Direct asymmetric hydrogenation of α-keto acids by using the highly efficient chiral spiro iridium catalysts

Article abstract of DOI:10.1039/c4cc07643e

A new efficient and highly enantioselective direct asymmetric hydrogenation of α-keto acids employing the Ir/SpiroPAP catalyst under mild reaction conditions has been developed. This method might be feasible for the preparation of a series of chiral α-hydroxy acids on a large scale.

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COMMUNICATION
Direct Asymmetric Hydrogenation of αꢀKeto Acids by Using the Highly Efficient
Chiral Spiro Iridium Catalysts
PuꢀCha Yan,a JianꢀHua Xie,b,c XiangꢀDong Zhang,a Kang Chen,a YuanꢀQiang Li,a QiꢀLin Zhou,*,b,c and
DaꢀQing Che*,a,c
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
TON (as high as 100,000).14 On the basis of this work, we
A new efficient and highly enantioselective direct asymmetric
50 speculate that the same strategy seems to be working in the direct
hydrogenation of αꢀketo acids. Herein we report that the
Ir/SpiroPAP (1) catalyzed direct asymmetric hydrogenation of αꢀ
keto acids (2) to provide the chiral αꢀhydroxy acids (3) with
excellent enantioselectivity (up to 99.2% ee) and high TON (as
55 high as 50,000) under mild reaction conditions (Scheme 1).
hydrogenation of αꢀketo acids employing the Ir/SpiroPAP
catalyst under mild reaction conditions has been developed.
10 This method might be feasible for the preparation of a series
of chiral αꢀhydroxy acids in large scale.
Optically active αꢀhydroxy acids and their derivatives are of
considerable significance as chiral building blocks in numerous
pharmaceuticals and chemical industries,1 and also are utilized as
15 resolving agents.2 Therefore various methodologies have been
developed for preparing optical pure αꢀhydroxy acids, including
the enantioselective reduction of prochiral αꢀketo esters,3 kinetic
resolution of racemic αꢀhydroxy esters,4 enzymatic or biomimetic
methods,5 Cannizzaro reactions,6 FriedelꢀCrafts reactions,7
20 synthesis of cyanohydrins as precursors,8 and hydrogen mediated
reductive CꢀC bond formation reactions.9 The transition metal
catalyzed asymmetric hydrogenation proved to be an efficient and
economically feasible method for preparing these important
chiral compounds.10 Although a few papers are devoted to the
25 development of straight forward procedures involving the direct
conversion of αꢀketo acids to chiral αꢀhydroxy acids, the direct
asymmetric hydrogenation of αꢀketo acids has rarely attracted
attention.11 To the best of our knowledge, only one example was
reported so far employing RuꢀSunphos catalyst for the conversion
30 of (E)ꢀ2ꢀoxoꢀ4ꢀarylbutꢀ3ꢀenoic acids and 2ꢀoxoꢀ4ꢀarybutanoic
acids directly into optically active 2ꢀhydroxyꢀ4ꢀarylbutanoic acids
in up to 89.5% ee and 92.6% ee respectively.12 Therefore, the
development of effective, high enantioselective, and direct
approaches to αꢀhydroxy acids is still of significance.
Scheme 1. Asymmetric hydrogenation of α-keto acids with Ir/SpiroPAP
catalysts.
As revealed in Table 1, we employed benzoylformic acid (2a)
60 as the model substrate to optimize the reaction conditions. The
effects of base quantity, solvents and ligands on reactivity and
enantioselectivity were screened. Hydrogenation of 2a was
initially carried out under similar conditions previously optimized
for the reaction of βꢀaryl βꢀketo esters ((R)ꢀ1b, S/C = 1000, 0.05
65 equiv base, 15 atm H2, 25−30 °C).[13b] However, only trace
product was obtained within 24 h (Table 1, entry 1). The same
35
Be different from αꢀketo ester, the αꢀketo acid has a carboxyl
group which might competitively coordinate to the center metal
and then cause deactivation of the catalyst, thus resulting in low
enantioselectivity and reactivity. On the other hand, the
hydrogenation product (αꢀhydroxy acid) usually serves as a
t
result was observed even when 0.5 equiv BuOK was added
(Table 1, entry 2). Dramatically improved reactivity was obtained
t
when 1.0 equiv BuOK was used, the hydrogenation reaction
70 could be completed smoothly within 10 h, giving (S)ꢀ3a in 87%
ee (Table 1, entry 3). We speculated that the catalyst might be
activated with a relatively weak base such as carboxylic acid
potassium salt. The reaction rate could be accelerated by adding
1.06 equiv tBuOK, and the full conversion was obtained within 2
75 h (Table 1, entry 4). Solvent screening showed that nꢀbutanol
gave the best enantioselectivity (Table 1, entries 5−8). By
comparison of various chiral SpiroPAP ligands, it was found that
the introduction of an alkyl group at the 6ꢀ position of the
40 ligand, restricting it liberation from the catalyst.12 The chiral
iridium catalysts containing SpiroPAP ligands (Ir/SpiroPAP)
developed by Xie and Zhou in 2011, have shown excellent
enantioselectivity and reactivity in the hydrogenation of simple
ketones and βꢀaryl βꢀketoesters,13 however, the hydrogenation of
45 α–phenyl αꢀketo ester gave almost racemic product. Recently, we
successfully applyed these catalysts for the hydrogenation of mꢀ
hydroxyacetophenone in the presence of more than one equiv
base obtaining high enantioselectivity (up to 97% ee) and an high
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DOI: 10.1039/C4CC07643E
pyridine ring of the ligand reduced the enantioselectivity
(compare entry 12 with entry 9), however, the presence of an
2ꢀ4 vs entries 5ꢀ11). For more sterically hindered oꢀ
methylbenzoylformic acid (2c), the hydrogenation was extremely
alkyl group at either the 3ꢀ or 4ꢀ position of the pyridine ring 35 fast and high enantioselective. Full conversion was completed
could increase the enantioselectivity (compare entries 8 and 10
with entry 9). Increasing the substrate concentration from 0.4 M
to 1.0 M resulted in slightly lower enantioselectivity (Table 1,
entry 11). Based on the above results, the optimized reaction
within 1 hour to give the (S)ꢀ2ꢀhydroxyꢀ2ꢀ(oꢀtolyl)acetic acid (3c)
in 98% ee (Table 2, entry 3). This was further supported by the
fact that the highest enantioselectivity (99.2% ee) was obtained
when 2ꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀoxoacetic acid (2l) was employed as
5
conditions were therefore set as follows: 0.1 mo% of (R)ꢀ1c as 40 the substrate (Table 2, entry 12). It is worth noting that only
t
n
the catalyst, 1.06 equiv BuOK as base, BuOH as the solvent
sporadic papers have been reported on the asymmetric
hydrogenation of orthoꢀsubstituted benzoylformic esters and the
enantioselectivities were usually not very high.3k, 3n, 16
10 with a substrate concentration of 0.4 M at room temperature.15
Table 1: Asymmetric hydrogenation of benzoylformic acid (2a).
Optimizing reaction conditions.a
Table 2: Asymmetric hydrogenation of αꢀketo acids 2 with (R)ꢀ1c.a
45
Yieldb
(%)
Eec
(%)
Time
(h)
Conv.c
(%)
Eed
(%)
Entry
(R)ꢀ1
B/Sb Solvent
Time
(h)
Entry
R
3
1
2
0.05
0.5
EtOH
EtOH
EtOH
EtOH
24
24
10
2
trace
trace
100
100
92
n.d.e
1b
1b
1b
1b
1b
1b
1b
1b
1a
1c
1c
1d
1
2
C6H5
1.5
1
96
93
98
97
94
95
97
94
97
97
96
98
93 (S)
91 (S)
98 (S)
92 (S)
91 (S)
92 (S)
94 (S)
90 (S)
88 (S)
90 (S)
90 (S)
99.2 (S)
3a
3b
3c
3d
3e
3f
n.d.e
2ꢀClꢀC6H4
2ꢀMeꢀC6H4
2ꢀOMeꢀC6H4
3ꢀClꢀC6H4
3ꢀMeꢀC6H4
3ꢀOMeꢀC6H4
4ꢀFꢀC6H4
3
1.0
87 (S)
87 (S)
78 (S)
87 (S)
88 (S)
89 (S)
85 (S)
93 (S)
91 (S)
83 (S)
3
1
4
1.06
4
3
5
1.06 MeOH
1.06 iPrOH
1.06 nPrOH
1.06 nBuOH
1.06 nBuOH
1.06 nBuOH
1.06 nBuOH
1.06 nBuOH
21
20
2
5
5
6
100
100
100
100
100
100
100
6
3
7
7
4
3g
3h
3i
8
2
8
5
9
3
9
4ꢀClꢀC6H4
4ꢀMeꢀC6H4
4ꢀOMeꢀC6H4
1ꢀNaphthyl
4
10
11f
1.5
1.5
2
10
11
12
4
3j
8
3k
3l
12
1
a
Reaction conditions unless otherwisely noted: 2.0 mmol scale,
91 (S)
13
2ꢀNaphthyl
12
98
3m
95 (S) d
15 [substrate] = 0.4 M, (R)ꢀ1 (0.1 mol%), Solvent (5.0 mL), 15 atm H2, room
temperature (25~30 oC). Base to substrate ratio. Determined by 1H
b
c
d
NMR spectroscopy. Determined by HPLC analysis on a chiral ODꢀH
column of the corresponding methyl ester. The absolute configuration of
14
15
Ph(CH2)2
1
2
96
95
56 (S) e
82 (S) f
3n
3o
e
3a is S by comparing the specific rotation with reported data. n.d. = not
Cyclohexyl
20 determined. f [substrate] = 1.0 M, Solvent (2.0 mL).
77 (R)f
16g
tBu
21
92
Under the optimal reaction conditions, we examined the scope
of substrate (Table 2). A series of αꢀketo acids (2aꢀp) were
hydrogenated to afford the corresponding chiral αꢀhydroxy acids
(3aꢀp) in high yield (92ꢀ98%) and moderate to excellent
25 enantioselectivity (56ꢀ99.2% ee). The results summarized in
Table 2 indicate that the influence of electronic properties is not
obvious, substrates with electronꢀdonating substituents only gave
3p
85 (R) d, f
a
Reaction conditions unless otherwisely noted: 2.0 mmol scale,
[substrate] = 0.4 M, (R)ꢀ1c (0.1 mol%, S/C = 1000), nBuOH (5.0 mL), 15
o
b
c
atm H2, room temperature (25~30 C). Isolated yield. Determined by
HPLC analysis on a chiral ODꢀH or ADꢀH column of the corresponding
50 methyl ester. The absolute configuration was determined by comparing
the specific rotation with reported data. (R)ꢀ1b was used as catalyst.
Determined by HPLC analysis on a chiral ODꢀH column of the
d
e
a
little better enantioselectivity than those with electronꢀ
f
withdrawing substituents. Apparently, steric hindrance played a
30 crucial role in the asymmetric hydrogenation of these substrates.
For the αꢀarylꢀαꢀketo acids, orthoꢀsubstituted benzoylformic acid
usually reacted rapidly and gave higher ee values (Table 2, entries
corresponding ethyl ester. Determined by HPLC analysis on a chiral
ODꢀH column of the corresponding benzyl ester. g 0.2 mol% catalyst was
55 used (S/C = 500).
The hydrogenation of 2ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀoxoacetic acid (2m)
2
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† Electronic Supplementary Information (ESI) available: Experimental
50 procedures, characterization data of compounds, 1H and 13 C NMR spectra,
and HPLC charts. See DOI: 10.1039/b000000x/
provided direct access to 3m in 91% ee. When (R)ꢀ1b was used
as catalyst, 3m was obtained in 95% ee (Table 2, entry 13).
Longer reaction time was needed presumably due to the poor
solubility of the corresponding carboxylic acid potassium salt.
Aliphatic αꢀhydroxy acids were also obtained in high yield, albeit
with only moderate to good enantioselectivities (56ꢀ85% ee,
Table 2, entry 14ꢀ16). For more sterically hindered 3,3ꢀdimethylꢀ
2ꢀoxobutanoic acid (2p), the hydrogenation was extremely
sluggish even when 0.2 mol% catalyst was used (Table 2, entry
1
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10 16). Interestingly, the absolute configuration of 3p was opposite
to that of other products.
The fast reaction rate of oꢀchlorobenzoylformic acid (2b)
prompted us to develop a practical preparation of optical pure oꢀ
chloromandelic acid which is a key intermediate for a platelet
15 aggregation inhibitor named Clopidogrel17 with high TON. When
the substrate/catalyst ratio was increased to 50,000 (Scheme 2),
the hydrogenation of 2b completed at room temperature under an
initial hydrogen pressure of 30 atm within 24 h without loss of
enantioselectivity. The ee value of 3b could be upgraded to >99%
20 by crystallization from toluene in 80% yield. This is a promising
procedure for a largeꢀscale or even industrial setting.
65
70
75
80
4
5
85
Scheme 2. Asymmetric hydrogenation of o-chlorobenzoylformic acid with
high TON.
25 Conclusions
90
In summary, we have developed a new efficient and highly
enantioselective direct asymmetric hydrogenation of αꢀketo acids
into optically active αꢀhydroxy acids employing the Ir/SpiroPAP
catalyst. The achieved catalyst performance (ee, TON) indicated
30 that this method might be feasible for the preparation of a series
of chiral αꢀhydroxy acids especially orthoꢀsubstituted αꢀhydroxy
phenylacetic acids in large scale. Further investigations are
focused on the application of this methodology to the synthesis of
chiral pharmaceuticals.
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China (973 Program, No.
2012CB821600), “111” Project of the Ministry of Education of
China (Grant No. B06005) for financial support.
95
6
7
100
105
110
115
35
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Notes and references
40 a Zhejiang Jiuzhou Pharmaceutical Co., Ltd., 99 Waisha Road, Jiaojiang
District, Taizhou City, Zhejiang Province, 318000, P. R. China. Fax:
0086ꢀ0571ꢀ87000702; Tel: 0086ꢀ0571ꢀ87000701; Eꢀmail: dqche@zbjz.cn
b State Key Laboratory and Institute of Elementoꢀorganic Chemistry,
Nankai University, Tianjin 300071, P. R. China. Fax: 0086ꢀ022ꢀ
45 23500011; Tel: 0086ꢀ022ꢀ23500011; Eꢀmail: qlzhou@nankai.edu.cn
c Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Tianjin 300071, P. R. China. Fax: 0086ꢀ022ꢀ23500011; Tel:
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15 Other bases such as KOH and K2CO3 were also tried in the
hydrogenation of 2a. When KOH was used under the optimized
reaction conditions, the hydrogenation completed within 4 hours and
gave the product in 92% ee. However, only 13% of conversion was
obtained in 24 hours when K2CO3 was used as base under the same
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