Rh(I)-catalyzed enantioselective hydrogenation of (E)- and (Z)-beta-(acylamino)acrylates using 1,4-bisphosphine ligands under mild conditions.

Article abstract of DOI:10.1021/ol0261884

[reaction: see text] Rh-Me-BDPMI (1a) complex can be an effective catalyst for the hydrogenations of (E)- and (Z)-beta-(acylamino)acrylates, in which the Z-isomers hydrogenated with the same or even higher ee values than the corresponding E-isomers. The conversion yield and enantioselectivity of E- and Z-isomers were largely dependent on the solvent, and thus, the E-isomers were hydrogenated more effectively in CH(2)Cl(2), whereas the Z-isomers were hydrogenated more effectively in polar MeOH solvent.

Full text of DOI:10.1021/ol0261884

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2429-2431
Rh(I)-Catalyzed Enantioselective
Hydrogenation of (E)- and
(Z)-â-(Acylamino)acrylates Using
1,4-Bisphosphine Ligands under Mild
Conditions
Sang-gi Lee* and Yong Jian Zhang
Life Sciences DiVision, Korea Institute of Science and Technology, P.O. Box 131,
Cheongryang, Seoul 130-650, Korea
sanggi@kist.re.kr
Received May 15, 2002
ABSTRACT
Rh−Me-BDPMI (1a) complex can be an effective catalyst for the hydrogenations of (E)- and (Z)-â-(acylamino)acrylates, in which the Z-isomers
hydrogenated with the same or even higher ee values than the corresponding E-isomers. The conversion yield and enantioselectivity of E-
and Z-isomers were largely dependent on the solvent, and thus, the E-isomers were hydrogenated more effectively in CH Cl2, whereas the
2
Z-isomers were hydrogenated more effectively in polar MeOH solvent.
Optically pure â-amino acids are crucial structural features
of numerous biologically active natural products as well as
important building blocks for the synthesis of â-peptides and
â-lactam antibiotics.1 Several stoichiometric chiral auxilaries
and catalytic methods have been developed to make chiral
â-amino acids.2 Among these methods, catalytic asymmetric
hydrogenation of â-dehydroamino acid derivatives potentially
offers one of the most convenient routes. However, in striking
contrast to R-amino acids, only a few chiral bisphosphine-
metal complexes (i.e., Rh(I) complexes of BPPM,3 BICP,4
and DuPhos4,5 and MiniPhos6 and Ru(II) complex of BI-
NAP7) have been applied as catalysts for the asymmetric
hydrogenation of â-acylamino acrylates. Moreover, the
intrinsic problem consists of the different catalytic behaviors
attributed to Z- and E-isomeric substrates. In general, an
E-isomer hydrogenated with higher enantioselectivity than
the corresponding Z-isomer. For examples, the Ru-BINAP
catalyst hydrogenated the (E)-methyl 3-acetamido-2-butenoate
(E)-2a in 96% ee, while its Z-isomer, (Z)-2a, hydrogenated
in only 5% ee with a different configuration.7 Recently,
Zhang et al. reported an important breakthrough on the
(1) (a) Hoekstra, W. J., Ed. The Chemistry and Biology of â-Amino
Acids. Curr. Med. Chem. 1999, 6, 905. (b) EnantioselectiVe Synthesis of
Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997. (c) Cole, D.
C. Tetrahedron 1994, 50, 9517. (d) Gellman, S. H. Acc. Chem. Res. 1998,
31, 173.
(3) (a) Achiwa, K.; Soga, T. Tetrahedron Lett. 1978, 13, 1119. (b)
Furukawa, M.; Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem. Pharm. Bull.
1979, 27, 2223.
(2) (a) Tang, T.; Ellman, J. A. J. Org. Chem. 1999, 64, 12. (b) Sibi, M.
P.; Shay, H. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615.
(c) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120,
431. (d) Chung, X. X. Tetrahedron: Asymmetry 1997, 8, 5. (e) Dumas, F.;
Mezrhab, B.; d’Angelo, J. J. Org. Chem. 1996, 61, 2293. (f) Davis, F. A.;
Szewczyk, J. M.; Reddy, R. E. J. Org. Chem. 1996, 61, 2222. (g) Enders,
D.; Wahl, H.; Bettray, W. Angew. Chem., Int. Ed. Engl. 1995, 34, 455.
(4) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907.
(5) Heller, D.; Holz, J.; Drexler, H.-J.; Lang, J.; Drauz, K.; Krimmer,
H.-p.; Bo¨rner, A. J. Org. Chem. 2001, 66, 6816
(6) Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T. Org. Lett.
2001, 3, 1701.
(7) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry
1991, 2, 543.
10.1021/ol0261884 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/19/2002

enantioselective hydrogenation of (Z)-alkyl 3-acetamido-2-
butenoates with Rh(I)-BICP complex. In the reduction of
(E)-2a and (Z)-2a, 96% ee and 88% ee, respectively, were
observed in nonpolar toluene solvent.4 It has been also
reported that the rate of hydrogenation of (Z)-2a using
Rh(I)-Me-DuPhos catalyst was dramatically increased in a
polar MeOH solvent.5 Nevertheless, the enantioselectivity
obtained from (Z)-2a (87.8% ee) was still lower than that
obtained from (E)-2a (98.2% ee). Therefore, the development
of a catalytic system exhibiting high enantioselectivity for
(Z)-2, which formed as a major isomer in most synthetic
protocols, is important. Here, we report enantioselective
hydrogenation of ethyl (E)- and (Z)-â-(acylamino)acrylates
2 using Rh(I)-(S,S)-BDPMI 1a, in which the Z-isomers
provided the same or even higher ee values than the
corresponding E-isomers.
Table 1. Rh-BDPMI-Catalyzed Asymmetric Hydrogenation of
(E)- and/or (Z)-2a
p
time convnb % eec
entry
ligand
2
solvent (psi) (h)
(%)
(conf)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
(E)-2a
(E)-2a
(Z)-2a
(Z)-2a
(E)-2a
(E)-2a
(Z)-2a
(Z)-2a
(E)-2a
(E)-2a
(Z)-2a
(Z)-2a
(E)-2a
(E)-2a
(Z)-2a
(Z)-2a
(E)-2a
(E)-2a
(Z)-2a
(Z)-2a
CH2Cl2 14.7 12
100
100
94.6 (R)
93.2 (R)
CH2Cl2 100
CH2Cl2 14.7 12
CH2Cl2 100
4
66.1 94.6 (R)
4
100
95.0 (R)
11.1 94.1 (R)
58.4 92.3 (R)
21.0 97.4 (R)
86.4 95.3 (R)
94.6 91.0 (R)
THF
THF
THF
THF
14.7 12
100
4
14.7 12
100
4
acetone 14.7 12
acetone 100
acetone 14.7 12
acetone 100
4
100
92.6 (R)
57.3 93.4 (R)
100
58.8 94.3 (R)
100
44.4 95.9 (R)
100
100
100
100
100
4
93.2 (R)
IPA
14.7 12
IPA
100
4
92.6 (R)
IPA
14.7 12
IPA
100
4
90.8 (R)
92.3 (R)
91.5 (R)
94.6 (R)
91.3 (R)
MeOH
14.7 12
MeOH 100
MeOH 14.7 12
MeOH 100
(E/ Z)-2a CH2Cl2 14.7 12
(E/ Z)-2a CH2Cl2 100
(E/ Z)-2a MeOH 14.7 12
CH2Cl2 14.7 12
MeOH 14.7 12
CH2Cl2 14.7 12
MeOH 14.7 12
CH2Cl2 14.7 12
4
4
21e 1a
22e 1a
23e 1a
52.0 95.1 (R)
100
4
92.6 (R)
93.4 (R)
87.0 (R)
70.1 (R)
83.7 (R)
33.3 (R)
94.0 (R)
94.0 (R)
93.0 (R)
92.0 (S)
91.9 (S)
91.2 (S)
90.3 (R)
90.1 (R)
89.4 (R)
75.6 (S)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
24
25
26
27
28
29
1b
1b
(E)-2a
(Z)-2a
(S,S)-DIOP (E)-2a
(S,S)-DIOP (Z)-2a
1a
1a
(E)-2b
(Z)-2b
(E/ Z)-2b MeOH
(E)-2c
(Z)-2c
(E/ Z)-2c MeOH
(E)-2d
(Z)-2d
(E/ Z)-2d MeOH
(E/ Z)-2e MeOH
Quite recently, we have demonstrated that Rh(I) complexes
of 1,4-bisphosphine ligands bearing an imidazolidin-2-one
backbone ((S,S)-BDPMI 1a) are highly enantioselective
catalyst for hydrogenation of an isomeric mixture of E- and
Z-enamides.8 Zhang’s Rh(I)-BICP9 and Burk’s Rh(I)-
DuPhos10 catalysts also effectively hydrogenated an isomeric
mixture of Z/E-enamides. Prompted by these results, we have
applied the Rh(I)-BDPMI catalyst to hydrogenation of ethyl
2-acylaminoacrylates 2a-e, which can be conveniently made
according to the reported procedure.3,7 The E- and Z-isomers
of 2a-d can be separated by silica gel column chromatog-
raphy except 2e. To search for the optimal conditions, we
have examined the hydrogenation of ethyl (E)- and (Z)-3-
acetoamido-2-butenoate (2a) using 1 mol % of [Rh((S,S)-
Me-BDPMI (1a)(COD))BF4] as precatalyst in various or-
ganic solvents under 14.7 and 100 psi of H2 pressure (Table
1). We were very pleased to find that the Z-isomer of 2a
was hydrogenated with almost the same or even higher
enantioselectivity than those obtained from the E-isomer of
2a. It is important to note that the conversion yields of (E)-
2a and (Z)-2a were largely dependent on the solvent used
and H2 pressure. For instance, (E)-2a could be hydrogenated
completely using Rh-1a catalyst in CH2Cl2 solvent at both
MeOH
14.7 12
14.7 12
30e 1a
31
32
1a
1a
CH2Cl2 14.7 12
MeOH
14.7 12
14.7 12
33e 1a
34f
35f
1a
1a
CH2Cl2 14.7 12
MeOH
14.7 12
14.7 12
36e,f 1a
37g 1a
40
12
1
a [Rh(COD)2]BF4/ligand/substrate ) 0.01:0.012:1. b Determined by H
NMR. c Determined by chiral GC using CP-Chirasil-Dex CB column.
d Determined by comparing the sign of optical rotations with that of the
reported ones.4 e E/Z ) 1:1. f Determined by chiral HPLC using Daicel
Chiracel OD-H column. g E/Z ) 1:1.7.
14.7 psi (94.6% ee, entry 1) and 100 psi (93.2% ee, entry 2)
of H2 pressures in high enantioselectivities. However, the
corresponding Z-isomer, (Z)-2a, was hydrogenated at 14.7
psi in only 66.1% conversion yield, but the same enantio-
selectivity (94.6% ee, entry 3) with (E)-2a was observed.
As the H2 pressure was increased, both the conversion
(100%) and enantioselectivity (95.0% ee) increased (entry
4). This is the first asymmetric hydrogenation of (Z)-â-
(acylamino)acrylates exhibiting higher enantioselectiVity than
the corresponding E-isomers. In THF solvent, both (E)- and
(Z)-2a were not completely converted at 14.7 and 100 psi
of H2 pressures, but the enantioselectivity of (Z)-2a was still
higher than those obtained from (E)-2a (compare entries 5
vs 7 and 6 vs 8). Similar catalytic activities were observed
in acetone and i-PrOH solvents at 14.7 psi, but the conver-
(8) Lee, S.-g.; Zhang, Y. J.; Song, C. E.; Lee, J. K.; Choi, J. H. Angew.
Chem., Int. Ed. 2002, 41, 847.
(9) (a) Zhu, G.; Cao, P.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1997,
119, 1799. (b) Zhu, G.; Zhang, X. J. Org. Chem. 1998, 63, 9560.
(10) Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996, 118,
5142.
2430
Org. Lett., Vol. 4, No. 14, 2002

sions were completed when the H2 pressure was increased
to 100 psi (entries 9-16). Interestingly, both of (E)-and (Z)-
2a were completely hydrogenated in MeOH at 14.7 psi [(E)-
2a: 92.3% ee, entry 17; (Z)-2a: 94.6% ee, entry 19] and
100 psi (entries 18 and 20) within 12 and 4 h, respectively.
However, a 1:1 mixture of (E)/(Z)-2a was hydrogenated in
CH2Cl2 at 14.7 psi in only 52% of conversion with 95.1%
Rh-BICP catalyst, the sense of enantioselection observed
for all E-isomers is the same as that for Z-isomers.4
Mechanistic studies by Imamoto with Rh-complexes of BisP*
and MiniPhos on the hydrogenation of enamides and (E)-
â-alkyl-â-(acylamino)acrylates indicated that the first hy-
drogen atom is transferred to the R-position yielding
monohydrides with a â-carbon atom bound to rhodium.6,11
Therefore, it could be expected that the sense of enantio-
selection in Rh-catalyzed hydrogenation of â-alkyl-â-(acyl-
amino)acrylates 2a-d is not strongly dependent on their E/Z
geometry.
1
ee (entry 21). In H NMR analysis, the remained starting
material was the Z-isomer, indicating that the E-isomer is
more reactive in CH2Cl2 solvent. When the same reaction
was conducted at 100 psi of H2 pressure, the conversion was
completed, but the ee value decreased to 92.6% (entry 22).
In contrast to the reaction in CH2Cl2, the hydrogenation of
a 1:1 mixture of (E)/(Z)-2a in MeOH proceeded completely
at 14.7 psi with 93.4% ee (entry 23). This ee value
corresponds to the mean value of the individual hydrogena-
tions of (E)-2a and (Z)-2a in MeOH solvent. These results
suggested that the hydrogenation of (E)-2a in CH2Cl2 solvent
became more effective, whereas the hydrogenation of (Z)-
2a in polar MeOH solvent was more effective. Although the
reason for the superiority of MeOH for the hydrogenation
of the Z-isomer is not clear yet, the intramolecular hydrogen
bond between the NH of acylamide and the carbonyl oxygen
of ester in (Z)-â-(acylamino)acrylates, which prevents the
desired bidentate coordination of the substrate to the metal
as pointed by Noyori,7 may be broken down easily in MeOH
solvent and thus allow the olefin to coordinate at the metal
center. We next examined the catalytic activities of Rh(I)-
(S,S)-1b and Rh(I)-(S,S)-DIOP complexes for the hydro-
genation of (E)-2a in CH2Cl2 and (Z)-2a in MeOH solvents
at 14.7 psi of H2 pressure. Both (E)-2a and (Z)-2a were
completely converted to 3a with low to moderate enantio-
selectivities (entries 24-27). The enantioselectivity differ-
ence between the ee values obtained from hydrogenations
of (E)- and (Z)-2a using ligand 1b (entries 24 and 25) is
much smaller than the that obtained using (S,S)-DIOP ligand
(entries 26 and 27). However, like other catalytic systems,
both of these catalysts hydrogenated (E)-2a with higher
enantioselectivities than the (Z)-2a.
In contrast to the â-alkyl-substituted prochiral compounds
2a-d, the â-phenyl-substituted substrate 2e was hydroge-
nated under 40 psi of H2 pressure in only moderate
enantioselectivity (75.6% ee, entry 37). It is notorious that
the enantioselectivities obtained from the hydrogenation of
â-aryl-â-(acylamino)acrylate such as 2e are not higher than
the â-alkyl-â-(acylamino)acrylates. During preparation of this
manuscript, Zhang reported highly effective chiral ortho-
substituted BINAP ligands (o-BINAPO), which showed
extremely high enantioselectivities in Ru-catalyzed asym-
metric hydrogenations of a mixture of (E)- and (Z)-â-aryl-
â-(acylamino)acrylates.12
In summary, we have found that Rh-Me-BDPMI (2a)
complex can be an effective catalyst for the hydrogenations
of (E)- and (Z)-â-(acylamino)acrylates in which the Z-
isomers provided the same or even the higher ee values than
the corresponding E-isomers. The conversion yields of E-
and Z-isomers were largely dependent on the solvent. The
E-isomers were hydrogenated in CH2Cl2 solvent more
effectively, whereas the Z-isomers were hydrogenated in
polar MeOH solvent. The Rh-Me-BDPMI catalyst is
especially effective for hydrogenation of a 1:1 mixture of
(E)/(Z)-â-alkyl-â-(acylamino)acrylates. The highly enantio-
selective hydrogenation provides a useful way to prepare
â-alkyl substituted â-amino acids. Further study with other
enamides, especially â-aryl-â-(acylamino)acrylates using
other transition metal complexes of BDPMI ligands, will be
explored.
A variety of E- and Z-isomers of ethyl â-alkyl-â-
(acylamino)acrylates (2b-d) and a 1:1.7 mixture of (E)/(Z)-
â-phenyl-â-(acylamino)acrylate (2e), which cannot be sepa-
rated by silica gel column chromatography, were hydrogented
using 1 mol % of Rh(I)-Me-BDPMI (1a) complex (entries
28-37). For E-isomers and Z-isomers, CH2Cl2 and MeOH
solvents, respectively, and MeOH solvent for a mixture of
E/Z-isomers have been used. High enantiomeric excesses
have been achieved with both of the (E)- and (Z)-â-alkyl-
â-(acylamino)acrylates 2a-d. Compared to the ee values
obtained from individual hydrogenations of E- and Z-isomers,
slightly decreased enantioselectivity was observed in the
hydrogenation of a 1:1 mixture of E/Z-isomer, which may
be due to the decreased enantioselectivity of E-isomer in
MeOH solvent. It has been also found that the enantio-
selectivity was slightly decreased as the size of â-alkyl
substituent was increased. Moreover, as found by Zhang with
Acknowledgment. This work was supported by a Korea
National Center for Cleaner Production, a National Research
Laboratory Program from MOST, the Center for Molecular
Design and Synthesis, and KIST.
Supporting Information Available: Experimental pro-
cedures for the syntheses of 2a-e and the asymmetric
hydrogenation. GC and HPLC chromatograms to determine
enantiomeric excesses of 3a-e. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0261884
(11) Gridnev, I. D.; Yasutake, M.; Higashi, N.; Imamoto, T. J. Am. Chem.
Soc. 2001, 123, 5268.
(12) Zho, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem.
Soc. 2002, 124, 4952.
Org. Lett., Vol. 4, No. 14, 2002
2431