Rhodium-catalyzed asymmetric hydrogenation through dynamic kinetic resolution: asymmetric synthesis of anti-β-hydroxy-α-amino acid esters

Article abstract of DOI:10.1016/j.tetasy.2006.01.040

Rhodium-catalyzed asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides through dynamic kinetic resolution is described. The hydrogenation proceeds with the catalyst derived from a Rh complex and a chiral ferrocenylphosphine under hydrogen in th

Full text of DOI:10.1016/j.tetasy.2006.01.040

Tetrahedron: Asymmetry 17 (2006) 481–485
Rhodium-catalyzed asymmetric hydrogenation through
dynamic kinetic resolution: asymmetric synthesis of
anti-b-hydroxy-a-amino acid esters
Kazuishi Makino, Takefumi Fujii and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 8 November 2005; revised 23 January 2006; accepted 25 January 2006
Available online 20 March 2006
This paper is dedicated to Dr. Jack Halpern on the occasion of his 80th birthday in recognition of his outstanding
contributions to the areas of transition metal-catalyzed asymmetric hydrogenation
Abstract—Rhodium-catalyzed asymmetric hydrogenation of a-amino-b-keto ester hydrochlorides through dynamic kinetic resolu-
tion is described. The hydrogenation proceeds with the catalyst derived from a Rh complex and a chiral ferrocenylphosphine under
hydrogen in the presence of sodium acetate in acetic acid to afford anti-b-hydroxy-a-amino acid esters with 58–83% ee in a diaste-
reomeric ratio of 92:8–97:3.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1. Introduction
H2
Ru - BINAP complex
R = alkyl
Rhodium (Rh) in combination with chiral phosphines
has played a central role in the area of asymmetric
hydrogenation and the mechanism for Rh-catalyzed
OH
O
O
O
1
R
OR'
NH •HCl
R
OR'
NH •HCl
asymmetric hydrogenation of olefinic substrates has
2
2
2
been elucidated by the pioneering work of Halpern.
H2
We herein report that Rh-chiral phosphines catalyze
asymmetric hydrogenation of ketonic substrates
through dynamic kinetic resolution (DKR) in asymmet-
ric synthesis of anti-b-hydroxy-a-amino acid esters.
DKR is a powerful method for synthesizing one enan-
tiomer from a racemic starting material with a labile ste-
Ir - MeO-BIPHEP complex
R = aryl
Figure 1. anti-Selective hydrogenation through DKR.
at the C4 position. From our efforts to overcome such a
limitation, we found that iridium (Ir) in combination
with axially chiral phosphines also catalyzes anti-selec-
tive asymmetric hydrogenation of a-amino-b-keto ester
hydrochlorides bearing an aromatic ring at the C4 posi-
tion of the substrates with almost complete diastereo-
selectivity and high enantiomeric excess, which is the first
example of DKR using the Ir axially chiral phosphine
3
reocenter. The ruthenium (Ru)-catalyzed DKR was
originally developed by Noyori et al. in the asymmetric
hydrogenation of a-substituted b-keto esters, in which
they disclosed an efficient synthesis of syn-b-hydroxy-
4
a-amino acid esters from a-acetoamido-b-keto esters.
As depicted in Figure 1, we have recently demonstrated
for the first time that the Ru-BINAP catalyst catalyzes
anti-selective asymmetric hydrogenation of a-amino-b-
keto ester hydrochlorides in the synthesis of anti-b-
hydroxy-a-amino acid esters with high diastereoselec-
6
catalyst. Over the course of the catalyst screening in
our DKR study, we recognized that Rh, in combination
with chiral phosphines, is a potential catalyst for this
anti-selective asymmetric hydrogenation. Prior to our
investigation, two groups have examined the Rh-cata-
lyzed DKR approach, which remains at the stage of
preliminary studies for low conversion and/or poor
5
tivities and enantiomeric excesses. This hydrogenation,
however, was limited to the substrates with alkyl groups
*
Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@
p.chiba-u.ac.jp
7
enantio- and diastereoselectivities.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.040

482
K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 481–485
2
. Results and discussion
yield, and the enantiomeric excess decreased remarkably
entry 4). Interestingly, the presence of a chloride ion
(
We first investigated the effects of several catalyst
precursors and chiral phosphines using methyl benzoyl-
glycinate hydrochloride 1 as shown in Table 1. The
catalyst was prepared prior to the hydrogenation by
mixing the catalyst precursor and chiral phosphine
proved to be essential for a satisfactory enantiomeric
excess (entry 5). After some trial and error, we found
that, surprisingly, the chemical yield is time dependent.
A reaction time of 30 min was found to be enough for
this hydrogenation and the chemical yield and enantio-
meric excess were maximized to 82% yield and 83% ee
8
(
1
1.3 equiv/Rh) in methylene chloride at 23 ꢁC for
1
0
0 min and, after concentration in vacuo, was used with-
(entry 7). These results indicate that the hydrogenation
is extremely rapid and that the product might decom-
pose under the hydrogenation conditions. The pressure
of hydrogen had no effect on the enantiomeric excess
but affected the chemical yield (entries 9 and 10). Longer
reaction times under moderate hydrogen pressure
(5 atm) caused decomposition of the substrates and no
effect on the chemical yield (entry 10). The low loading
(0.3 mol %) of the catalyst was fruitless and gave only
24% yield of the product (entry 11). Using the optimized
conditions, we carried out the asymmetric hydrogena-
tion of several aromatic substrates as shown in Table
3. As can be seen from the results in Table 3, the reac-
tion time for giving the maximized yield proved to vary
for each substrate. Although the yields are moderate,
the enantiomeric excess and diastereoselectivities are
satisfactory. It should be noted that this asymmetric
hydrogenation using the Rh-ferrocenylphosphine is not
only the first practically successful example of rho-
dium-catalyzed dynamic kinetic resolution but also
demonstrates new potential of rhodium-catalyzed asym-
metric synthesis.
out any purification. The hydrogenation of 1 was carried
out using 3 mol % of the catalyst under 50 atm of hydro-
gen in the presence of sodium acetate (1 equiv) in acetic
acid at 23 ꢁC for 12 h. The solvent and additive were
chosen according to the case of the iridium-catalyzed
6
DKR developed. The enantiomeric purity and diaste-
reomeric ratio of the product were determined after con-
version to the N-tert-butoxycarbonyl derivative 2. The
use of the neutral and cationic Rh-catalyst from (S)-
MeO-BIPHEP 3 proved disappointing in both yields
and enantiomeric excesses (entries 1 and 2). Chiral ferro-
9
cenylphosphines 4 and 5 developed by Togni were
superior to axially chiral phosphines in this asymmetric
hydrogenation (entries 3–5). There was a slight improve-
ment in the chemical yield when the cationic rhodium
complex, [Rh(nbd) ]BF , was used as the catalyst pre-
2
4
cursor (entries 3 and 4). In particular, the cationic Rh-
t
catalyst from [Rh(nbd) ]BF and (R,S)-PPF-P Bu 4
2
4
2
afforded anti-b-hydroxy-a-amino acid ester 2 in 70%
yield with 75% ee and diastereomeric ratio of 94:6 (entry
4
). The bulkier substituent at the phosphorus of the
ligand affected the enantioselectivity (entries 4 and 5).
Next, using the catalyst from [Rh(nbd) ]BF and 4, we
We next investigated the reaction mechanism of this
unique rhodium-catalyzed hydrogenation. Generally,
rhodium-catalyzed hydrogenation proceeds through a
dihydride mechanism, which differs from a mono-
hydride mechanism of ruthenium-catalyzed hydrogena-
tion. Therefore, it was anticipated that the mechanism
2
4
carried out further optimization as shown in Table 2.
The substrate concentration tended to vary the chemical
yield but not the enantioselectivity (entries 1–3). When
the hydrogenation was performed using the toluenesulf-
onic acid salt as the substrate instead of 1, the chemical
a
Table 1. anti-Selective asymmetric hydrogenation catalyzed by Rh-chiral phosphines
1
.
Rh-Ligand complex
H2 (50 atm)
O
O
OH O
AcONa, AcOH
Ph
OMe
Ph
OMe
NHBoc
NH •HCl
2. (Boc) O, NaHCO3
2
2
1
1,4-dioxane, H2O
2
b
c
d
Entry
Rh precursor
[Rh(cod)Cl]
[Rh(cod) ]BF
[Rh(nbd)Cl]
Ligand
anti:syn
Yield (%)
ee (%)
1
2
3
4
5
2
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(R,S)-PPF-P Bu
(R,S)-PPF-P Bu
>90:10
>90:10
>90:10
>90:10
>90:10
26
8
58
70
70
5
48
74
75
5
2
4
t
2
2
t
[Rh(nbd)
[Rh(nbd)
2
]BF
]BF
4
2
2
4
2
(R,S)-PPF-PCy ÆEtOH
a
The hydrogenation was carried out by using Rh-phosphine (prepared from Rh precursor (3 mol %) and ligand (4 mol %) prior to the hydroge-
nation) and sodium acetate (1 equiv) in acetic acid at 23 ꢁC for 12 h.
Determined by H NMR spectra of the reaction mixture.
Isolated yield in two steps.
Determined by HPLC analysis.
b
c
1
d
t
-Bu
cHex
cHex
Ph
Ph
P
P
MeO
MeO
PPh2
PPh2
P
t-Bu
P
Fe
4
Fe
5
H CH3
H CH3
EtOH
Ph
Ph
•
3
t
(
S
)-MeO-BIPHEP
(R
,
S
)-PPF-P Bu2
(R,S)-PPF-PCy2•EtOH

K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 481–485
483
a
Table 2. Effects of hydrogen pressure and reaction time
t
1
. Rh-(R,S)-PPF-P Bu complex
2
O
O
OH O
H2
AcONa , AcOH
Ph
OMe
Ph
OMe
NH2•HCl
NHBz
2.
Bz2O, TEA, THF
2
1
b
c
d
Entry
Concentration (M)
Time
H
2
(atm)
anti:syn
Yield (%)
ee (%)
1
2
3
0.088
0.044
0.022
0.088
0.088
0.088
0.088
0.088
0.088
0.088
0.088
48 h
48 h
48 h
48 h
48 h
1 h
30 min
10 min
10 min
1 h
50
50
50
50
50
50
50
50
100
5
94:6
93:7
91:9
96:4
94:6
94:6
94:6
96:4
93:7
93:7
94:6
71
55
49
15
44
75
82
26
62
73
83
79
36
73
84
83
77
80
80
82
e
4
5
f
6
7
8
9
1
1
g
0
1
34 (37)
24
h
12 h
50
a
t
The hydrogenation was carried out by using Rh-catalyst (prepared from [Rh(nbd)
2
]BF
4
(3 mol %) and (R,S)-PPF-P Bu
2
(4 mol %) prior to the
hydrogenation) and sodium acetate (1 equiv) in acetic acid at 23 ꢁC.
b
c
d
e
f
1
Determined by H NMR spectra of the reaction mixture.
Isolated yield in two steps.
Value of the anti-3-hydroxyamino acid ester. Determined by HPLC analysis.
The toluenesulfonic acid salt as the substrate instead of 1 was used.
To the conditions in entry 4, tetrabutylammonium chloride was added.
Isolated yield after 48 h.
g
h
The hydrogenation was carried out by using 0.3 mol % of the Rh-catalyst.
t
a
Table 3. anti-Selective asymmetric hydrogenation catalyzed by Rh-(R,S)-PPF-P Bu
2
complex
t
1
. Rh-(
R
,
S
)-PPF-P Bu complex
2
O
O
OH
O
H
(50 atm), 23 °C
2
AcONa (1 eq), AcOH (0.088 M)
R
OR'
NH2•HCl
R
OR'
2. Bz O, TEA, THF
2
NHBz
0
b
c
d
Entry
1
R
R
Time (h)
5
anti:syn
Yield (%)
ee (%)
O
Et
97:3
61
80
O
BnO
Br
2
3
4
5
Me
Me
Et
3
92:8
96:4
97:3
93:7
53
73
66
84
77
79
2.5
1.5
1.5
S
Me
63
58
O
a
t
The hydrogenation was carried out by using Rh-catalyst (prepared from [Rh(nbd)
2
]BF
4
(3 mol %) and (R,S)-PPF-P Bu
2
(4 mol %) prior to the
hydrogenation) and sodium acetate (1 equiv) in acetic acid at 23 ꢁC.
Determined by H NMR analysis.
Isolated yield for two steps.
Determined by HPLC analysis.
b
c
1
d
of the Rh-catalyzed hydrogenation might differ from
that of the Ru-catalyzed hydrogenation. In addition,
the anti-product should also be obtained by hydrogena-
tion of the enol form 7 of the substrates as shown in Fig-
ure 2. In order to elucidate the origin of the extremely
high anti-selectivity, we carried out hydrogenation of a
substrate with a quaternary carbon at the C2 position,
which should disclose whether the reaction proceeds
by hydrogenation of keto form 6 or enol form 7.
Thus, racemic 2-amino-2-methyl-3-oxo-3-phenylpropionic

484
K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 481–485
RhLn
References
O
NH2
1
. For reviews, see: (a) Ohkuma, T.; Kitamura, M.; Noyori,
R. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I.,
Ed.; Wiley-VCH, 2000; pp 1–110; (b) Chi, Y.; Tang, W.;
Zhang, X. In Modern Rhodium-Catalyzed Organic Reac-
tions; Evans, P. A., Ed.; Wiley-VCH, 2005; pp 1–31.
R
R
CO R'
2
O
O
keto form 6
OH
O
R
OR'
NH •HX
R
OR'
NH2•HX
2. (a) Halpern, J. Science 1982, 217, 401–407; (b) Halpern, J.
In Chiral Catalysis; Morrison, J. D., Ed.; Asymmetric
Synthesis; Academic Press, 1985; Vol. 5, pp 41–69.
3. For reviews on dynamic kinetic resolution, see: (a) Noyori,
R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn.
2
RhLn
OH
NH2
CO R'
2
1
1
8
995, 68, 36–56; (b) Ward, R. S. Tetrahedron: Asymmetry
995, 6, 1475–1490; (c) Pellissier, H. Tetrahedron 2003, 59,
291–8327.
enol form 7
Figure 2.
4
. Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.;
Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.;
Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem.
Soc. 1989, 111, 9134–9135.
. (a) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew.
Chem., Int. Ed. 2004, 43, 882–884; (b) Hamada, Y.;
Makino, K. World Patent WO2005/005371 A1, 2005.
. Makino, K.; Hiroki, Y.; Hamada, Y. J. Am. Chem. Soc.
t
Rh-(R,S)-PPF-P Bu2
complex (3 mol%)
H2 (50 atm)
5
O
O
OH
O
Ph
OMe
Ph
OMe
Me NH2
(2R,3S)-9
17%, syn:anti = 73:27
6
Me NH3Cl
AcONa, AcOH
2005, 127, 5784–5785.
8
23°C, 1.5 h
7. (a) Ishizumi, K.; Terashima, T.; Kojima, A. Jpn. Kokai
Tokkyo Koho, Jpn. H02-172956, 1990; (b) Genet, J. P.;
Pinel, C.; Mallart, S.; Juge, S.; Thorimbert, S.; Laffitte, J.
A. Tetrahedron: Asymmetry 1991, 2, 555–567.
then NaHCO , H2O
3
Scheme 1.
8
. Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39,
537–5540.
5
acid methyl ester 8,11 a non-enolizable substrate, was
subjected to asymmetric hydrogenation as shown in
Scheme 1. The reaction also proceeded under the condi-
tions described above to afford after 1.5 h, a mixture of
9. (a) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.;
Landert, H.; Tijiani, A. J. Am. Chem. Soc. 1994, 116,
4
062; (b) Togni, A. Angew. Chem., Int. Ed. 1996, 35, 1475.
0. General procedure: A mixture of [Rh(nbd) ]BF (2.5 mg,
.0066 mmol) and (R,S)-PPF-P Bu (4.8 mg, 0.0088
1
2
4
t
0
2
two corresponding b-hydroxy-a-amino acid esters in
mmol) in CH Cl (1.0 mL) was degassed by three freeze–
1
2
2
1
7% yield with a ratio of 73:27 (judged by the
H
thaw cycles. The mixture was stirred for 10 min at 23 ꢁC
under an argon atmosphere. The resulting yellow solution
was dried over in vacuo. Methyl benzoylglycinate (50 mg,
0.22 mmol), sodium acetate (18 mg, 0.22 mmol), and
acetic acid (2.5 mL) were added to the freshly prepared
yellow Rh-catalyst and the mixture stirred at 23 ꢁC under
hydrogen pressure (50 atm) for 30 min. The reaction
mixture was added to 1 M HCl (3.0 mL) and concentrated
in vacuo to dryness below 40 ꢁC. The resulting residue was
dissolved in methanol and the mixture concentrated in
vacuo. This cycle was repeated five times. The residue was
used in the next step without any purification. Benzoic
anhydride (55 mg, 0.24 mmol) followed by a solution of
triethylamine (92 lL, 0.66 mmol) in THF (3 mL) was
added dropwise to a solution of the above residue in THF
NMR spectrum). The major isomer was found to be
6% ee by HPLC analysis and confirmed as (2R,3S)-
9
1
2
syn by comparison to the literature value, although
the absolute stereochemistry of the minor anti-isomer
remains to be determined. Nevertheless, this result clearly
indicates that the Rh-catalyzed asymmetric hydrogena-
tion of the a-amino-b-keto esters takes place through
reduction of the C@O double bond to produce the b-
hydroxy-a-amino acid esters with anti-stereochemistry.
3. Conclusion
(
3 mL) at 0 ꢁC. After stirring the mixture at 23 ꢁC
In conclusion, we have succeeded in the development of
a rhodium-catalyzed asymmetric hydrogenation of
a-amino-b-keto ester hydrochlorides through dynamic
kinetic resolution in the synthesis of anti-aromatic
b-hydroxy-a-amino acid esters. Further investigations
on the mechanism and optimization of this unique rho-
dium-catalyzed dynamic kinetic resolution are under
way in this laboratory.
overnight, the mixture was quenched with water and
diluted with ethyl acetate. The organic layer was washed
with 1 M HCl, saturated aqueous sodium hydrogen
carbonate, and brine, dried over sodium sulfate, filtered,
and concentrated in vacuo. The residue was purified by
column chromatography (ethyl acetate/n-hexane = 1:2) to
give methyl (2S,3S)-2-benzoylamino-3-hydroxy-3-phenyl-
6
propionate. The diastereomeric ratio was determined by
the H NMR spectrum and the enantiomeric excess was
1
determined by HPLC.
1
1. Compound 8 was prepared from (S)-alanine methyl ester
hydrochloride in four steps: (1) formation of alanine
methyl ester benzophenone imine by exchange reaction
with benzophenone imine, (2) C-benzoylation of the
benzophenone imine with benzoyl chloride in the presence
of potassium tert-butoxide at 23 ꢁC in THF and sub-
sequent treatment with 3 M hydrochloric acid, (3) N-
Acknowledgments
This work was financially supported in part by a Grant-
in-Aid for Scientific Research (B) from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.

K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 481–485
485
protection of the resulting 2-methyl-alanine methyl ester
for purification with di-tert-butyldicarbonate in the pres-
ence of triethylamine in THF, (4) N-deprotection with
Liebigs Ann. Chem. 1981, 2407–2418; (b) Avenoza, A.;
Cativiela, C.; Corzana, F.; Peregrina, J. M.; Zurbano, M.
M. Tetrahedron: Asymmetry 2000, 11, 2195–2204. The
enantiomeric excess of 9 was determined to be 96% ee by
HPLC analysis of the N-Bz derivative using Daicel
Chiralcel AD (0.46 B · 25 cm, n-hexane/2-PrOH = 85:15,
flow 0.5 mL/min): (2S,3R)-isomer, 28.3 min (minor),
(2R,3S)-isomer, 31.9 min (major).
4
M HCl-dioxane.
23
25
D
1
2. (2R,3S)-9: ½aꢀ ¼ ꢁ15 (c 0.25, CHCl
3
) {lit. ½aꢀ ¼ ꢁ10:9
D
1
(
3 3
c 0.44, CHCl )}; H NMR (400 MHz, CDCl ) d 1.21 (d,
J = 6.0 Hz, 3H), 3.77 (s, 3H), 4.90 (s, 3H), 7.30–7.35 (m,
5
H), see (a) Sch o¨ llkopf, U.; Groth, U.; Hartwig, W.