Diastereo- and enantioselective hydrogenation of α-amino-β-keto ester hydrochlorides catalyzed by an iridium complex with MeO-BIPHEP and NaBArF: Catalytic cycle and five-membered chelation mechanism of asymmetric hydrogenation

Article abstract of DOI:10.1002/chem.201001298

The development of Ir-catalyzed asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides is described. This reaction proceeds through a dynamic kinetic resolution to produce anti-β-hydroxy- α-amino acid esters in a high diastereo- and enantioselective manner. Mechanistic studies have revealed that this unique asymmetric hydrogenation proceeds through reduction of the ketone moiety via the five-membered transition state involving the chelation between the oxygen of the ketone and the nitrogen of the amine function. The relationship studies between the hydrogen pressure and the stereoselectivity have disclosed two mechanisms dependent on hydrogen pressure. Under low hydrogen pressure (<15 atm), the reaction rate proportionally increased with the hydrogen pressure. However, under the high hydrogen conditions, the reaction rate exponentially accelerated along with the increasing hydrogen pressure, which suggests the participation of two or more of hydrogen atoms. Apply some pressure: The Ir-catalyzed asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides proceeds through a dynamic kinetic resolution to produce anti-β-hydroxy-α-amino acid esters in a high diastereo- and enantioselective manner (see scheme). Mechanistic studies revealed that this unique asymmetric hydrogenation proceeds through reduction of the ketone moiety via the five-membered transition state.

Full text of DOI:10.1002/chem.201001298

DOI: 10.1002/chem.201001298
Diastereo- and Enantioselective Hydrogenation of a-Amino-b-Keto Ester
Hydrochlorides Catalyzed by an Iridium Complex with MeO-BIPHEP and
NaBArF: Catalytic Cycle and Five-Membered Chelation Mechanism of
Asymmetric Hydrogenation
Tsukuru Maeda, Kazuishi Makino, Masamichi Iwasaki, and Yasumasa Hamada*[a]
Abstract: The development of Ir-cata-
lyzed asymmetric hydrogenation of a-
amino-b-keto ester hydrochlorides is
described. This reaction proceeds
through a dynamic kinetic resolution to
produce anti-b-hydroxy-a-amino acid
esters in a high diastereo- and enantio-
selective manner. Mechanistic studies
have revealed that this unique asym-
metric hydrogenation proceeds through
reduction of the ketone moiety via the
five-membered transition state involv-
ing the chelation between the oxygen
of the ketone and the nitrogen of the
amine function. The relationship stud-
ies between the hydrogen pressure and
the stereoselectivity have disclosed two
mechanisms dependent on hydrogen
pressure. Under low hydrogen pressure
(<15 atm), the reaction rate propor-
tionally increased with the hydrogen
pressure. However, under the high hy-
drogen conditions, the reaction rate ex-
ponentially accelerated along with the
increasing hydrogen pressure, which
suggests the participation of two or
more of hydrogen atoms.
Keywords: amino acids · asymmet-
ric hydrogenation · dynamic kinetic
resolution · iridium · reaction mech-
anisms
Introduction
Catalytic asymmetric hydrogenation through dynamic kinet-
ic resolution (DKR) is one of the most efficient methods for
the preparation of optically active compounds.[1] As illustrat-
ed in Scheme 1, the reaction of a rapidly racemizing sub-
strate under the stated reaction conditions with a highly
enantioselective catalyst, when the racemization rate is high
enough compared to the reaction rate, can proceed through
DKR and finally, all of the substrate can be converted into a
single diastereomer in a, theoretically, 100% yield in a ste-
reocontrolled fashion through a single operation.
Scheme 1. Asymmetric hydrogenation of racemic ketones through dy-
namic kinetic resolution.
In 1989, Noyoriꢀs group reported for the first time that a
chiral Ru–BINAP complex catalyzes the syn-selective asym-
metric hydrogenation[2] of a-acylamino-b-keto esters via
DKR to produce the syn-b-hydroxy-a-acylamino acid deriv-
atives,[3] which are useful chiral building blocks for the syn-
thesis of natural products and medicines[4] with high diaster-
eo- and enantioselectivity. Recently, as a complementary
method for Noyoriꢀs asymmetric hydrogenation, we have
succeeded in the development of the direct anti-selective
asymmetric hydrogenation of a-amino-b-keto ester hydro-
chloride salts by DKR, catalyzed by an Ru,[5] Rh,[6] Ir,[7] or
Ni[8] complex with a bisphosphine ligand (Scheme 2),[9]
which provides anti-b-hydroxy-a-amino acid esters—impor-
tant building blocks needed for our synthetic studies of cy-
clodepsipeptides.[10]
[a] T. Maeda, Dr. K. Makino, M. Iwasaki, Prof. Y. Hamada
Graduate School of Pharmaceutical Sciences, Chiba University
Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
Fax : (+81)43-290-2987
E-mail: hamada@p.chiba-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001298.
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FULL PAPER
ingly low level of asymmetric induction prompted us to ex-
amine other transition metals for the anti-selective asym-
metric hydrogenation of 3a. Interestingly, in addition to the
known ruthenium catalyst Rh and Ir proved to be potential
catalysts for the highly anti-selective asymmetric hydrogena-
tion through DKR. Therefore, we first carried out the opti-
mization of the Ir-catalyzed anti-selective asymmetric hydro-
genation. The selected conditions for the optimization are
summarized in Table 1.[12]
Scheme 2. Direct anti-selective asymmetric hydrogenation.
The reversal of diastereoselectivity from syn to anti was
achieved based on our working hypothesis that the use of a
protection-group free a-amino-b-keto ester as a substrate
should induce a change in the transition state from the six-
membered cyclic transition state (TS) 1 to the five-mem-
bered cyclic TS 2 to yield an anti-b-hydroxy-a-amino acid
ester as shown in Scheme 3.
Table 1. Optimization of the Ir-catalyzed asymmetric hydrogenation.[a]
Entry
Additive
(3 mol%)
H2 [atm]
Time[b]
Yield [%][b]
ee [%][c]
AHCTUNGTRENNUNG
1[d]
2
3
4
5
–
–
NaI
KI
100
100
100
100
100
100
4.5
1
3
3
24
24
24
3
24
96
96
96
96
90
77
82
57
55
100
100
91
90
100
98
69
77
90
87
87
74
93
92
92
92
92
I2
6
7
8
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
9[e]
10[f]
11[g]
1
4.5
4.5
Scheme 3. Direct stereodivergent asymmetric hydrogenation.
[a] The Ir catalyst was prepared from [IrACHTUNRGTNEUNG(cod)Cl]2, ligand, and additive in
CH2Cl2 prior to hydrogenation. [b] Yield in two steps. [c] Determined by
HPLC analysis. [d] (S)-BINAP was used. [e] No freeze–thaw operation.
[f] 1 mol% catalyst was used. [g] 0.5 mol% catalyst was used.
The Ru-axially chiral bisphosphine-catalyzed asymmetric
hydrogenation of an a-amino-b-keto ester hydrochloride
with an alkyl group at the g-position exclusively gave an anti
product with an excellent enantioselectivity in high yield.
This method has a serious problem in that substrates with
an aromatic ring at the g-position have a poor reactivity and
enantioselectivity. In our efforts to address this problem, we
developed new efficient Ir catalysts for the anti-selective
asymmetric hydrogenation of the aromatic substrates.[7] We
now report the details of the Ir-catalyzed direct anti-selec-
tive asymmetric hydrogenation of a-amino-b-keto ester hy-
drochlorides by DKR as well as mechanistic studies using
isotope labeling experiments, NMR spectroscopy analysis,
and kinetics. Although mechanistic studies for the Ir-cata-
lyzed hydrogenation of alkenes, ketones, and imines have
been reported by several groups,[11] the mechanism for the
Ir-catalyzed asymmetric hydrogenation of a-amino-b-keto
ester hydrochlorides through DKR has never been reported.
The hydrogenated product was isolated as the N-benzoyl
derivative for HPLC analysis. Reactions in polar solvents,
such as alcohols and acetic acid rather than dichlorome-
thane, tended to proceed smoothly, exclusively giving an
anti product in a high yield with a moderate enantiomeric
excess. The presence of triethylamine or sodium acetate as a
base in an alcoholic solvent caused a decreased yield due to
the significant decomposition of the substrate, while the ad-
dition of sodium acetate in acetic acid improved the enan-
tioselectivity from 27 to 69% ee with a strongly enhanced
reactivity (90% yield after 3 h; entry 1). The other bases
with a different counter cation, such as lithium or ammoni-
um acetate, were inferior to sodium acetate in yield. The
choice of the chiral phosphine ligand was critical for pro-
moting the anti-selective asymmetric hydrogenation through
DKR. The axially chiral bidentate phosphines formed an ef-
Results and Discussion
ficient catalyst with [IrACTHNUTRGNE(UGN cod)Cl]2, but the use of other phos-
Development of catalytic asymmetric hydrogenation of a-
amino-b-keto esters by DKR: The Ru-axially chiral phos-
phine-catalyzed asymmetric hydrogenation of methyl C-ben-
zoylglycinate hydrochloride (3a), an aromatic substrate, re-
sulted in the formation of the racemic amino acid 4a in a
diastereomeric ratio of 93:7 and 31% yield. This disappoint-
phines, such as a DIOP or NORPHOS, resulted in no reac-
tion.
Among several axially chiral phosphines, MeO-BIPHEP
with an electron-donating group and a large bite angle, was
very effective, and the enantioselectivity reached 77% ee
(entry 2). To further improve the enantioselectivity, various
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Y. Hamada et al.
Table 2. Ir-catalyzed anti-selective asymmetric hydrogenation.
additives used in the preparation of the Ir complex were ex-
amined. The addition of phthalimide,[13] potassium fluoride,
tetrabutylammonium bromide or silver trifluoroacetate was
either not or less effective in yield and stereoselectivity, but
iodine or iodide salts were found to be effective additives
that improved the enantioselectivity (entries 3–5).[14,15] Espe-
cially, the use of the Ir complex prepared from [IrACHTNUGTRENUNG(cod)Cl]2
(0.015 equiv), (S)-MeO-BIPHEP (0.04 equiv), and sodium
iodide (0.06 equiv) led to a remarkable improvement in the
enantiomeric excess from 77 to 90% (entry 3).
The first-generation iridium catalyst, that is, the Ir-(S)-
MeO-BIPHEP-I complex, has a number of problems. For
instance, the reaction required a high hydrogen pressure
(100 atm) and tedious degassing operation with freeze-thaw
cycles for the preparation of the catalyst and during assem-
bling an apparatus prior to hydrogenation for a smooth re-
action. In addition, longer reaction times were required for
completion. Therefore, we sought an additive(s), other than
iodine or the iodide ion, for a more efficient catalyst than
the first-generation Ir catalyst. Recently, Pfaltzꢀs group re-
Entry
Substrate
1st Ir catalyst[a]
Yield [%] ee [%]
2nd Ir catalyst[b]
Yield [%] ee [%]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
82
81
83
–
90
94
87
–
100
92
100
97
100
96
76
67
–
92
92
90
91
93
82
74
67
–
80
87
–
94
75
–
–
–
ported the effect of a tetrakisACHTNUTRGNE[UNG 3,5-bis(trifluoromethyl)phe-
9
80
95
72
75
74
47
45
–
93
86
88
92
88
82
81
–
nyl]borate (BArF) counterion, which serves to stabilize the
Ir-PHOX catalyst and enhances its catalytic activity.[16,17] In-
spired by this report, we applied the Ir-PHOX catalyst to
the asymmetric hydrogenation of 3a by DKR, but no reac-
tion was observed. The addition of NaBArF during the prep-
10
11
12
13
14
15
16
94
97
94
61
33
9
90
90
96
84
85
87
91
aration of the Ir catalyst from [IrACTHNUTRGNEG(NU cod)Cl]2 and (S)-MeO-
100
BIPHEP resulted in the completion of the reaction with the
quantitative isolated yield of 4a, but the enantioselectivity
remained at a similar level to that under a high hydrogen
pressure (100 atm, entry 6). After several preliminary ex-
periments, a key discovery was made when the effect of the
hydrogen pressure was examined. We found that the enan-
tioselectivity increased when the hydrogen pressure was re-
duced. The change in the hydrogen pressure from 100 to
4.5 atm enhanced the enantiomeric excess of 4a from 74 to
93% (entry 7).
To our surprise, the hydrogenation proceeded even below
1 atm hydrogen with a similar stereoselectivity and excellent
isolated yield (entry 8). The addition of sodium acetate was
essential for this asymmetric hydrogenation. This cationic Ir-
(S)-MeO-BIPHEP-BArF complex, the second-generation iri-
dium catalyst, can be readily prepared by mixing [Ir-
[a] Hydrogenation was carried out by using the Ir-(S)-MeO-BIPHEP-I
catalyst (3 mol%) under hydrogen pressure (100 atm) at 27~308C for
96 h. [b] The hydrogenation was carried out by using the Ir-(S)-MeO-
BIPHEP-BArF catalyst (1 mol%) under hydrogen pressure (4.5 atm) at
238C for 96 h.
generally applicable to g-aromatic a-amino-b-keto esters,
which exclusively produced the corresponding anti products.
Compared to the first-generation Ir catalyst, the second-
generation Ir catalyst showed higher yields and enantiose-
lectivities under moderate hydrogen pressures. Halogen
atoms in the substrates were compatible under the hydro-
ACHUTNGRENgNUG enACHUTNGTRENaNGUN tion conditions, but the presence of an electron-with-
drawing substituent on the g-aromatic ring resulted in a
slight decrease in the enantioselectivities (entries 6–8).
These results showed that the stereoselectivity of the Ir-cata-
lyzed anti-selective asymmetric hydrogenation is seriously
influenced by the electronic environment of the substrates.
a-Amino-b-keto esters with a heteroaromatic ring contain-
ing a sulfur or an oxygen atom were good substrates for this
hydrogenation (entries 12 and 13).
In the case of g-alkyl substrates, such as those in which R
is n-propyl, isopropyl, or cyclohexyl, either no or low con-
version was observed (entries 14 and 15). Interestingly, hy-
drogenation of the highly hindered substrate 3p with a tert-
butyl group proceeded stereoselectively to provide the b-hy-
droxy-a-amino acid ester 4p with a diastereomeric ratio of
>99:1 in a quantitative yield and 91% ee (entry 16).
ACHTUNGTRENNUNG(cod)Cl]2 (0.5 equiv), (S)-MeO-BIPHEP (1.3 equiv), and
NaBArF (1 equiv) in methylene chloride at 238C, and can be
easily handled without a strict degassing operation and an-
hydrous conditions (entry 9). The catalyst loading can be re-
duced from 3 to 0.5 mol% without any loss in stereoselectiv-
ities and yield (entry 11).
Under the optimized reaction conditions, we investigated
the scope and limitation of these Ir catalysts. The results are
summarized in Table 2. For the second-generation Ir catalyst
the hydrogenation reactions were carried out in the pres-
ence of the catalyst (1 mol%) and sodium acetate (1 equiv)
in acetic acid under 4.5 atm of hydrogen at 238C for 96 h.
For practical reasons, 4.5 atm hydrogen was employed. The
Ir-catalyzed asymmetric hydrogenation through DKR was
In order to investigate the potential of this second-genera-
tion Ir catalyst, the hydrogenation of N-methyl- and N,N-di-
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Diastereo- and Enantioselective Hydrogenation of a-Amino-b-Keto Ester Hydrochlorides
FULL PAPER
methyl a-amino-b-keto esters 5a and 5b were attempted as
shown in Table 3.
Table 3. Asymmetric hydrogenation of N-methyl- and N,N-dimethyl a-
amino-b-keto esters.
Scheme 4. Possible reaction pathway through ketone and/or enol reduc-
tion.
Entry
Substrate
Catalyst
[mol%]
H2
Time
[h]
Conversion
yield [%][a]
ee
[%]
G
N
1
2
5a
5b
1
3
4.5
100
96
120
99
64
7
60
any complication caused by the deuterium-exchange reac-
tion between the gas and solvent (Table 4).
1
[a] Determined by H NMR spectroscopy analysis.
Table 4. Isotope experiment with the second-generation Ir catalyst.
In stark contrast to the N-nonsubstituted 3a, the hydro-
genation of 5a proceeded diastereoselectively, but afforded
N
ACHTUNGTRENNUNG
almost only the racemic amino acid ester 6a, while 5b
needed extreme reaction conditions, that is, 100 atm hydro-
gen and 120 h, to yield the amino acid ester 6b with a mod-
erate enantioselectivity. These results indicated that the
presence of a nonsubstituted amino group in a substrate is
essential for efficient Ir-catalyzed anti-selective asymmetric
hydrogenation through DKR.
Nonetheless, the results of the above asymmetric hydro-
ACHTUNGTRENNUNGgenACHTUNGTRENNUNGation are noteworthy, not only because the Ir-catalyzed
Entry Substrate Conditions Yield [%] Ratio of deuterio isomers[a]
4a-dd 4a-dh 4a-hd 4a-hh
anti-selective hydrogenations produced results complemen-
tary to those of a Ru-axially chiral phosphine catalyst, but
also because the Ir-catalyzed asymmetric hydrogenation
through DKR has never been reported so far.[18]
1
2
3
3a-d
3a-h
3a-h
H2
CD3CO2D
HD
CH3CO2H
D2
17
8
47
0
26
41
53
0
74
59
0
0
3
0
0
CH3CO2H
Isotope labeling experiments: To elucidate the reaction
mechanism of this unique anti-selective asymmetric hydro-
genation, we carried out isotope labeling experiments. For
this hydrogenation, the substrate a-amino-b-keto ester is as
an equilibrating mixture of keto and enol tautomers through
tautomerism. One simple question to pose is: which tauto-
mer is hydrogenated? As for the Ru-catalyzed asymmetric
hydrogenation by DKR, Noyori and co-workers have unam-
biguously elucidated by isotope labeling experiments that
the syn-selective asymmetric hydrogenation proceeds
through the reduction of a keto tautomer.[3a] We have also
disclosed that the Ru-catalyzed anti-selective asymmetric
hydrogenation can be ascribed to the hydrogenation of an
enol tautomer.[5f] As in Noyoriꢀs experiments, we performed
the Ir-catalyzed asymmetric hydrogenation of the deuterio
substrate 7.
1
[a] Determined by H NMR spectroscopy.
The reaction of the deuterio compound 3a-d with H2
(1 atm) in the presence of sodium acetate in CD3COOD for
3 h at 238C by using the Ir-(S)-MeOBIPHEP-BArF complex
(3 mol%) afforded a 47:53 mixture of 4a-dd and 4a-hd
(17% conversion). Under the same conditions, except for
the use of HD and CH3COOH, compound 3a-h was con-
verted to a 26:74 mixture of 4a-dh and 4a-hh (8% conver-
sion). The hydrogenation of compound 3a-h with D2 in
CH3CO2H gave 4a-dh and 4a-hh in a ratio of 41:59 (3%
conversion). All these results suggested that this cationic Ir-
catalyzed asymmetric hydrogenation by DKR proceeded
through the keto and not the enol form. The unexpected
mixing, that is, the incorporation of a deuterium at the C3
position, could be explained by the H/D exchange process
between a dihydride amino tautomer and a dihydrogen-
monohydride amido tautomer proposed by Dahlenburg and
Gçtz.[11e] The dihydride–amino complex 13 with an acidic
As depicted in Scheme 4, when the reaction of 7 proceeds
through intermediate 8 of the ketone reduction, the deuteri-
um at the C2 position should remain in product 9. On the
other hand, hydrogenation of enol tautomer 10 should give
the deuterium-free amino acid 12 as the major product. All
reactions were stopped after a low conversion to minimize
À
N D bond, a possible intermediate in the Ir-catalyzed hy-
drogenation reaction, equilibrates with the h2-HD–monohy-
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Y. Hamada et al.
dride amido complex 14, which can be converted to the deu-
teride-hydride-amino complex 15. Complex 13 gives the hy-
drogenated product with a hydrogen, but complex 15 gives
one with a deuterium at the C3 position (Scheme 5).
To obtain further insight into the unusual relationship be-
tween the enantioselectivity and hydrogen pressure, the ini-
tial rates were investigated under various pressures
(Figure 1). Up to 10 atm of hydrogen, the initial rate linearly
Scheme 5. Deuterium-exchange mechanism.
Figure 1. Plot of hydrogen pressure against initial rate.
We also performed deuterium-incorporation studies under
various hydrogen pressures. As shown in Table 5, elevation
of H2 pressure up to 30 atm increased H/D incorporation
depended on the hydrogen pressure. At hydrogen pressures
higher than 20 atm, the initial rate remained constant and a
pseudo-zero-order dependency on the hydrogen pressure
was observed. Above 40 atm the initial rate again increased
nonlinearly. These kinetic studies lead us to conclude that
the rate of the Ir-catalyzed hydrogenation at low hydrogen
pressure conditions (<15 atm) is proportional to the concen-
trations of the catalyst, sodium acetate, and hydrogen, which
are involved in the rate-determining step.
Table 5. H/D incorporation ratio at C3 position under various hydrogen
pressures.
Entry[a]
H2 [atm]
4a-dd/4a-hd[a]
1
2
3
4
5
1
10
20
30
100
47:53
64:36
21:79
20:80
19:81
NMR spectroscopy experiments: The cationic Ir complex
17, Ir-cod-(S)-MeO-BIPHEP-BArF, was prepared by mixing
[IrACHTNUGTRENNU(G cod)Cl]2, (S)-MeO-BIPHEP, and NaBArF in CH2Cl2 at
1
[a] Determined by H NMR spectroscopy analysis.
238C for 1 h, and then purified by silica gel column chroma-
tography. The precatalyst structure composed of iridium, cy-
clooctadiene, (S)-MeO-BIPHEP, and BArF was confirmed
by high resolution mass spectroscopy and 1H, 13C, and
31P NMR spectroscopy as shown in Scheme 6.
To elucidate the intermediates in the catalytic cycle of the
second-generation Ir catalyst, we conducted 31P NMR spec-
troscopic experiments on the Ir complexes (Figure 2). The
chemical shift (14.5 ppm) of the prepared Ir-cod-(S)-MeO-
BIPHEP-BArF complex (17) was uninfluenced by the addi-
tion of substrate 3a (100 equiv to the Ir catalyst) and
ratios at the C3 position. Above 30 atm H/D incorporation
ratios at the C3 position were almost constant; this implies
the presence of another reaction pathway, such as via com-
plex 16, derived from the reaction of 15 with a hydrogen
molecule under high hydrogen pressure.[11f]
Kinetics of hydrogenation: To gain insight into the actual
species formed during the Ir-catalyzed asymmetric hydro-
ACHTUNGTRENNUNGgenACHTUNGTRENNUNGation, we initially investigated a nonlinear effect. During
hydrogenation of the a-amino-b-keto ester 3a, the correla-
tion between the ee of (S)-MeO-BIPHEP and that of the
product was carefully examined, and it was concluded that
no nonlinear effects were evident at 1 and 120 atm of hydro-
gen pressure. These results indicate that the obtained enan-
tiomeric excess from this asymmetric hydrogenation through
DKR was not influenced by the aggregation of the chiral Ir
complex.[12]
Next, we performed the initial kinetic studies of the Ir-
catalyzed asymmetric hydrogenation at 1 atm hydrogen. The
reaction was first order with respect to the concentration of
the Ir catalyst and sodium acetate, and independent of the
concentration of substrate.[12]
Scheme 6. Preparation of complex 17.
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Diastereo- and Enantioselective Hydrogenation of a-Amino-b-Keto Ester Hydrochlorides
FULL PAPER
acetate promoted the coordination of substrate 3a to the Ir-
(S)-MeO-BIPHEP-BArF complex.
Our proposed five-membered cyclic structure of the Ir-
(S)-MeO-BIPHEP-substrate-BArF complex was supported
by comparing the chemical shifts in the 31P NMR spectra of
the analogous Ir complexes with other substrates. The com-
plexation of an a-amino ketone with the Ir complex 18 gave
new peaks at À7.4 and À12.3 ppm along with the original
peaks of the Ir complex (À1.8 and À7.8 ppm). When the Ir-
(S)-MeO-BIPHEP-BArF complex (18) was treated with a b-
keto ester, no change was observed with the À1.8 and
À7.8 ppm peaks of the 31P NMR spectrum. These results
support the fact that the amino group in the a-amino-b-keto
ester 3a plays an important role in coordination to the Ir
complex.
Figure 2. 31P NMR spectra of Ir complexes.
Proposed catalytic cycle: Based on the kinetics, NMR spec-
troscopy, and isotope labeling experiments, the plausible cat-
alytic cycles of the asymmetric hydrogenation by using the
second-generation Ir catalyst under low-pressure conditions
are illustrated in Scheme 8. The cationic Ir catalyst 17 is
formed during the preparation step of the catalyst. The hy-
drogenation of 17 then produces the unsaturated Ir catalyst
18 with the reductive elimination of cyclooctadiene, which
coordinates with the substrate through chelation between
the oxygen of the ketone and the nitrogen of the amine
sodium acetate (100 equiv) in CD3COOD under an argon
atmosphere. However, when the resulting mixture was
stirred under hydrogen (1 atm) at 238C for 0.5 h, the release
1
of cyclooctane was detected by H NMR spectroscopy anal-
ysis and two new peaks appeared at 2.7 and À4.7 ppm in the
31P NMR spectrum. These results showed that the complexa-
tion of the Ir complex with 3a occurred after the hydrogena-
tive removal of 1,5-cyclooctadiene as a cyclooctane. The ap-
pearance of new peaks in the 31P NMR spectrum suggested
the formation of an Ir-(S)-MeO-BIPHEP-substrate-BArF
complex.
On the other hand, exposure of the Ir-cod-(S)-MeO-
BIPHEP-BArF complex (17) to hydrogen (1 atm) for 0.5 h
in CD3COOD without the addition of substrate 3a and
sodium acetate produced a species with two peaks at À1.8
and À7.8 ppm in the 31P NMR spectrum. This suggested that
the 1,5-cyclooctadiene on the Ir-cod-(S)-MeO-BIPHEP-
BArF complex was hydrogenated to afford the Ir-(S)-MeO-
BIPHEP-BArF complex (18) as the solvated form
(Scheme 7).
Scheme 7. Hydrogenation of complex 17.
To obtain further information about the observed NMR
signals, substrate 3a and sodium acetate were added to Ir
complex 18. The addition of only substrate 3a (50 equiv for
the Ir complex) produced the appearance of two signals at
2.6 and À4.9 ppm along with the original signals (À1.8 and
À7.8 ppm; Figure 2c). The intensities of these new signals
were enhanced by the presence of both 3a and sodium ace-
tate (Figure 2d). This means that the presence of sodium
Scheme 8. Plausible catalytic cycle for the anti-selective asymmetric hy-
drogenation by using the second-generation Ir catalyst
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Y. Hamada et al.
out in oven-dried glassware and stirred magnetically unless otherwise
noted.
function, to produce the five-membered intermediate 19.
The oxidative addition of hydrogen to the intermediate gen-
erates the dihydride complex 20, which can easily equili-
brate with the amide complex 21. This equilibration has no
effect on the yield and enantioselectivity. The deprotonation
of 21 with sodium acetate then produces the amide complex
22. This process would be a slow step during this hydrogena-
tion, based on the fact that the reaction has a first-order de-
pendence on sodium acetate. The insertion reaction of the
carbonyl group in 22, the reductive elimination of the amide
complex 23, followed by the ligand-exchange reaction to-
gether with protonation then furnishes the b-hydroxy-a-
amino acid ester 24 and the regeneration of the real catalyst
18.
For asymmetric hydrogenation under high pressure condi-
tions, the participation of two molecules of hydrogen is sug-
gested, because the reaction rate increases remarkably in re-
sponse to increasing hydrogen pressure. It is known that an
iridium complex is oxidatively added with two molecules of
hydrogen to generate the more reactive trivalent iridium
complex.[11f]
Preparation of the cationic Ir catalyst, Ir-cod-(R)-MeO-BIPHEP-BArF
(17):
A mixture of [IrACHTUNTGNRUEGN(cod)Cl]2 (13.2 mg, 0.0197 mmol), (R)-MeO-
BIPHEP (25.2 mg, 0.0433 mmol) and NaBArF (37.0 mg, 0.0394 mmol) in
dry CH2Cl2 (2.0 mL) was stirred for 1 h at room temperature under
argon atmosphere and concentrated in vacuo. The resulting residue was
purified by silica gel column chromatography (CH2Cl2/Et2O, 3:1) to give
17 as a green oil (68.9 mg, 0.0394 mmol, quant). 1H NMR (400 MHz,
C6D6): d=1.05 (m, 2H), 1.35 (m, 2H), 1.71 (m, 2H), 1.91 (m, 2H), 2.76
(s, 6H), 3.75 (m, 2H), 4.11 (m, 2H), 5.84 (d, J=8,4 Hz, 2H), 6.62 (t, J=
8.4 Hz, 1H), 6.63 (t, J=8.4 Hz, 1H), 6.77 (t, J=6.8 Hz, 4H), 6.87~6.99
(m, 8H), 7.13~7.18 (m, 6H), 7.28~7.32 (m, 4H), 7.62 (s, 4H), 8.40 ppm
(s, 8H); 13C NMR (100 MHz, C6D6): d=26.6, 33.2, 53.7, 86.0, 89.3, 111.7,
117.4, 120.5, 122.4, 123.2, 125.9, 127.9, 128.5, 128.6, 129.1, 129.4, 130.5,
130.8, 133.7, 134.7, 157.5, 161.4, 161.9, 162.4, 162.8 ppm; HRMS (FAB,
NBA) calcd for C46H44O2P2Ir: 883.2446 [MÀBArF]+, found: 883.2449.
General procedure for anti-selective asymmetric hydrogenation through
DKR by using the second-generation Ir-catalyst (Ir-(S)-MeO-BIPHEP-
BArF complex: The reaction was carried out in autoclaved glassware. A
mixture of [IrACTHUNRGTNEUNG(cod)Cl]2 (1.5 mg, 0.0022 mmol), (S)-MeO-BIPHEP
(3.3 mg, 0.0057 mmol) and NaBArF·3H2O (4.1 mg, 0.0044 mmol) in
CH2Cl2 (1.0 mL) was stirred for 1 h at 238C under air atmosphere. The
resulting yellow solution was concentrated and dried in vacuo. a-Amino-
b-keto ester hydrochloride (0.435 mmol), sodium acetate (35.7 mg,
0.435 mmol) and acetic acid (2.2 mL) were added to the prepared Ir cata-
lyst. The mixture was stirred at 238C under 4.5 atm of hydrogen for 96 h.
Aqueous HCl (1m in H2O, 3.0 mL) was added and the resulting mixture
was concentrated in vacuo to dryness below 408C. The obtained residue
was dissolved in MeOH and the mixture was concentrated in vacuo. This
cycle was repeated five times. The residue was used for the next step
without any purification.
Conclusion
We have succeeded in the development of the Ir-catalyzed
asymmetric hydrogenation of a-amino-b-keto ester hydro-
chlorides; this proceeds through DKR to produce anti-b-hy-
droxy-a-amino acid esters in a high diastereo- and enantio-
selective manner. Mechanistic studies have revealed that
this unique asymmetric hydrogenation proceeds through re-
duction of the ketone moiety via the five-membered com-
plex involving the chelation between the oxygen of the
ketone and the nitrogen of the amine function. The relation-
ship studies between the hydrogen pressure and stereoselec-
tivity have disclosed two mechanisms dependent on hydro-
gen pressure. Under low hydrogen pressure condition (<
15 atm), the reaction rate proportionally increases with the
hydrogen pressure. However, under high hydrogen pressure,
the reaction rate exponentially accelerates along with the in-
creasing hydrogen pressure, which suggests the participation
of two or more molecules of hydrogen.
A solution of Et3N (0.18 mL, 1.29 mmol) in THF (2 mL) was added drop-
wise to a stirred mixture of the above residue and benzoic anhydride
(108 mg, 0.477 mmol) in THF (6 mL) at 08C. After being stirred at 238C,
overnight, the reaction mixture was diluted with ethyl acetate. The organ-
ic layer was washed with aqueous hydrochloric acid (1m in H2O), saturat-
ed aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by silica gel column chromatog-
raphy to give a-benzoylamino-b-hydroxy ester.
Methyl (2S,3S)-2-benzoylamino-3-(3-chlorophenyl)-3-hydroxypropionate
(2S,3S) (4g): Prepared according to the general procedure: 76% yield,
anti/syn, 99:1, 74% ee; HPLC analysis by using CHIRALCEL OD-H
and n-hexane/iPrOH (85:15, 0.4 mLminÀ1); tR for (2R,3R): 17.6 min, for
(2S,3S): 27.4 min; m.p.: 115–1188C; [a]2D2 =+97.0 (c=1.00 in CHCl3);
1H NMR (400 MHz, CDCl3): d=3.78 (s, 3H), 4.81 (d, J=5.6 Hz, 1H),
5.19 (dd, J=3.2, 6.8 Hz, 1H), 5.36 (br, 1H), 6.95 (d, J=6.4 Hz, 1H),
7.14–7.16 (m, 1H), 7.23–7.29 (m, 3H), 7.44 (t, J=8 Hz), 7.52–7.56 (m,
1H), 7.74–7.76 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=52.9, 59.5,
74.8, 124.1, 126.2, 127.2, 128.2, 128.7, 129.6, 132.3, 132.8, 134.3,
141.3 ppm; IR (KBr) n˜ =3905, 3306, 1742, 1645, 1578, 1534, 1438, 1272,
1025, 790, 691 cmÀ1
; HR-FABMS (NBA) calcd for C17H17ClNO4:
334.0846 [M+H]+; found: 334.0817.
Experimental Section
Methyl (2S,3S)-2-benzoylamino-3-(3-fluorophenyl)-3-hydroxypropionate
(2S,3S) (4h): Prepared according to the general procedure: 67% yield,
anti/syn, 99:1, 67% ee; HPLC analysis by using CHIRALCEL OD-H
and n-hexane/iPrOH (85:15, 0.4 mLminÀ1), tR for (2R,3R): 17.5 min, for
(2S,3S): 28.9 min; m.p.: 132–1338C; [a]2D1 =+106.7 (c=1.00 in CHCl3);
1H NMR (400 MHz, CDCl3): d=3.79 (s, 3H), 4.85 (d, J=5.6 Hz, 1H),
5.21 (dd, J=3.2, 6.8 Hz, 1H), 5.38 (dd, J=3.2, 5.2 Hz, 1H), 6.95–7.04 (m,
4H), 7.26–7.31 (m, 1H), 7.42–7.46 (m, 2H), 7.52–7.56 (m, 1H), 7.74–
7.76 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=52.8, 59.5, 74.6,
113.0 (d, J=22.3 Hz), 114.9 (d, J=20.6 Hz), 121.5 (d, J=3.2 Hz), 127.1,
128.7, 129.8 (d, J=8.2 Hz), 132.3, 132.8, 141.9 (d, J=6.6 Hz), 162.8 (d,
J=245 Hz), 168.7, 169.7 ppm; IR (KBr) n˜ =3420, 3328, 1720, 1646, 1531,
1270, 1023, 792, 693 cmÀ1; HR-FABMS (NBA) calcd for C17H17FNO4:
318.1142 [M+H]+; found: 318.1163.
General: Melting points were measured with a SIBATA NEL-270 melt-
ing point apparatus. Optical rotations were measured on a JASCO DIP-
14-polarimeter and JASCO P-1020 polarimeter with a sodium lamp
(589 nm). Infrared spectra were recorded on a JASCO FT/IR-230 Fourier
transform infrared spectrophotometer. NMR spectra were recorded on a
JEOL JNM-GSX 400a (400 MHz) and JNM ECP400 spectrometers
(400 MHz), unless otherwise indicated. Chemical shifts were recorded in
parts per million (ppm) downfield from tetramethylsilane as an internal
standard. Mass spectra were obtained on a JEOL HX-110A (LRFAB,
LREI) spectrometer. HPLC analyses were carried out on a chiral column
indicated in each experiment. Column chromatography was performed
with silica gel BW-820MH (Fuji Davison, Co.). All reactions were carried
11960
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Chem. Eur. J. 2010, 16, 11954 – 11962

Diastereo- and Enantioselective Hydrogenation of a-Amino-b-Keto Ester Hydrochlorides
FULL PAPER
Methyl
(2S,3S)-2-benzoylamino-3-hydroxy-3-(naphthalen-2-yl)-propio-
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1065; b) Y. Hamada, K. Makino in Asymmetric Synthesis and Appli-
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nate (2S,3S) (4j): Prepared according to the general procedure: 94%
yield, anti/syn, 99:1, 90% ee; HPLC analysis by using CHIRALCEL
OD-H and n-hexane/iPrOH (75:25, 0.5 mLminÀ1), tR for (2R,3R):
15.5 min, for (2S,3S): 19.4 min; m.p.: 134–1368C (ethyl acetate-n-
hexane); [a]2D3 =+107 (c=1.02 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=3.77 (s, 3H), 4.68 (brd, J=6.0 Hz, 1H), 5.32 (dd, J=3.2, 6.8 Hz, 1H),
5.50–5.58 (m, 1H), 6.92 (brd, J=6.8 Hz, 1H), 7.37–7.55 (m, 6H), 7.73–
7.84 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=52.7, 59.6, 75.4,
123.7, 125.1, 126.1, 126.2, 127.2, 128.0, 128.1, 128.7, 132.2, 133.0, 133.1,
133.2, 136.6, 168.7, 169.9 ppm; IR (KBr) n˜ =3333, 1741, 1646, 1523, 1488,
1437, 1363, 1217, 712, 479 cmÀ1; elemental analysis calcd for C21H19NO4:
C 72.19, H 5.48, N 3.94; found: C 72.08, H 5.28, N 3.95.
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Acknowledgements
This work was financially supported in part by a Grant-in-Aid for Scien-
tific Research (B) from the Ministry of Education, Culture, Sports, Sci-
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Received: May 13, 2010
Published online: September 3, 2010
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Chem. Eur. J. 2010, 16, 11954 – 11962