Enantio- and diastereoselective hydrogenation via dynamic kinetic resolution by a cationic iridium complex in the synthesis of β-hydroxy-α-amino acid esters

Article abstract of DOI:10.1021/ol061796v

Anti-selective asymmetric hydrogenation of α-amino-β-keto esters via dynamic kinetic resolution under low hydrogen pressure has been achieved by an easily-handled cationic iridium complex with tetrakis[3,5- bis(trifluoromethyl)phenyl]borate (BARF) as a co

Full text of DOI:10.1021/ol061796v

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4573-4576
Enantio- and Diastereoselective
Hydrogenation via Dynamic Kinetic
Resolution by a Cationic Iridium
Complex in the Synthesis of
â
-Hydroxy-r-amino Acid Esters
Kazuishi Makino, Masamichi Iwasaki, and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity,
Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
hamada@p.chiba-u.ac.jp
Received July 21, 2006
ABSTRACT
Anti-selective asymmetric hydrogenation of
r-amino-â-keto esters via dynamic kinetic resolution under low hydrogen pressure has been
achieved by an easily-handled cationic iridium complex with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF) as a counterion.
Catalytic asymmetric hydrogenation of R-amino-â-keto esters
through dynamic kinetic resolution (DKR) is a powerful
Scheme 1. Asymmetric Hydrogenation via Dynamic Kinetic
methodology for the synthesis of chiral â-hydroxy-R-amino
acids, which are an important class of amino acids broadly
found in nature as components of complex natural products.
It was reported by Noyori and Geneˆt for the first time that
a chiral Ru-BINAP complex catalyzed asymmetric hydro-
genation of R-acylamino-â-keto esters via DKR to gives syn-
â-hydroxy-R-acylamino acid derivatives with high diastereo-
and enantioselectivities (Scheme 1).1,2
Resolution
In the context of our ongoing studies on total synthesis of
cyclodepsipeptides, papuamides, polyoxypeptins, and GE3,3
we have developed for the first time a direct anti-selective
asymmetric hydrogenation of R-amino-â-keto ester hydro-
chloride salts via DKR catalyzed by the Ru, Ir, or Rh
complex.4a,5,6 In particular, DKR in the presence of the Ir
catalyst is a first example, and this hydrogenation can be
carried out in an environmentally benign solvent using
commercially available chiral phosphines. This method is
effective for the synthesis of anti-aromatic â-hydroxy-R-
amino acids. However, high hydrogen pressure (100 atm)
and tedious degas operation by freeze-thaw cycles in the
preparation of the catalyst and the stage prior to hydrogena-
(1) For reviews on dynamic kinetic resolution, see: (a) Noyori, R.;
Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36-56. (b)
Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475-1490. (c) Ohkuma,
T.; Kitamura, M.; Noyori, R. Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: 2000; pp 1-110. (d) Pellissier, H. Tetrahedron
2003, 59, 8291-8327. (e) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005,
44, 3974-4001.
10.1021/ol061796v CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/06/2006

Table 1. Asymmetric Anti-Selective Hydrogenation Using the Ir Catalysta
entry
Ir catalyst (mol %)
ligand
additive
H2 (atm)
time (h)
yieldb (%)
anti/sync
eed (%)
1
2
3
4
5
6
7
8e
9
10
11
12
13
14
3
3
3
3
3
3
3
3
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-MeO-BIPHEP
(S)-BINAP
100
100
100
60
30
4.5
1
3
24
3
71
82
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
78
90
74
80
84
93
92
92
92
92
83
84
91
NaI
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
NaBARF
quant
quant
quant
quant
91
90
quant
98
87
82
87
n.r.
12
24
24
96
96
96
96
96
96
24
24
1
1
4.5
4.5
4.5
4.5
4.5
4.5
0.5
0.5
0.5
3
(S)-Tol-BINAP
(S)-SEGPHOS
(S)-MOP
1
a The reaction was carried out by using the Ir-ligand-NaBARF complex (Ir/ligand/NaBARF ) 1:1.3:1) and NaOAc (1 equiv) in AcOH under hydrogen
1
atmosphere. b Yield in two steps. c Determined by H NMR analysis. d Determined by HPLC analysis. e No freeze-thaw operation.
tion are essential for smooth reaction and make it difficult
to run this hydrogenation in a practical sense. Herein, we
report an anti-selective asymmetric hydrogenation of R-amino-
â-keto esters via DKR under low hydrogen pressure cata-
lyzed by an easy-handled cationic iridium complex with
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF) as a
counterion.
In our effort to expand the utility of the first-generation Ir
catalyst into hydrogenation via DKR under mild reaction
conditions, we examined various additive effects in the
preparation of the catalyst (Table 1). The first-generation
iridium complex prepared from [IrCl(cod)]2, (S)-MeO-
BIPHEP, and sodium iodide previously reported by us5
afforded the anti-â-hydroxy-R-amino ester with 90% ee in
82% yield under high hydrogen pressure (100 atm) (entries
1 and 2). The enantioselectivity could be improved by the
addition of sodium iodide,7 which, however, was found to
retard the reaction. Therefore, we chose the condition
whereby sodium iodide was removed from the first-genera-
tion catalyst as the starting point for reoptimization. So we
examined again various additives, such as phthalimide,8
tetrabutylammonium bromide, potassium fluoride, or silver
trifluoroacetate instead of sodium iodide, but no improvement
was observed in the stereoselectivity, yield, and efficiency
of the catalyst. Recently, Pfaltz’s group9 reported highly
enantioselective hydrogenation of alkenes using the Ir-
PHOX catalyst in combination with the BARF counterion,10
which is known to stabilize the Ir complex and accelerate
(3) (a) Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. Tetrahedron:
Asymmetry 2001, 12, 1353-1358. (b) Reference 2i. (c) Makino, K.; Henmi,
Y.; Hamada, Y. Synlett 2002, 613-615. (d) Makino, K.; Kondoh, A.;
Hamada, Y. Tetrahedron Lett. 2002, 43, 4695-4698. (e) Okamoto, N.; Hara,
O.; Makino, K.; Hamada, Y. J. Org. Chem. 2002, 67, 9210-9215. (f)
Makino, K.; Suzuki, T.; Awane, S.; Hara, O.; Hamada, Y. Tetrahedron
Lett. 2002, 43, 9391-9395. (g) Henmi, Y.; Makino, K.; Yoshitomi, Y.;
Hara, O.; Hamada, Y. Tetrahedron: Asymmetry 2004, 15, 3477-3481. (h)
Suzuki, T.; Makino, K.; Hamada, Y. Peptide Sci. 2003, 2004, 57-60. (i)
Makino, K.; Henmi, Y.; Terasawa, M.; Hara, O.; Hamada, Y. Tetrahedron
Lett. 2005, 46, 555-558. (j) Makino, K.; Nagata, E.; Hamada, Y.
Tetrahedron Lett. 2005, 46, 6827-6830.
(4) For anti-selective asymmetric hydrogenation via DKR using Ru
catalyst, see: (a) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew.
Chem., Int. Ed. 2004, 43, 882-884. (b). Lei, A.; Wu, S.; He, M.;. Zhang,
X. J. Am. Chem. Soc. 2004, 126, 1626-1627. (c) Mordant, C.; Dunkelmann,
P.; Ratovelomanana-Vidal, V.; Geneˆt, J. P. Chem. Commun. 2004, 1296-
1297. (d) Mordant, C.; Dunkelmann, P.; Ratovelomanana-Vidal, V.; Geneˆt,
J.-P. Eur. J. Org. Chem. 2004, 3017-3026.
(2) For syn-selective asymmetric hydrogenation via DKR using Ru
catalyst, see: (a) 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. (b) Geneˆt,
J.-P.; Mallart, S.; Juge, S. French Patent 8911159, 1989. (c) Mashima, K.;
Matsumura, Y.; Kusano, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki,
T.; Akutagawa, S.; Takaya, H. J. Chem. Soc., Chem. Commun. 1991, 609-
610. (d) Geneˆt, J.-P.; Pinel, C.; Mallart, S.; Juge, S. Thorimbert, S.; Laffitte,
J. A. Tetrahedron: Asymmetry 1991, 2, 555-567. (e) Kitamura, M.;
Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152. (f)
Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.; Kumoba-
yashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J.
Org. Chem. 1994, 59, 3064-3076. (g) Geneˆt, J.-P.; de Andrade, M. C. C.;
Ratovelomanana-Vidal, V. Tetrahedron Lett. 1995, 36, 2063-2066. (h)
Coulon, E.; de Andrade, M. C. C.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P.
Tetrahedron Lett. 1998, 39, 6467-6470. (i) Makino, K.; Okamoto, N.; Hara,
O.; Hamada, Y. Tetrahedron: Asymmetry 2001, 12, 1757-1762. (j) Mohar,
B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.; Mioskowski, C.
Chem. Commun. 2001, 2572-2573.
(5) Makino, K.; Hiroki, Y.; Hamada, Y. J. Am. Chem. Soc. 2005, 127,
5784-5785.
(6) Makino, K.; Fujii, T.; Hamada, Y. Tetrahedron: Asymmetry 2006,
17, 481-485.
(7) Additive effect of I-: (a) Spindler, F.; Pugin, B.; Blaser, H.-U. Angew.
Chem., Int. Ed. 1990, 29, 558-559. (b) Morimoto, T.; Nakajima, N.;
Achiwa, K. Chem. Pharm. Bull. 1994, 42, 1951-1953. (c) Morimoto, T.;
Nakajima, N.; Achiwa, K. Synlett 1995, 748-750.
(8) Additive effect of phthalimide: (a) Morimoto, T.; Suzuki, N.; Achiwa,
K. Heterocycles 1996, 43, 2557-2560. (b) Morimoto, T.; Achiwa, K.
Tetrahedron: Asymmetry 1995, 6, 2661-2664.
(9) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed.
1998, 37, 2897-2899. (b) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Ho¨rmann,
E.; McIntyre, S.; Menges, F.; Scho¨nleber, M.; Smidt, S. P.; Wu¨stenberg,
B.; Zimmermann, N. AdV. Synth. Catal. 2003, 345, 33-43.
4574
Org. Lett., Vol. 8, No. 20, 2006

to 93% ee. Furthermore, the reaction progressed even under
1 atm of hydrogen with similar stereoselectivity in excellent
yield. This cationic Ir-(S)-MeO-BIPHEP-BARF complex
can be readily prepared by mixing [IrCl(cod)]2, (S)-MeO-
BIPHEP, and NaBARF in methylene chloride at 23 °C for
1 h under air atmosphere and can be easily handled without
a strictly degassed anhydrous condition (entry 8). The catalyst
loading can be lowered from 3 mol % to 0.5 mol % without
loss of the yield and diastereo- and enantioselectivities
(entries 9 and 10). A survey of several chiral phosphines
revealed that (S)-MeO-BIPHEP was the most efficient in
terms of yield and enantioselectivity (entries 11-14). (S)-
SEGPHOS was somewhat inferior to (S)-MeO-BIPHEP in
terms of the chemical yield and enantioselectivity (entries 6
and 13). Under the optimized reaction conditions, the present
catalytic direct anti-selective asymmetric hydrogenation
under low hydrogen pressure was applied to various aromatic
substrates (Table 2). The hydrogenation was carried out by
using the second-generation Ir-(S)-MeO-BIPHEP-BARF
catalyst prepared from [IrCl(cod)]2 (0.005 equiv), (S)-MeO-
BIPHEP (0.013 equiv), and NaBARF (0.01 equiv) in the
presence of sodium acetate (1 equiv) in acetic acid under
4.5 atm of hydrogen at 23 °C for 96 h. From a practical
point of view, we employed 4.5 atmospheric pressure of
hydrogen. The yields and enantioselectivities were improved
in comparison with our previous data by using the first-
generation Ir catalyst.5 The introduction of an electron-
withdrawing group at the para position on the phenyl ring
resulted in a slight decrease of the enantionselectivity (82%
ee), but the anti selectivity and yield were excellent (entry
7). The cationic Ir complex was also applicable to heteroaro-
matic substrates containing a sulfur or on oxygen atom. In
the case of aliphatic substrates, such as R ) n-Pr and cyclo-
hexyl substrates, at the C4 position, no or low conversion
was observed. Surprisingly, hydrogenation of the highly hin-
dered substrate with a tert-butyl group stereoselectively pro-
ceeded to provide â-hydroxy-R-amino acid ester with the anti/
syn ratio of >99:1 in quantitative yield and 91% ee (entry
Table 2. Asymmetric Anti-Selective Hydrogenation through
DKR Using Ir Catalysta
a The reaction was carried out by using Ir-(S)-MeOBIPHEP-BARF
complex (prepared from [IrCl(cod)]2 (0.005 equiv), (S)-MeOBIPHEP (0.013
equiv), and NaBARF (0.01 equiv) in CH2Cl2 prior to the hydrogenation)
and NaOAc (1 equiv) in AcOH. b Yield over two steps. c Determined by
1H NMR analysis. d Determined by HPLC analysis. e Ir-(S)-MeOBIPHEP-
BARF complex prepared from [IrCl(cod)]2 (0.015 equiv), (S)-MeOBIPHEP
(0.04 equiv), and NaBARF (0.03 equiv).
the reaction rate. Interestingly, when the Ir-PHOX catalyst
was applied to the asymmetric hydrogenation of R-amino-
â-keto ester hydrochloride salts via DKR, no reaction was
observed. However, the addition of NaBARF to the iridium
catalyst prepared from [IrCl(cod)]2 and (S)-MeO-BIPHEP
effected increase of the isolated yield to 100%, but the
diastereo- and enantioselectivity remained at a similar level
with the case of the reaction under high hydrogen pressure
(100 atm) (entry 3). After some trial and error, we were
pleased to find an unusual relationship between hydrogen
pressure and enantioselectivity.11 Thus, lowering hydrogen
pressure enhanced enantioselectivity (entries 4-7). Under
4.5 atm of hydrogen, the enantioselectivity was improved
(10) Nishida, H.; Takada, N.; Yoshimura, M.; Sonoda, T.; Kobayashi,
H. Bull. Chem. Soc. Jpn. 1984, 57, 2600-2604.
(11) Hydrogen pressure effects on enantioselectivity using Ir complex:
Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J. H.;
Burgess, K. J. Am. Chem. Soc. 2003, 125, 113-123.
Figure 1. Dependence of the initial rate on the H2 pressure.
Org. Lett., Vol. 8, No. 20, 2006
4575

11). It is noted that this result is the highest value for the
tert-butyl substrate and is superior to that of the Ru-BINAP-
catalyzed anti-selective hydrogenation developed by us.
To obtain further insight into the relationship between the
enantioselectivity and the hydrogen pressure, the initial rate
kinetics of the (2S,3S)-product and its enantiomer using the
Ir-(S)-Me-OBIPHEP-BARF catalyst were investigated. The
results are summarized in Figure 1. Interestingly, the
relationship between the initial rate of the major (2S,3S)-
product and the increase of hydrogen pressure showed a
linear fashion. On the other hand, in the case of the (2R,3R)-
product, a nonlinear increase of the product with the increase
in the hydrogen pressure was observed. This result indicates
that the hydrogenation of the R-amino-â-keto esters using
the Ir-(S)-Me-OBIPHEP-BARF catalyst proceeds through
two different mechanisms at least.
MeO-BIPHEP-BARF complex, which is readily prepared
from commercially available chiral phosphine and iridium
complex and the resulting catalyst can be easily handled
without care. This hydrogenation can be also used for
efficient asymmetric synthesis of anti-hindered aliphatic
â-hydroxy-R-amino acid esters. It is noted that this method
does not require special instruments and techniques and can
be carried out even by use of the hydrogen-balloon technique.
In addition, this hydrogenation using the Ir-(S)-MeO-
BIPHEP-BARF catalyst can be applied to the synthesis of
various pharmaceutical and natural products. Further inves-
tigation on the scope and mechanism of this unique
hydrogenation is currently in progress.
Supporting Information Available: Experimental pro-
cedures, characterization of the products, and the data for
mechanistic studies. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, we have developed an efficient synthesis
of anti-aromatic â-hydroxy-R-amino acid esters through
direct anti-selective asymmetric hydrogenation via DKR
under very low hydrogen pressure catalyzed by the Ir-(S)-
OL061796V
4576
Org. Lett., Vol. 8, No. 20, 2006