hughes,
M. Kimura, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 11253–
11258; c) B. H. Lipshutz, J. M. Servesko, B. R. Taft, J. Am. Chem.
Soc. 2004, 126, 8352–8353.
[6] a) Y. Tsuchiya, Y. Kanazawa, T. Shiomi, K. Kobayashi, H. Nishiya-
ma, Synlett 2004, 2493–2496; b) Y. Kanazawa, Y. Tsuchiya, K. Ko-
bayashi, T. Shiomi, J.-i. Itoh, M. Kikuchi, Y. Yamamoto, H. Nishiya-
ma, Chem. Eur. J. 2006, 12, 63–71.
[7] a) A. Lightfoot, P. Schnider, A. Pfaltz, Angew. Chem. 1998, 110,
3047–3050; Angew. Chem. Int. Ed. 1998, 37, 2897–2899; b) D. Liu,
W. Tang, X. Zhang, Org. Lett. 2004, 6, 513–516; c) J. Zhao, K. Bur-
gess, J. Am. Chem. Soc. 2009, 131, 13236–13237; d) X. Cui, K. Bur-
gess, Chem. Rev. 2005, 105, 3272–3296; e) T. L. Church, P. G. Ander-
sson, Coord. Chem. Rev. 2008, 252, 513–531; f) D. H. Woodmansee,
A. Pfaltz, Iridium Catalyzed Asymmetric Hydrogenation of Olefins
with Chiral N,P and C,N Ligands, Springer, Berlin Heidelberg, 2010;
g) S. J. Roseblade, A. Pfaltz, Acc. Chem. Res. 2007, 40, 1402–1411;
h) D. H. Woodmansee, A. Pfaltz, Chem. Commun. 2011, 47, 7912–
7916; i) D. Rageot, D. H. Woodmansee, B. Pugin, A. Pfaltz, Angew.
Chem. 2011, 123, 9772–9775; Angew. Chem. Int. Ed. 2011, 50, 9598–
9601; j) S.-M. Lu, C. Bolm, Angew. Chem. 2008, 120, 9052–9055;
Angew. Chem. Int. Ed. 2008, 47, 8920–8923.
Experimental Section
Typical catalyst synthesis: (R)-2-Mesityl-4-methyl-6,7-dihydro-5H-cyclo-
penta[b]pyridine-7-ol (50 mg, 189 mmol) was added to a dry Young tube
that was evacuated and backfilled with argon three times. Potassium hy-
dride (11 mg, 281 mmol) was added followed by di-tert-butylchlorophos-
phine (34 mg, 189 mmol) and DMF (450 mL). The reaction mixture was
stirred for 48 h and the solvent evaporated at high vacuum using a hot
water bath (608C) to afford a red foam that was redissolved in dry THF
(500 mL). The resulting suspension was filtered using a syringe and a
micron filter inside a glove box and the filtrate (including 2ꢃ500 mL
washings with THF) was collected into a vial containing a solution of [Ir-
(cod)2]BArF
(BArF=tetrakisACHTGUNTERNNU[G bis-3,5-(trifluoromethyl)phenyl]borate;
240 mg, 189 mmol) in THF (1 mL). The resulting dark red solution was
stirred for 6 h and adsorbed onto silica gel. Column chromatography
(SiO2, 2ꢃ10 cm hexane/diethyl ether (1:1)) followed by elution of the
product with CH2Cl2 afforded a dark red solid that was dissolved in
CH2Cl2 (1 mL) and layered with hexane (4 mL). The biphasic mixture
was stored in a refrigerator for 48 h to yield catalyst 2 as dark red crystals
(120 mg, 76.2 mmol, 40%). For analytical data, see ref. [8].
Typical procedure for Ir-catalyzed hydrogenation: Catalyst 1 (24.0 mg,
15.8 mmol, 1.0 mol%) was added to a solution of (E)-ethyl 3-phenylbut-
2-enonate (S1, 300 mg, 1.58 mmol) in dry CH2Cl2 (7.9 mL). The reaction
vial was equipped with a magnetic stirrer bar and placed in an autoclave
that was pressurized to 50 bar with H2. The reaction mixture was stirred
at 800 rpm for 2 h and, after this time, hydrogen was released and the sol-
vent removed under reduced pressure. The mixture was filtered through
a plug of silica gel (1ꢃ8 cm) using a mixture of pentane/diethyl ether
(1:1, 50 mL). After evaporation of the solvent, the analytically pure hy-
drogenation product P1 (292 mg, 1.52 mmol, 96%) was obtained as a col-
orless liquid. Catalyst screening was performed on a 0.1 mmol scale. For
analytical data, see ref. [4b]. For separation conditions, see ref. [7i].
[8] D. H. Woodmansee, M.-A. Mꢀller, M. Neuburger, A. Pfaltz, Chem.
Sci. 2010, 1, 72–78.
[9] a) S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. 2006, 118, 5318–
5321; Angew. Chem. Int. Ed. 2006, 45, 5194–5197; b) Q.-B. Liu, C.-
B. Yu, Y.-G. Zhou, Tetrahedron Lett. 2006, 47, 4733–4736.
[10] C. Hedberg, K. Kallstrom, P. Brandt, L. K. Hansen, P. G. Andersson,
J. Am. Chem. Soc. 2006, 128, 2995–3001.
[11] a) M. Schçnleber, R. Hilgraf, A. Pfaltz, Adv. Synth. Catal. 2008, 350,
2033–2038; b) J. Mazuela, J. J. Verendel, M. Coll, B. Schꢄffner, A.
Bçrner, P. G. Andersson, O. Pꢅmies, M. Diꢆguez, J. Am. Chem. Soc.
2009, 131, 12344–12353; c) A. K. H. Knçbel, I. H. Escher, A. Pfaltz,
Synlett 1997, 1429–1431.
For complete experimental procedures and analytic data see the Support-
ing Information.
[12] K. Tiefenbacher, L. Trçndlin, J. Mulzer, A. Pfaltz, Tetrahedron 2010,
66, 6508–6513.
[13] a) J. A. F. Boogers, D. Sartor, U. Felfer, M. Kotthaus, G. Steinbauer,
B. Dielemans, L. Lefort, A. H. M. de Vries, J. G. de Vries, Asym-
metric Hydrogenation of a 2-isopropylcinnamic acid derivative en
&
6
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Hydrogenation of a,b-Unsaturated Carboxylic Esters
FULL PAPER
route to the blood pressure-lowering agent Aliskiren, Wiley-VCH,
Weinheim, 2010, pp. 127–150; b) W. Chen, F. Spindler, U. Netteko-
ven, B. Pugin, Solvias AG, Switzerland, WO2008101868, 2008,
p. 53pp.
[14] Y. Zhu, Y. Fan, K. Burgess, J. Am. Chem. Soc. 2010, 132, 6249–
6253.
Received: July 5, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

A. Pfaltz et al.
Asymmetric Synthesis
D. H. Woodmansee, M.-A. Mꢀller,
L. Trçndlin, E. Hçrmann,
A. Pfaltz* ...................... &&&& — &&&&
Enantioselective conjugate reduction
of a wide range of a,b-unsaturated car-
boxylic esters was achieved using
tion catalysts. The resulting saturated
esters with a stereogenic center in the
a or b position were obtained in high
enantiomeric purity (see scheme).
Asymmetric Hydrogenation of a,b-
Unsaturated Carboxylic Esters with
Chiral Iridium N,P Ligand Complexes
chiral Ir N,P complexes as hydrogena-
&
8
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!