Chiral iridium catalysts bearing spiro pyridine-aminophosphine ligands enable highly efficient asymmetric hydrogenation of β-aryl β-ketoesters

Article abstract of DOI:10.1002/anie.201105780

Tons of TONs: Chiral iridium catalysts bearing ligand 1 are highly efficient for the asymmetric hydrogenation of β-substituted β-ketoesters. The product β-hydroxyesters are delivered in high yield with excellent enantioselectivities and high turnover numbers (TONs). cod= 1,5-cyclooctadiene.

Full text of DOI:10.1002/anie.201105780

Angewandte
Chemie
DOI: 10.1002/anie.201105780
Synthetic Methods
Chiral Iridium Catalysts Bearing Spiro Pyridine-Aminophosphine
Ligands Enable Highly Efficient Asymmetric Hydrogenation of b-Aryl
b-Ketoesters**
Jian-Hua Xie,* Xiao-Yan Liu, Xiao-Hui Yang, Jian-Bo Xie, Li-Xin Wang, and Qi-Lin Zhou*
Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday
Optically active b-hydroxy acids and their derivatives are
activation of the [RuCl (diphosphine)(diamine)] catalysts
2
versatile chiral building blocks for many useful molecules,
enolizes the b-ketoester substrates instead of activating the
catalysts.
[1]
including pharmaceuticals and natural products. Catalytic
asymmetric hydrogenation of b-ketoesters is an efficient and
economically feasible method for preparing these important
Recently, we developed chiral iridium catalysts containing
a chiral SpiroPAP ligand, and these catalysts show excellent
enantioselectivity (up to 99.9% ee) and an extremely high
TON (as high as 4550000) for the hydrogenation of simple
[
2]
chiral compounds. Pioneered by Noyori and co-workers, the
chiral ruthenium diphosphine complexes [RuX2-
diphosphine)] (X = Cl or Br) and their analogues have
become by far the most popular catalysts for this trans-
[11]
(
ketones. These Ir/SpiroPAP catalysts are likely to have a
“metal–ligand bifunctional catalysis” mechanism, similar to
[
3]
[12]
formation. Many of them show excellent enantioselectivity
> 99% enantiomeric excess (ee)] and extraordinarily high
activity (turnover number (TON) of up to 100000) for the
the [RuCl (diphosphine)(diamine)] catalysts. The aromatic
2
[
NÀH of the Ir/SpiroPAP catalysts is more acidic than the
aliphatic NÀH of [RuCl (diphosphine)(diamine)] catalysts
2
[4]
hydrogenation of b-alkyl b-ketoesters. However, only a few
of these complexes exhibit high enantioselectivity for the
hydrogenation of b-aryl b-ketoesters. Zhang et al. reported
that the ruthenium catalysts bearing the ligands xylyl-o-
(the proton resonances of the NH or NH2 group of the
catalysts are as follows: Ir[IrH ((R)-1a)Cl]: d = 5.3 ppm
2
(CDCl ), [RuCl ((R)-Tol-binap)((R,R)-dpen)] (dpen = 1,2-
3
2
[
13]
diphenylethylenediamine): d = 3.3 and 3.5 ppm (C D ) ),
6
6
[
5]
binapo (3,3’-bis(3,5-dimethylphenyl)-2,2’-bis(diphenylphos-
thus indicating that the Ir/SpiroPAP catalysts may be more
easily activated with a relatively weak base such as the
enolate salt of a b-ketoester. To confirm this possibility, we
tested Ir/SpiroPAP catalysts for the hydrogenation of b-
ketoesters and found that the catalysts were extremely
efficient for hydrogenation of b-aryl b-ketoesters. Herein,
we report that the Ir/SpiroPAP-catalyzed asymmetric hydro-
genation of b-aryl b-ketoesters 2 provide the chiral b-hydroxy
esters 3 with excellent enantioselectivity (up to 99.8% ee) and
extremely high TONs (as high as 1230000) under mild
reaction conditions (8 atm H2 at room temperature;
Scheme 1).
[
6]
phinoxy)-1,1’-binaphthyl) and C *-TunePhos give up to
3
9
9% ee for the hydrogenation of b-aryl b-ketoesters. Using
ruthenium complexes of 4,4’-substituted binap ligands
binap = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl), Lin
(
[
7]
et al. obtained up to 99.8% ee for the hydrogenation of a
range of b-aryl b-ketoesters. The highest TON (10000) was
[8]
achieved by Saito and co-workers in the asymmetric hydro-
genation of methyl 3-oxo-3-phenylpropanoate. Note that
chiral rhodium or iridium complexes, which efficiently
catalyze olefin and imine hydrogenation, are seldom used
[9]
for the asymmetric hydrogenation of b-ketoesters. Further-
more, chiral [RuCl (diphosphine)(diamine)] complexes,
The reaction conditions were optimized for the hydro-
genation of ethyl 3-oxo-3-phenylpropanoate (2a). When the
reaction was carried out at room temperature under 8 atm of
2
which catalyze the hydrogenation of simple ketones
extremely efficiently, are also inert for the hydrogenation of
[
10]
b-ketoesters. The major reason for the inertness may be
that the strong base, such as KOtBu, that is required for
[*] Prof. J.-H. Xie, X.-Y. Liu, X.-H. Yang, J.-B. Xie, Prof. L.-X. Wang,
Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-Organic Chemistry
Nankai University
Tianjin 300071 (China)
E-mail: jhxie@nankai.edu.cn
qlzhou@nankai.edu.cn
[
**] We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (2010CB833300), and
the “111” project (B06005) of the Ministry of Education of China for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105780.
Scheme 1. Asymmetric hydrogenation of b-ketoesters with Ir/SpiroPAP
catalysts. cod=1,5-cyclooctadiene.
Angew. Chem. Int. Ed. 2012, 51, 201 –203
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
201

.
Angewandte
Communications
[
a]
Table 1: Asymmetric hydrogenation of ethyl 3-oxo-3-phenylpropanoate
Table 2: Asymmetric hydrogenation of b-ketoesters 2 with Ir/(R)-1b.
[
a]
(2a). Optimizing reaction conditions.
[
b]
[c]
Entry
R
C
Product
t [h]
Yield [%]
ee [%]
[
b]
[c]
[d]
Entry Ligand Solvent t [h]
Conv. [%]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
6
H
5
3a
3b
3c
3d
3e
3 f
3g
3h
3i
1.0
0.4
0.7
1.0
0.8
0.7
1.7
1.7
1.0
0.8
4.0
20
98
97
95
94
96
95
93
95
94
94
97
90
98
4-MeC H
4-MeOC H
4-ClC H
4-BrC H
3-MeC H
3-MeOC H
3-BrC H
4
2-MeC H
99.3
99.3
96
99
99.2
96
6
4
1
2
3
4
5
6
7
8
9
1
1
1
1
(R)-1b EtOH
(R)-1b MeOH
(R)-1b nPrOH
(R)-1b iPrOH
1.0
0.7
2.5
100
100
100
100
43
100
100
100
100
100
100
>99
82
98
95
95
94
40
95
98
97
97
96
96
98
78
98
86
73
85
99.2
98
98
93
96
89
76
98
98
[
[
[
e]
e]
e]
6
4
6
4
6
4
15
6
4
(R)-1b toluene 15
[
[
f]
6
4
4
(R)-1b EtOH
(R)-1b EtOH
(R)-1a EtOH
3.0
95
g]
6
0.7
2.0
2.5
1.5
1.5
99.8
99.5
99.3
88
6
4
1
1
1
0
1
2
2-MeOC H
2-ClC H
iPr
3j
3k
3l
6
(R)-1c
(R)-1d EtOH
(R)-1e EtOH
EtOH
6
4
0
1
2
3
[
[
h]
i]
(R)-1b EtOH
(R)-1b EtOH
19
96
[a] Reaction conditions were the same as those used for the reaction in
entry 1 of Table 1. [b] Yield of isolated product. [c] Determined by HPLC
analysis using a chiral stationary phase (see the Supporting Informa-
tion); the absolute configuration of the product is S.
[a] Reaction conditions: 1.5 mmol scale, [substrate]=2.1m, [{Ir-
(
cod)Cl} ] (0.05 mol%), ligand (0.11 mol%), [KOtBu]=0.02m, solvent
2
1
(
2.0 mL), room temperature (25–308C). [b] Determined by H NMR
spectroscopy. [c] Yield of isolated product. [d] Determined by HPLC
analysis using a chiral stationary phase. The absolute configuration of
the product is S. [e] The hydrogenation product contains a certain
amount of intere-esterification product. [f] At 158C. [g] At 508C. [h] S/
Under the optimal reaction conditions, various b-aryl b-
ketoesters (2a–k) were hydrogenated over Ir/(R)-1b at S/C =
1000 to afford the corresponding chiral b-hydroxy esters 3a–k
in high yield (93–98%) and excellent enantioselectivity (95–
C=100,000, 50 atm H (initial). [i] S/C=1500000, at 508C, 100 atm H
2
2
(
initial).
9
9.8% ee). The results listed in Table 2 indicate that the
electronic properties of the group on the phenyl ring of the b-
aryl b-ketoester had little effect on the enantioselectivity;
however, ortho-chloro substitution resulted in a longer
reaction time (entry 11). The catalyst Ir/(R)-1b was less
efficient for the hydrogenation of b-alkyl b-ketoesters such as
b-isopropyl b-ketoester (2l; entry 12).
hydrogen with Ir/(R)-1b generated in situ from 0.05 mol%
{Ir(cod)Cl} ] and 0.11 mol% (R)-1b, the hydrogenation
product (S)-ethyl 3-hydroxy-3-phenylpropanoate (3a) was
obtained in 98% yield and 98% ee (Table 1, entry 1), along
with a small amount of (E)-ethyl 3-phenylacrylate (< 2%),
which was generated by elimination of the b-hydroxy group of
[
2
Catalytic asymmetric hydrogenation of b-keto amides is
an efficient approach to the synthesis of optically pure chiral
[
14]
3
a under the basic conditions. Solvent experiments showed
b-hydroxy amides, which are useful building blocks for the
synthesis of biologically active compounds. For example, the
optically pure chiral b-hydroxy amide 5a (R = Me) has been
used in the enantioselective synthesis of the antidepressants
that the reaction was faster in a less bulky alcohol solvent and
that EtOH gave the best enantioselectivity (entries 1–4).
Enantioselectivity as high as 99.2% ee was obtained in
toluene, but, the conversion was quite low (entry 5). The
reaction temperature had little effect on the enantioselectiv-
ity, but reducing the temperature lowered the reaction rate
[
15]
fluoxetine and tomoxetine (Scheme 2). We were delighted
to find that Ir/(R)-1b efficiently catalyzed the asymmetric
(
compare entry 1 with entries 6 and 7). Comparison of various
chiral SpiroPAP ligands indicated that the introduction of an
alkyl group at the 6-position of the pyridine ring of the ligand
reduced the enantioselectivity (compare entry 8 with
entries 10 and 11); however, the presence of an alkyl group
at either the 3- or 4-position of the pyridine ring increased the
enantioselectivity (compare entry 8 with entries 1 and 9).
When the catalyst loading was lowered from 0.1 to
0
.001 mol% (S/C = 100000), Ir/(R)-1b worked well and
yielded the hydrogenation product (S)-3a in 98% yield and
8% ee within 19 hours at an initial hydrogen pressure of 50
9
atm (entry 12). When the catalyst loading was additionally
lowered to 0.000067 mol% (S/C = 1500000), the reaction had
to be carried out at 508C and at an initial hydrogen pressure
of 100 atm; (S)-3a was obtained in 78% yield with a
conversion of 82% (TON = 1230000) and the same level of
enantioselectivity (entry 13).
Scheme 2. Asymmetric hydrogenation of the b-keto amides 4 and 1,3-
diketone 6.
2
02
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Chemie
hydrogenation of b-keto amides. For example, the b-phenyl b-
ketoamides 4 were hydrogenated to give the chiral b-hydroxy
amides 5a and 5b in high yield (93 and 91%, respectively)
with excellent enantioselectivity (96 and 98% ee, respec-
tively). Moreover, Ir/(R)-1b also efficiently catalyzed the
hydrogenation of 1,3-diketone 6 to afford the 1,3-dialkanol 7
in 92% yield with greater than 99.9% ee and a diastereomeric
excess of 92%.
In conclusion, we have developed a highly efficient
asymmetric hydrogenation of b-aryl b-ketoesters catalyzed
by Ir/SpiroPAP complexes. The reaction provides a readily
accessible method for the synthesis of b-hydroxy esters in
excellent enantioselectivity (up to 99.8% ee) and extremely
high TONs (up to 1230000), which represents the highest
level of efficiency in the asymmetric hydrogenation of b-
ketoesters.
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solution. The vessel was then placed in an autoclave and purged with
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1
.0 h under 1 atm of H . After releasing the pressure, the b-ketoester
2
À1
(1.5 mmol) and a solution of tBuOK in EtOH (0.13 mmolmL
,
[
0
.3 mL, 0.04 mmol) were added through the injection port. The
autoclave was then pressurized to 8 atm of H2 and the reaction
mixture was stirred at room temperature (25–308C) until no obvious
hydrogen pressure drop was observed. After releasing the hydrogen
pressure, the reaction mixture was concentrated in vacuum and
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Received: August 16, 2011
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Keywords: enantioselectivity · hydrogenation · iridium ·
ligand effects · synthetic methods
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[
Angew. Chem. Int. Ed. 2012, 51, 201 –203
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203