Practical, catalytic enantioselective hydrogenation to synthesize N -unprotected β-amino esters

Article abstract of DOI:10.1021/op2001035

Practical and simple catalytic enantioselective hydrogenation reactions to synthesize N-unprotected β-amino esters have been developed: (1) asymmetric hydrogenation of N-unprotected β-enamine ester and (2) asymmetric direct reductive amination of β-keto esters using ammonium salts. A Ru-DM-SEGPHOS complex was used as the catalyst in both cases and gave high enantioselectivity, high reactivity, and wide substrate applicability. These protocols greatly reduced reaction time and waste compared to conventional synthetic routes. The direct reductive amination route was demonstrated on a >100 kg scale.

Full text of DOI:10.1021/op2001035

ARTICLE
pubs.acs.org/OPRD
Practical, Catalytic Enantioselective Hydrogenation to Synthesize
N-Unprotected β-Amino Esters
Kazuhiko Matsumura,* Xiaoyong Zhang, Kiyoto Hori, Toshiyuki Murayama, Tadamasa Ohmiya,
Hideo Shimizu, Takao Saito, and Noboru Sayo
Corporate Research and Development Division, Takasago International Corporation, 4-11, Nishiyawata 1-chome, Hiratsuka City,
Kanagawa 254-0073, Japan
ABSTRACT: Practical and simple catalytic enantioselective hydrogenation reactions to synthesize N-unprotected β-amino esters
have been developed: (1) asymmetric hydrogenation of N-unprotected β-enamine ester and (2) asymmetric direct reductive
amination of β-keto esters using ammonium salts. A RuÀDM-SEGPHOS complex was used as the catalyst in both cases and gave
high enantioselectivity, high reactivity, and wide substrate applicability. These protocols greatly reduced reaction time and waste
compared to conventional synthetic routes. The direct reductive amination route was demonstrated on a >100 kg scale.
1. INTRODUCTION
Scheme 1. Strategy to develop a synthetic route to β-amino
ester
β-Amino acids are attracting increasing attention as chiral
1
building blocks, especially in the pharmaceutical industry. Several
methods for the synthesis of this class of compounds have been
2
3
developed. In large-scale synthesis, optical resolution and deriva-
4
tion from chiral pool are commonly employed methods, and
biocatalytic approaches are also becoming promising recently.
5
Catalytic asymmetric hydrogenation is also a potentially powerful
method because it has intrinsic operational efficiency (feasibility of
a high substrate concentration) and is highly atom economical
6
(low waste). However, despitea large numberof reportedstudies,
asymmetric hydrogenation has never been considered a main-
stream technology in this field. The main reason has been the lack
of a direct method for obtaining β-amino acids using hydrogena-
tion, which has required circuitous synthetic routes involving extra
functional group interconversion steps.
The starting material for the synthesis of β-amino acids by
asymmetric hydrogenation are β-keto esters, and conventional
approaches are classified into two types (Scheme 1): (1) after asym-
metric hydrogenation of a β-keto ester, the hydroxyl group is
converted to an amino group (conventional route 1), and (2) a
β-enamide, prepared from the β-keto ester, is subjected to asym-
metric hydrogenation (conventional route 2).
amino group. In most examples, substrates are N-acetylated since
it was strongly believed that acyl group protection of the enamine
was necessary for efficient asymmetric hydrogenation. While this
10
reaction has a long history and has been the subject of many
2,11
In the first step of conventional route 1, an optically active
β-hydroxyl ester is prepared by the asymmetric hydrogenation of
a β-keto ester. The β-hydroxyl group is then converted to an
appropriate leaving group, which is subjected to nucleophilic
studies, there are still some unsolved problems. Asymmetric
hydrogenation of (E)- and (Z)-enamides often results in different
12,13
reaction rates and enantioselectivities.
Thus, the synthesis of
pure (E)- or (Z)-substrate has been necessary to obtain high
enantioselecticity. However, selective synthesis of (E)-enamide
is difficult, and chromatographic separation of the (E)/(Z)
7
8
substitution by a nitrogen source. Methods via azide and β-lactam
intermediates have been reported. Our old synthetic route to
methyl 3-aminobutyrate (1a) via an azide intermediate (5a) is
shown as an example in Scheme 2. In this route, the asymmetric
hydrogenation step itself was near perfect in terms of the
14
mixture has been required. In recent years, this issue has been
addressed by the emergence of catalysts that are highly enantio-
15
selective for both geometric isomers. Nonetheless, when un-
9
enantioselectivity and the catalytic activity, and the yield of each
protected β-amino acids are targeted, there remains the inherent
step was high. However, the route suffered from two disadvan-
tages: it used an azide intermediate that requires special care in
handling, and more importantly, it was too long.
Conventional route 2 is more straightforward because it can
circumvent the stepwise conversion of hydroxyl group to the
Special Issue: Asymmetric Synthesis on Large Scale 2011
Received: April 15, 2011
Published: August 03, 2011
r 2011 American Chemical Society
1130
dx.doi.org/10.1021/op2001035
|Org. Process Res. Dev. 2011, 15, 1130–1137

Organic Process Research & Development
ARTICLE
Scheme 2. Synthetic route via an azide compound
a
Table 1. Asymmetric hydrogenation of 6a
1
a
GC area %
b
c
d
entry
L*
S/C
solvent
AcOH (equiv)
% yield
% ee
1a
6a
9a
10a
1
2
3
4
5
6
7
TolBINAP
TolBINAP
TolBINAP
BINAP
100
100
200
200
200
200
200
MeOH
TFE
none
trace
76
none
92
82
83
82
95
93
76
88
79
87
70
93
0
0
1
0
3
0
8
5
5
2
2
2
1
3
MeOH
MeOH
MeOH
MeOH
MeOH
1
1
1
1
1
90
84
12
9
XylBINAP
SEGPHOS
DM-SEGPHOS
89
77
24
2
93
a
b
Unless otherwise stated, reactions were conducted under 3 MPa of H for 7 h at 80 °C using 6a in solvent (5 mL/g of 6a) containing a Ru complex.
Substrate-to-catalyst molar ratio. Assayed by GC analysis of the N-Boc derivative or HPLC analysis of the acetamide derivative. Assayed by chiral
2
c
d
HPLC analysis of the p-nitrobenzamide derivative.
problem of step counts due to protection and deprotection. In
addition, amide hydrolysis is a troublesome reaction that requires
heating under strongly acidic conditions.
In this report, we present the results of our efforts to develop a
new direct synthetic route leading to β-amino acids. The new
asymmetric direct reductive amination of methyl acetoacetate
was conducted on a >100-kg scale.
15b
We envisioned that a fundamental improvement could be
realized by identifying a new catalyst system that can mediate the
asymmetric hydrogenation of unprotected β-enamine esters.
Furthermore, even more ambitiously, we wished to develop a
direct reductive amination of β-keto esters (Scheme 1). Similar
to our strategy, several direct syntheses of unprotected β-amino
2. RESULTS AND DISCUSSION
2.1. Asymmetric Hydrogenation of Unprotected β-Enam-
ine Esters. We used the structurally simplest methyl 3-amino-
7,16,17
18
16b
acids using asymmetric hydrogenation have been reported.
crotonate (6a) as a starting motif of investigation. The first
attempt conducted under typical conditions for Ru-catalyzed
asymmetric hydrogenation (MeOH as a solvent, initial hydrogen
pressure of 3 MPa, reaction temperature of 80 °C and reaction
time of 7 h) resulted in trace conversion (Table 1, entry 1).
For example, Merck and Solvias that reported the RhÀJosiphos
complexes catalyze the asymmetric hydrogenation of unpro-
tected β-enamine esters and amides with excellent enantioselec-
16a
tivity, which is an important breakthrough.
1
131
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Table 2. Screening of acid additives under the condition in
Table 1, entry 7
they had been reported to be inactive in the asymmetric
hydrogenation of β-keto esters, while they mediate the hydro-
a
9a
genation of unprotected enamines (see section 2.1.). As ex-
pected, the asymmetric hydrogenation of β-keto ester 2a
catalyzed by the Ru diacetate complex RuÀI in the presence of
1
a
GC area %
b
c
entry
additive (pK
a
)
yield (%) % ee 1a 6a 9a 10a
ammonium acetate (NH OAc) as a nitrogen source led to
4
1
2
3
4
5
6
ClCH
2
CO
H (3.77)
H (4.20)
2
H (2.86)
87
41
95
98
93
88
93
94
91
93
93
92
65
0
0
2
6
3
1
3
1
selective formation of the desired product 1a, and β-hydroxyl
ester 3a was scarcely detected (Table 3, entry 1). A considerable
amount of dimer-like byproduct 9a derived from condensation
between 2a and 1a (or 6a) was formed. Fortunately, 9a was inert
to hydrogenation, and gradually dissociated back to 2a and 1a (or
HCO
2
47 11 27
PhCO
2
96
91
93
89
0
0
0
0
0
4
2
7
p-anisic acid (4.47)
AcOH (4.76)
6a) with a prolonged reaction time. As a result, the yield of 1a was
propionic acid (4.88)
ultimately improved (entry 2). The addition of acid was also
found to accelerate the dissociation of 9a, which led to comple-
tion of the reaction in a shorter period of time (entry 3). An
investigation of catalysts revealed that the anionic dimer complex
RuÀIII gave performance similar to that of RuÀI (entry 5) while
the cationic complex RuÀII resulted in low conversion (entry 4).
The catalyst solution RuÀIV that was prepared in situ from
a
Unless otherwise stated, reactions were conducted under 3 MPa of H
2
for 7 h at 80 °C using 6a in methanol (5 mL/g of 6a) containing
Ru(OAc) [(R)-dm-segphos] (S/C = 200). Assayed by GC analysis
b
2
of the N-Boc derivative or HPLC analysis of the acetamide derivative.
c
Assayed by chiral HPLC analysis of the p-nitrobenzoylated
derivative.
[
RuCl (p-cymene)] , (R)-DM-SEGPHOS, and ammonium
2 2
We reasoned that the nucleophilic amine moiety of the substrate
and/or product blocked the coordination site of Ru and func-
acetate in 1,4-dioxane, also gave the acceptable performance
(entry 6).
19
tioned as a catalyst poison. On the basis of this working
hypothesis, we decided to acidify the reaction media to reduce
Optimization of the major reaction parameters (initial hydro-
gen pressure and temperature) is presented in Figure 1. With
regard to hydrogen pressure, higher pressure was essential for a
faster reaction, and 3 MPa was sufficient to reach higher
conversion (Figure 1(a)). With respect to the reaction tempera-
ture, the reaction was accelerated at a higher temperature, but
excessive temperature led to the formation of deaminated
byproducts 10a. The optimal temperature was around 80 °C.
This catalytic reaction has been scaled up without any troubles.
Direct reductive amination of 2a (66.6 kg) under the conditions
in Table 3, entry 6, gave 1a in 86% yield and 95% ee. Subsequent
crystallization as a p-toluenesulfonic acid salt allowed the isola-
20
the nucleophilicity of the amino group. The reaction gave the
corresponding β-amino ester (1a) in 76% yield and 92% ee by
20
the use of 2,2,2-trifluoroethanol (TFE) as an acidic solvent,
although it was accompanied by a small amount of dimer-like
byproduct (9a) and deaminated byproduct (10a) (entry 2).
Independently, Merck and Solvias reported a similar protocol
16a
using a RhÀJosiphos catalyst system. The use of TFE as a
solvent was critical in their system too, which confirmed that the
presence of acid was essential in the hydrogenation of unpro-
tected β-enamine esters.
Although TFE gave excellent results, its use on a manufactur-
ing scale was not desirable because of its relatively high cost.
Since we were convinced that the acidity within the reaction
system was the key, we thought we could replace TFE with more
process-friendly media by using an acidic reagent. The use of
acetic acid (1 equiv) and methanol as an additive and solvent,
tion of 117.2 kg of 1a TsOH in >99% ee (Scheme 3).
3
The substrate scope of the reaction was expanded by careful
choice of the type of ammonium salt. The results of the substrate
scope study are summarized in Table 4. As has been reported
17f
regarding the reductive amination of β-keto amides, the use of
ammonium salicylate (NH SA) was key to achieving a higher yield
4
respectively, gave 1a AcOH salt in 90% yield, albeit with a
in the reductive amination of methyl benzoylacetate (2b) (entry 1
3
17g
1
0% drop in enantioselectivity (entry 3). This drop in ee was
vs 2). The addition of 2 equiv of ammonium salicylate led to a
higher yield (entry 3). The use of ammonium salicylate generally
resulted in a faster reaction with high chemo- and enantioselec-
tivities (entries 4À7). However, when R of the substrate was a
methyl group (2a), the enantioselectivity was reduced (entry 8).
A plausible mechanism for this reaction is depicted in Scheme 4.
In addition to the desired reaction pathway (2f6f1), three other
pathways leading to byproducts can be considered: (1) competitive
reduction of ketone (2f3), (2) formation of dimer-like byproduct
(1 + 2 (or 6)f9), and (3) formation of elimination products
(1f10). Our observations on these side reactions made during
this study are summarized below.
recovered by the proper choice of chiral diphosphine ligands.
Careful ligand screening revealed that DM-SEGPHOS gave 1a in
both high yield (93%) and high enantioselevtivity (93% ee)
(
entries 4À7).
Screening of acid additives identified an ideal range of acidity.
Acids with a wide range of pK values were tested (Table 2). The
a
results showed that a pK range of 4.2 (benzoic acid)À4.8 (acetic
a
acid) was ideal for high yield (>90%) and high enantioselectivity
(
93À94% ee) (entries 3À6). On the other hand, stronger acids
such as chloroacetic acid (pK = 2.86) and formic acid (pK =
a
a
3
.77) led to a decrease in yield (entries 1 and 2). On the basis of a
consideration of selectivity, handling, and price, acetic acid was
still judged to be the best. This success in the asymmetric
hydrogenation of an unprotected β-enamine ester realized a
two-step synthetic route to a β-amino ester from a β-keto ester.
(1) Competitive reduction of ketone (2f3)
In this study, this concern about chemoselectivity was shown
to be unfounded. This is attributed to the reluctance of a Ru
diacetate complex to hydrogenate β-keto esters. Although the
anionic dimer complex RuÀIII which smoothly hydrogenates
2
.2. Direct Reductive Amination. Direct reductive amination
9
of a β-keto ester was a bigger challenge because of competing
hydrogenation of the ketone. In order to obtain the amine in high
yield, the formation of the alcohol needed to be minimized. We
envisioned that Ru diacetate complexes might be useful, since
β-keto esters gave the same results as Ru diacetate RuÀI, its
selectivity can be explained considering the presence of acetate
ions in the reaction system and the likelihood of the in situ
formation of Ru diacetate. The ability of acetate to suppress the
1
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a
Table 3. Initial screening results for the asymmetric reductive amination of 2a
1
a
GC area %
b
c
entry
RuÀL*
time (h)
% yield
% ee
1a
2a + 3a
6a
9a
10a
1
2
RuÀI
RuÀI
RuÀI
RuÀII
RuÀIII
7
10
7
70
92
95
26
92
84
96
95
93
96
96
95
70
87
93
22
81
91
<1
<1
1
3
<1
0
26
7
1
3
0
1
2
3
d
3
0
4
5
6
10
10
9
3
30
1
43
15
5
<1
<1
e
RuÀIV
1
a
Unless otherwise stated, reactions were conducted under 3 MPa of H at 80 °C using 2a in methanol (10 mL/g of 2a) containing a Ru complex
2
b
c
(
2a/catalyst (Ru atom) = 500). Assayed by HPLC analysis of the acetamide derivative. Assayed by chiral HPLC analysis of the p-nitrobenzoylated
d e
derivative. AcOH (2 equiv was added). The mixture of [RuCl
2 2
(p-cymene)] (2a/Ru = 500), (R)-DM-SEGPHOS (1 equiv to Ru), and ammonium
acetate (5 equiv to Ru) in 1,4-dioxane was refluxed for 5 h, and then the resulting mixture was cooled to room temperature and used as a catalyst.
Figure 1. Effects of hydrogen pressure (a) and temperature (b) in the asymmetric reductive amination of 2a. Conditions: 4.3 mmol of 2a in 5 mL of
methanol, RuÀI (S/C = 500), 10 h, reactions were conducted using a 100-mL autoclave. (a) 80 °C. (b) H
2
(3 MPa).
Scheme 3. Scalable synthesis of (R)-1a TsOH via direct asymmetric reductive amination
3
hydrogenation of β-keto ester was supported by a control experi-
ment. When sodium acetate was added to the typical conditions
for the hydrogenation of methyl acetoacetate (2a), the catalytic
activity of RuÀIII decreased drastically (Scheme 5). Presumably,
the anionic dimer complex RuÀIII was converted to the Ru
acetate complex RuÀI in the presence of sodium acetate.
1
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a
Table 4. Asymmetric reductive amination of β-keto esters 2
Scheme 5. Effect of acetate anion on the asymmetric hydro-
genation of methyl acetoacetate (2a)
b
c
d
entry
2
NH
4
X (equiv)
% yield
% ee
config.
1
2
3
4
5
6
7
8
2b
2b
2b
2c
2d
2e
2f
NH
NH
NH
NH
NH
NH
NH
NH
4
OAc (1)
SA (1)
SA (2)
SA (2)
SA (2)
SA (4)
SA (2)
SA (2)
19
69
84
83
89
75
88
99
96
98
98
97
S
S
S
S
S
4
4
4
4
4
4
4
e
f
98
S
97
R
R
g
e
2a
95
83
a
Unless otherwise stated, reactions were conducted under 3 MPa of H
for 7 h at 85 °C using 2 in methanol (5 mL/g of 2) containing RuÀI
2
b
c
(
S/C = 500). Isolated yield of the free amine. Assayed by chiral HPLC
d
e
analysis. Determined by the sign of rotation. Assayed by chiral HPLC
analysis of the p-nitrobenzoylated derivative. Determined by the sign of
rotation of the corresponding HCl salt. Assayed by GC analysis of the
f
g
N-Boc derivative.
Figure 2. PMI (raw materials input per kilogram of (R)-1a TsOH
3
produced) of the conventional azide route (Scheme 2) versus the
reductive amination (Scheme 3).
Scheme 4. Plausible mechanism for the asymmetric reduc-
tive amination of β-keto esters
A prolonged reaction time and high reaction temperature are
the likely causes of the formation of 10 through β-elimination.
The addition of an acid additive is effective to suppress the
formation of 10, although enantioselectivity tends to be slightly
lower (Table 3, entry 3). To obtain 1 in high yield, it is essential
to appropriately control the reaction time, hydrogen pressure,
and reaction temperature.
3. CONCLUDING REMARKS
In this study, ruthenium catalyzed asymmetric hydrogenation
of an N-unprotected β-enamine ester was realized with the
addition of acid. As a further advanced protocol, direct reductive
amination of a β-keto ester catalyzed by Ru diacetate complex
was developed. Especially, the latter made it possible to synthe-
size a β-amino ester in a single step from the corresponding
β-keto ester. This new short-cut method helps to dramatically
reduce the time and waste associated with the reaction. Figure 2
compares the process mass intensity (PMI, defined as the raw
(
2) Formation of dimer-like byproduct (1 + 2 (or 6)f9)
Significant amount of dimer-like byproduct 9 was formed
initially in the reaction, but its concentration gradually decreased
with the progress of the reaction (6f1) as a result of equilibrium
shift. The acidic additive is considered to accelerate the equilib-
rium, and the type of acid is dependent on the substrate. In the
case of methyl acetoacetate (2a), the reaction proceeded with
formation of 9 without acid additive (Table 3, entries 1 and 2).
On the other hand, the addition of 2 equivalents of acetic acid
effectively suppressed the formation of 9. The role of the acid is
presumably the suppression of the dimer formation and/or the
promotion of the dimer dissociation, releasing 1 and 2 (or 6)
22
material input per kilogram of the product) for (R)-1a TsOH
3
for both the conventional azide route (Scheme 2) and the
reductive amination route (Scheme 3). Compared to the azide
route, the reductive amination route reduced PMI by ∼60%,
which indicates that it is a green protocol. Most strikingly, the
amount of aqueous waste produced in the process was reduced to
zero. Moreover, the reductive amination route reduced the total
reaction time by ∼70%, which contributes to operational effi-
ciency. This direct reductive amination is not only applicable to a
wide range of substrates through the appropriate choice of the
ammonium salt but can also be easily scaled up. Asymmetric
(
Table 3, entry 3). In the case of methyl benzoylacetate (2b), the
addition of more acidic ammonium salicylate (pK of salicylic
acid = 2.98) was found to suppress the formation of 9 most
effectively.
a
(3) Formation of elimination products (1f10)
1
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hydrogenation of unprotected β-enamine esters and direct
reaction time of 12 h, the autoclave was cooled and the hydrogen
reductive amination reactions are becoming a new standard for
was carefully vented. The mixture was concentrated (40 °C/
7,16,17
β-amino acid synthesis.
5.3 kPa) to give as the crude 1a AcOH (111 kg). The crude
3
product was assayed to contain 87.2 kg (492 mol, 85.8% assay
yield) of 1a AcOH which was 95.0% ee.
4
. EXPERIMENTAL SECTION
3
To a solution of a crude 1a AcOH in methyl acetate (166 L)
3
General Remarks. All reactions and manipulations were
was added a solution of p-TsOH H
2
O (92.2 kg, 485 mol)
3
conducted under a nitrogen atmosphere unless otherwise noted.
Reagents and solvents were used as received from commercial
suppliers. Hydrogen of 99.99% purity (Showa Denko) was used.
GC analysis was performed on Agilent 6890 instruments. HPLC
analysis was performed on GL Science 7400 instruments. The
content of 1a, 6a, 9a, and 10a were determined GC analysis
in methyl acetate (332 L) dropwise for 60 min at 51À54 °C.
The batch solution was then cooled to 35 °C and seeded with
1a TsOH (15 g). The batch was agitated for 30 min at 30À33 °C
3
and gradually cooled to À12 °C for 16 h. The slurry was then
filtered, and the wet cake was washed with cold methyl acetate
(65 L Â 2) to give (R)-1a TsOH as wet white crystals (133.6 kg,
3
(
column, HP-1, df = 0.25 μm, 0.32 mm i.d. Â 30 m; carrier gas,
98.5% ee).
helium (100 kPa); column temperature, 40 °C, 5 min hold,
The wet cake of (R)-1a TsOH was dissolved in methanol
3
heating to 100 °C at a rate of 5 °C/min, then heating to 250 °C at
(63 L) and methyl acetate (313 L) at 55 °C. The batch solution
a rate of 10 °C/min; detection, FID; t of 1a AcOH, 5.6 min; t
was then cooled to 44 °C and seeded with 1a TsOH (15 g). The
R
3
R
3
of 6a, 10.8 min; t of 9a, 23.1 min, t of 10a, 2.2 and 2.6 min).
batch was agitated for 30 min at 42À45 °C and cooled to 23 °C
for 1.5 h. The slurry was stirred over 12 h at 23 °C, and then
cooled to À12 °C. The slurry was then filtered, and the wet cake
was washed with cold methyl acetate (41.5 L Â 2). The wet cake
R
R
The assay yield of 1a was determined by HPLC analysis of the
corresponding acetamide (column, YMC J’sphere ODS-H80,
4
.6 mm i.d. Â 250 mm, 4 μm particles; eluent, 10 mM K HPO
2
4
in water (pH adjusted to 6.8 with H PO ):methanol = 90:10;
was dried at 40À50 °C in vacuo to give (R)-1a TsOH (white
3 4
3
flow, 1.0 mL/min; column temperature, 35 °C; detection,
crystals, 117.2 kg, 71% yield from 2a, 99.6% ee). Melting point
2
4
220 nm; t of the acetylated 1a, 13.0 min) or GLC analysis of the
114À116 °C. [R]
D
À10.7 (c 1.01, CH
OH), N-Boc-1a:
3
20
R
18
23
corresponding tert-butyl carbamate (column, HP-1, df = 0.25 μm,
.32 mm i.d. Â 30 m; carrier gas, helium (100 kPa); column
temperature, 40 °C, 5 min hold, heating to 100 °C at a rate of
°C/min, then heating to 250 °C at a rate of 10 °C/min;
detection, FID; t of the N-Boc-1a, 20.7 min; t of tetraglyme
[R]
D
positive (CH
3
OH) (lit. for N-Boc-1a: [R]
D
+8.4
1
0
(c 1.04, CH
3
OH), 96% ee (R)). H NMR (500 MHz, DMSO-d
6
)
δ 1.22 (d, J = 6.6 Hz, 3H), 2.30 (s, 3H), 2.59 (dd, J = 7.0,
16.5 Hz, 1H), 2.68 (dd, J = 6.3, 16.5 Hz, 1H), 3.49À3.56
(m, 1H), 3.65 (s, 3H), 7.11À7.13 (m, 2H), 7.49À7.51 (m,
5
R
R
13
(internal standard), 22.9 min). The enantiomeric excess of 1a
2H), 7.77 (br s, 3H). C NMR (126 MHz, DMSO-d
6
) δ 18.1
(CH ), 20.6 (CH ), 38.0 (CH ), 43.6 (CH), 51.6 (CH ), 125.3
3 3 2 3
was determined by HPLC analysis of the p-nitrobenzoylated
derivative (column, CHIRALCEL OD-H, 4.6 mm i.d. Â 250 mm,
(CH), 127.9 (CH), 137.5 (C), 145.6 (C), 170.1 (C). HRMS
+
+
5
μm particles; eluent, hexane:2-propanol = 80:20; flow, 0.5 mL/min;
(ESI ), m/z 118.0859, calcd for [C
5
H
11NO
2
+ H] : 118.0863.
): δ;
1
column temperature, 30 °C; detection, 254 nm; t of the p-
nitrobenzoylated (R)-1a, 19.9 min; t of the p-nitrobenzoylated
Dimer-like Byproduct 9a. H NMR (200 MHz, CDCl
3
R
1.24 (d, J = 6.4 Hz, 3H), 1.96 (s, 3H), 2.40À2.60 (m, 2H), 3.61
R
(
S)-1a, 24.7 min). NMR spectra were measured on a Bruker
(s, 3H), 3.69 (s, 3H), 3.90À4.07 (m, 1H), 4.42 (s, 1H), 8.56 (br
1 13
+
+
AVANCE III 500 ( H: 500 MHz, C: 126 MHz) and Varian
Mercury 200 ( H: 200 MHz). NMR chemical shifts are reported
d, 1H). MS (EI ) m/z 215 ([M] ).
1
General Procedure for the Asymmetric Hydrogenation of
Methyl 3-Aminocrotonate (6a) (Table 1 and 2). To a 100-mL
stainless steel autoclave equipped with a glass inner lining and a
Teflon-coated stirring bar were added Ru catalyst (0.017 mmol)
and methyl 3-aminocrotonate (6a) (400 mg, 3.5 mmol). The
atmosphere was replaced with nitrogen gas, and this was followed
by the addition of methanol (2 mL) and an acid (3.5 mmol).
Hydrogen was initially introduced into the autoclave at a pressure
of 1 MPa before being reduced to 0.1 MPa by carefully releasing
the stop valve. After this procedure was repeated three times,
hydrogen was introduced at 3 MPa and the solution was stirred at
80 °C for 7 h. The solution was cooled to 20 °C and hydrogen gas
was then carefully vented. Assay yield and enantiomeric excess of
1a were determined by GC analysis and HPLC analysis (see
General Remarks).
1
in ppm relative to CHCl (7.26 ppm for H, and 77.0 ppm for
3
1
3
1
13
C) or DMSO (2.50 ppm for H, and 39.5 ppm for C). Optical
rotation was measured on a Jasco P-1020. Melting points were
measured on a Yanaco MP500D. HRMS was recorded on a
Shimadzu LC/MS-IT-TOF.
Methyl (3R)-3-Aminobutyrate p-toluenesulfonate ((R)-1a
3
TsOH). Under a nitrogen atmosphere, a mixture of [RuCl (p-
cymene)] (0.351 kg, 0.574 mol), (R)-DM-SEGPHOS (0.850 kg,
2
2
1
.176 mol), and ammonium acetate (0.442 kg, 5.74 mol) in 1,4-
dioxane (6.7 L) was refluxed for 5 h and then cooled to room
temperature. The resultant mixture was added to a mixture of
methyl acetoacetate (2a, 66.6 kg, 574 mol), ammonium acetate
3
(44.2 kg, 574 mol) and methanol (666 L) in a 1-M stainless steel
autoclave. The air present in the gas inlet tube was removed by
flushing with a stream of hydrogen. Hydrogen was initially
introduced into the autoclave at a pressure of 0.3 MPa, before
being reduced to 0.1 MPa by carefully releasing the stop valve.
After this procedure was repeated three times, the hydrogen
pressure was set to 2.3 MPa and heating was started. After a
reaction temperature of 80 °C was reached, the pressure was
slightly increased to 3.0 MPa. During hydrogenation, the hydro-
gen pressure was maintained within the range of 2.9À3.0 MPa. A
conversion of 92% (determined by GC area%, conversion (%) =
General Procedure for the Asymmetric Reductive Amina-
tion of β-Keto Ester 2bÀ2f (Table 4). To a 100-mL stainless
steel autoclave equipped with a glass inner lining and a Teflon-
coated stirring bar were added Ru(OAc) [(R)-dm-segphos]
2
(RuÀI, 4.7 mg, 0.005 mmol), β-keto ester 2 (2.5 mmol) and
ammonium salicylate (0.778 g, 5.0 mmol). The atmosphere was
replaced with nitrogen gas, and this was followed by the addition
of methanol (2.5 mL). Hydrogen was initially introduced into the
autoclave at a pressure of 1 MPa before being reduced to 0.1 MPa
by carefully releasing the stop valve. After this procedure was
(
1a/(1a + 6a + 9a)) Â 100) was reached after 11 h. After a total
1
135
dx.doi.org/10.1021/op2001035 |Org. Process Res. Dev. 2011, 15, 1130–1137

Organic Process Research & Development
ARTICLE
repeated three times, hydrogen was introduced at 3 MPa, and the
Acids, 2nd ed.; John Wiley & Sons: Hoboken, NJ, 2005. (d) Weiner, B.;
Szyma ꢀn ski, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc.
Rev. 2010, 39, 1656–1691.
solution was stirred at 85 °C for 7 h. The solution was cooled to
2
0 °C, and hydrogen gas was then carefully vented.
(3) For example, see: Cohen, J. H.; Bos, M. E.; Cesco-Cancian, S.;
After evaporation of the solvent, 5% aq Na CO (15 mL) and
2
3
Harris, B. D.; Hortenstine, J. T.; Justus, M.; Marynanoff, C. A.; Mills, J.;
Muller, S.; Roessler, A.; Scott, L.; Sorgi, K. L.; Villani, F. J., Jr.; Webster,
R. R. H.; Weh, C. Org. Process Res. Dev. 2003, 7, 866–872.
ethyl acetate (15 mL) were added to the residue, and the mixture
was stirred for 30 min. The ethyl acetate layer was washed with
water, dried over Na SO , and then evaporated. The residue was
2
4
(4) For example, see: Ikemoto, N.; Tellers, D. M.; Dreher, S. D.; Liu,
purified by silica gel chromatography, eluted with 97:3 ethyl acetateÀ
J.; Huang, A.; Rivera, N. R.; Njolito, E.; Hsiao, Y.; McWilliams, J. C.;
Williams, J. M.; Armstrong, J. D., III; Sun, Y.; Mathre, D. J.; Grabowski,
E. J. J.; Tillyer, R. D. J. Am. Chem. Soc. 2004, 126, 3048–3049.
(5) (a) Arto Liljeblad, A; Kanerva, L. T. Tetrahedron 2006, 62, 5831–
5854. (b) Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.;
Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.;
Huisman, G.. W.; Hughes, G. J. Science 2010, 329, 305–309.
triethylamine to give the pure free β-amino ester 1bÀ1f.
16a
21
D
Methyl (3S)-3-amino-3-phenylpropanote ((S)-1b): [R]
À
2
1.0 (c1.12, CHCl ) (lit. [R] À22.4 (c1.8, CHCl ), 96.1% ee (S)),
3
D
3
9
8% ee, HPLC conditions: column, CHIRALPAK AS-RH, 4.6 mm
i.d. Â 150 mm, 5 μm particles; eluent, 20 mM NH HCO in H O/
4
3
2
CH CN = 80:20; flow, 0.5 mL/min; column temperature, 30 °C;
3
(6) Juaristi, E.; Guti ꢀe rrez-García, V. M.; L ꢀo pez-Ruiz, H. In Enantio-
detection, 220 nm; t of (S)-1b, 10.9 min; t of (R)-1b, 9.3 min.
R
Methyl (3S)-3-amino-3-(4-methoxyphenyl)propanoate ((S)-
R
selective Synthesis of β-Amino Acids, 2nd ed.; Juaristi, E.; Soloshonok, V.,
Eds.; John Wiley & Sons: Hoboken, NJ, 2005; Chapter 7; pp 159À179.
1
6a
21
1
c): [R]
+1.9 (c 2.09, CH OH) (lit. [R] +3.08 (c 2.1,
D
3
D
(7) Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Acc.
CH OH), 95.0% ee (S)), 98% ee, HPLC conditions: column,
3
Chem. Res. 2007, 40, 1385–1393.
CHIRALPAK AS-RH, 4.6 mm i.d. Â 150 mm, 5 μm particles;
(8) Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.;
eluent, 20 mM NH HCO in H O/CH CN = 80:20; flow,
Palucki, M.; Rivera, N.; Steinhuebel, D.; Armstrong, J. D., III; Askin, D.;
4
3
2
3
0
.5 mL/min; column temperature, 30 °C; detection, 220 nm; t
Grabowski, E. J. J. Org. Process Res. Dev. 2005, 9, 634–639.
R
of (S)-1c, 15.2 min; t of (R)-1c, 12.5 min.
(9) (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856–
5858. (b) Ohta, T.; Tonomura, Y.; Nozaki, K.; Takaya, H. Organome-
tallics 1996, 15, 1521–1523. (c) Mashima, K.; Nakamura, T.; Matsuo, Y.;
Tani, K. J. Organomet. Chem. 2000, 607, 51–56.
R
Methyl (3S)-3-amino-3-(4-fluorophenyl)propanoate ((S)-1d):
2
4
2
D
1
20
[
9
R] À18.6 (c 1.00, CHCl ) (lit. [R] +18.5 (c 1.0, CHCl3),
3
D
9% ee (R)), 97% ee, HPLC conditions: column, CHIRALPAK
AS-RH, 4.6 mm i.d. Â 150 mm, 5 μm particles; eluent, 20 mM
(
(
10) Achiwa, K.; Soga, T. Tetrahedron Lett. 1978, 19, 1119–1120.
11) For some recent representative reviews, see: (a) Liu, M.; Sibi,
NH HCO in H O/CH CN = 80:20; flow, 0.5 mL/min;
4
3
2
3
column temperature, 30 °C; detection, 220 nm; t of (S)-1d,
R
M. P. Tetrahedron 2002, 58, 7991–8035. (b) Bruneau, C.; Renaud, J.-L.;
Jerphagnon, T. Coord. Chem. Rev. 2008, 252, 532–544.
(12) Lubbell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asym-
metry 1991, 2, 543–554.
(13) Drexler, H.-J.; You, J.; Zhang, S.; Fischer, C.; Baumann, W.;
Spannenberg, A.; Heller, D. Org. Process Res. Dev. 2003, 7, 355–361.
1
4.5 min; t of (R)-1d, 12.0 min.
R
Methyl (3S)-3-amino-3-(thiophen-2-yl)propanoate ((S)-1e).
2
1
21
[
(
9
R]
À11.6 (c 0.99, CHCl ), HCl salt: [R]
negative
3
D
3
D
1
6d
20
D
CH OH) (lit. for HCl salt: [R]
À7.6 (c 1.0, CH OH),
3
5% ee (S)), 98% ee, HPLC conditions for the p-nitrobenzoy-
(14) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907–6910.
lated derivative: column, SUMICHIRAL 4100R, 4.6 mm i.d. Â
(15) (a) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159–4161. (b) Birch,
2
0
50 mm, 5 μm particles, hexane/2-propanol = 80:20; flow,
.5 mL/min; column temperature, 30 °C; detection, 254 nm;
M.; Challenger, S.; Crochard, J.-P.; Fradet, D.; Jackman, H.; Luan, A.;
Madigan, E.; McDowall, N.; Meldrum, K.; Gordon, C. M.; Widegren,
M.; Yeo, S. Org. Process Res. Dev. 2011, DOI: 10.1021/op2001639.
tR of the p-nitrobenzoylated (S)-1e, 16.2 min; t of the
R
1
p-nitrobenzoylated (R)-1e, 13.9 min. H NMR (500 MHz,
CDCl ) δ 2.72 (d, J = 9.1, 16.0 Hz, 1H), 2.81 (dd, J = 4.4,
(16) Asymmetric hydrogenation of unprotected β-enamine esters, see:
3
(a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang,
F.; Sun, Y.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R. D.; Spindler,
F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918–9919.(b) Matsumura,
K.; Zhang, X.; Saito, T. U.S. Patent 7,015, 348 B2, 2004. (c) Hansen,
K. B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.;
Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.-K.; Spindler,
F.; Malan, C.; Grabowski, E. J. J.; Armstrong, J. D. J. Am. Chem. Soc. 2009,
1
6.0 Hz, 1H), 3.70 (s, 3H), 4.69À4.71 (m, 1H), 6.94À6.96 (m,
13
2
H), 7.19À7.21 (m, 1H). C NMR (126 MHz, CDCl ) δ 44.5
3
(
(
CH ), 48.6 (CH), 51.7 (CH ), 123.0 (CH), 124.0 (CH), 126.7
2 3
+
CH), 149.2 (C), 172.0 (C). HRMS (EI ), m/z 186.0584, calcd
+
for [C H NO S + H] : 186.0583.
8
11
2
16a
21
D
Methyl (3R)-3-amino-4-phenylbutyrate ((R)-1f): [R]
131, 8798–8804. (d) Hou, G.; Li, W.; Ma, M.; Zhang, X.; Zhang, X.
À1.1 (c 1.13, CH OH) (lit. À1.85 (c 0.19, CH OH), 93.3% ee
3
3
J. Am. Chem. Soc. 2010, 132, 12844–12846.(e) Birch, M.; Challenger, S.;
Crochard, J.-P.; Fradet, D.; Jackman, H.; Luan, A.; Madigan, E.; Mathew,
J. S.; McDowall, N.; Meldrum, K.; Gordon, C. M.; Peach, P.; Yeo, S. Org.
Process Res. Dev., submitted for publication.
(17) Asymmetric direct reductive amination of β-keto esters, see:
(a) Matsumura, K.; Saito, T. PCT Patent Appl. WO 2005/028419 A3,
(
R))., 97% ee, HPLC conditions: column, CHIRALPAK AS-RH,
.6 mm i.d. Â 150 mm, 5 μm particles, eluent, 20 mM NH HCO
4
4
3
in H O/CH CN = 85:15; flow, 0.5 mL/min; column tempera-
2
3
ture, 30 °C; detection, 220 nm; t of (S)-1f, 15.4 min; t of (R)-
1
R
R
f, 17.4 min.
2
005. (b) Bunlaksananusorn, T.; Rampf, F. Synlett 2005, 17, 2682–2684. (c)
Huang, X.; O’Brien, E.; Thai, F.; Cooper, G. Org. Process Res. Dev. 2010,
4, 592–599. (d) Mattei, P.; Moine, G.; P €u ntener, K.; Schmid, R. Org. Process
’
AUTHOR INFORMATION
1
Corresponding Author
Res. Dev. 2011, 15, 353–359. (e) Busscher, G. F.; Lefort, L.; Cremers, J. G. O.;
Mottinelli, M.; Wiertz, R. W.; de Lange, B.; Okamura, Y.; Yusa, Y.;
Matsumura, K.; Shimizu, H.; de Vries, J. G.; de Vries, A. H. M. Tetrahedron:
Asymmetry 2010, 21, 1709–1714. Asymmetric direct reductive amination of
β-keto amides, see: (f) Steinhuebel, D.; Sun, Y.; Matsumura, K.; Sayo, N.;
Saito, T. J. Am. Chem. Soc. 2009, 131, 11316–11317.
(18) The configuration of 6a is almost exclusively the (Z)-config-
uration due to the intramolecular hydrogen bond; see: S ꢀa nchez, A. G.;
Valle, A. M. J. Chem Soc., Perkin Trans. 2 1973, 15–20.
*kazuhiko_matsumura@takasago.com
’
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