Highly efficient synthesis of chiral β-amino acid derivatives via asymmetric hydrogenation

Article abstract of DOI:10.1021/ol026935x

(Formula Presented) The Rh-TangPhos complex is an efficient hydrogenation catalyst for making chiral β-amino acid derivatives. With the Rh-TangPhos system, high enantioselectivities (up to 99.6%) and turnover numbers have been obtained in the hydrogenatio

Full text of DOI:10.1021/ol026935x

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4159-4161
Highly Efficient Synthesis of Chiral
â-Amino Acid Derivatives via
Asymmetric Hydrogenation
Wenjun Tang and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity, 152 DaVey Laboratory,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received September 19, 2002
ABSTRACT
The Rh−TangPhos complex is an efficient hydrogenation catalyst for making chiral â-amino acid derivatives. With the Rh−TangPhos system,
high enantioselectivities (up to 99.6%) and turnover numbers have been obtained in the hydrogenation of E/Z isomeric mixtures of both
â-alkyl and â-aryl â-(acylamino)acrylates.
The synthesis of chiral â-amino acids has drawn a great deal
of attention due to its importance in biomedical research and
the pharmaceutical industry. Enantiomerically pure â-amino
acids and their derivatives have been used as important
building blocks for the synthesis of â-peptides, â-lactam
antibiotics, and many important drugs.1 Although several
stoichiometric and catalytic methods have been reported for
the synthesis of â-amino acids,2 a practical and efficient
synthesis is still highly desirable. Direct hydrogenation of
3-aminoacrylic acid derivatives represents one of the simplest
and most efficient routes. While good to excellent enanti-
oselectivities have been reported in Ru-3 or Rh-catalyzed4
asymmetric hydrogenation of (E)-â-(acylamino)acrylates
derivatives with the use of chiral bisphosphine ligands such
as BINAP,3 BICP,4 DuPhos,4b,c and BisP*,4a the results of
hydrogenation of (Z)-â-(acylamino)acrylates derivatives are
less than satisfying.5 For example, hydrogenation of (E)-
methyl 3-acetamido-2-butenoate with an Ru-BINAP system
gave 96% ee, while (Z)-methyl 3-acetamido-2-butenoate gave
only 5% ee with the opposite configuration. Since both (Z)-
Perkin Trans. 1 1993, 1375. (k) Juaristi, E.; Escalante, J.; Lamatsch, B.;
Seebach, D. J. Org. Chem. 1992, 57, 2396. (l) Deng, L.; Jacobsen, E. N. J.
Org. Chem. 1992, 57, 4320. (m) Hawkins, J. M.; Fu, G. C. J. Org. Chem.
1986, 51, 2820.
(3) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry
1991, 2, 543.
(4) (a) Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T. Org. Lett.
2001, 3, 1701. (b) Heller, D.; Holz, J.; Drexler, H. J.; Lang, J.; Drauz, K.;
Krimmer, H.-P.; Bo¨rner, A. J. Org. Chem. 2001, 66, 6816. (c) Zhu, G.;
Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907. (d) Furukawa, M.;
Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem. Pharm. Bull. 1979, 27,
2223. (e) Achiwa, K.; Soga, T. Tetrahedron Lett. 1978, 1119.
(5) Lee recently reported a new ligand, BMDPI, which shows good ees
for both (Z)- and (E)-isomeric substrates, see: Lee, S.-G.; Zhang, Y. J.
Org. Lett. 2002, 4, 2429.
(1) (a) Hoekstra, W. J., Ed. The Chemistry and Biology of â-Amino
Acids. Curr. Med. Chem. 1999, 6, 905. (b) EnantioselectiVe Synthesis of
â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997. (c) Guenard,
D.; Guritte-Voegelein, R.; Potier, P. Acc. Chem. Res. 1993, 26, 160.
(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. (h)
Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem. 1994, 59, 5104.
(i) Hattori, K.; Miyata, M.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115,
1151. (j) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc.,
10.1021/ol026935x CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/25/2002

and (E)-isomeric substrates are formed simultaneously in
most synthetic protocols, the development of a new catalytic
system that can work well for both isomeric substrates is
needed. This is especially important in the situation where
the (Z)- and (E)-substrates cannot be easily separated and
only their mixture can be employed as the starting material.
Herein, we disclose a new catalyst, the Rh-TangPhos
system, for hydrogenation of â-aminoacrylic acid derivatives.
High enantioselectivities have been obtained for both (Z)-
and (E)-isomeric substrates with the Rh-TangPhos system.
We have previously demonstrated that the Rh-TangPhos
complexes are highly efficient catalysts for hydrogenation
of dehydroamino acids and E/Z mixtures of enamides.6 The
structure of TangPhos has been confirmed by comparison
with the X-ray structure of its corresponding phosphine sufide
17 (Figure 1). To further expand the utility of this electronic-
[Rh(TangPhos)nbd]SbF6 (nbd ) 3,5-norbornadiene) as the
catalyst precursor. It was found that, with the Rh-TangPhos
catalyst, both (Z)- and (E)-isomers were hydrogenated to
form (R)-methyl 3-acetamidobutanoate. Our study showed
that the solvent had a pronounced influence on both the
reactivity and the enantioselectivity of the reaction (Table
1). While the (E)-isomer showed complete conversions in
most solvents except toluene (entries 1-5), the (Z)-isomer
showed lower reactivities (entries 6-10). THF was found
to be an excellent solvent for the reaction, as complete
conversions were obtained for both (Z)- and (E)-isomers. To
our surprise, excellent enantioselectivities (E ) 99.6% ee;
Z ) 98.5% ee) were obtained for both (Z)- and (E)-isomers
(entries 2 and 7). To the best of our knowledge, these are
among the highest enantioselectiVities to date for hydrogena-
tion of methyl 3-acetamido-2-butenoate, especially for
hydrogenation of the (Z)-isomer (other ligands: Me-DuPhos,
87.8% ee;4b BICP, 86.9% ee;4c BINAP, 5% ee3). A 1:1 E/Z
isomeric mixture of methyl 3-acetamido-2-butenoate was also
subjected to hydrogenation. When THF was used as the
solvent, (R)-methyl 3-acetamidobutanoate was obtained in
100% yield and 99.5% ee (entry 11). The H2 pressure had a
large influence on the enantioselectivity. Higher H2 pressure
deteriorated the ee, which was consistent with Bo¨rner’s
observation.4b When the hydrogenation of the 1:1 E/Z
isomeric mixture was conducted under 80 psi of H2 pressure,
a lower ee (96.5%) was obtained.
Figure 1. Structure of TangPhos and its phosphine sulfide 1.
To test the synthetic utilities of the Rh-TangPhos system
for the synthesis of â-amino acid derivatives, a series of
â-alkyl- and â-aryl-substituted â-(acylamino)acrylates were
tested for hydrogenation. As shown in Table 2, a wide array
of â-alkyl and â-aryl â-amino acid derivatives were obtained
in excellent ees. For hydrogenation of (E)-â-alkyl â-(acyl-
amino)acrylates, extremely high enantioselectivities (98-
100%) have been obtained (entries 1 and 3-6). These results
are comparable with those obtained with Imamoto’s BisP*.4a
Entries 1 and 2 showed another example in which both (Z)-
and (E)-isomeric substrates gave the hydrogenation product
with the same configuration in high ees. These results further
demonstrated that an E/Z mixture of â-(acylamino)acrylates
could be hydrogenated in high ee with the Rh-TangPhos
system.
Asymmetric hydrogenation of â-aryl â-(acylamino)acry-
lates remains a challenging task. Since the (Z)- and (E)-
isomeric substrates are not separable by column chromatog-
raphy, hydrogenation of their E/Z mixtures is crucial for the
synthesis of chiral â-aryl â-amino acid derivatives. While
many â-aryl â-amino acid derivatives have been important
intermediates for drug synthesis,8 little success has been
rich phosphine in asymmetric hydrogenation, the Rh-
TangPhos system was employed for hydrogenation of both
(Z)- and (E)-isomers of methyl 3-acetamido-2-butenoate.
(Table 1) The hydrogenation was conducted at room tem-
perature under 20 psi of H2 in the presence of 0.5 mol %
Table 1. Solvent Effect of Hydrogenation of Methyl
3-Acetamido-2-butenoate with the Rh-TangPhos System
conversion
(%)
ee
entrya
substrate
(E)-2
(E)-2
(E)-2
(E)-2
(E)-2
(Z)-2
(Z)-2
(Z)-2
(Z)-2
(Z)-2
(E)-2/(Z)-2 (1:1)
solvent
(%)
1
2
3
4
5
6
7
8
9
CH3OH
THF
100
100
82
100
100
13
100
55
88
97.0
99.6
98.0
99.4
99.5
83.7
98.5
96.9
98.5
98.5
99.5
toluene
CH2Cl2
EtOAc
CH3OH
THF
toluene
CH2Cl2
EtOAc
THF
(6) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612.
(7) Crystallographic data for the X-ray structure of 1 have been deposited
with Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC-190907. For a graphical structure, see Supporting Information.
(8) (a) Boesch, H.; Cesco-Cancian, S.; Hecker, L. R.; Hoekstra, W. J.;
Justus, M.; Maryanoff, C. A.; Scott, L.; Shah, R. D.; Solms, G.; Sorgi, K.
L.; Stefanick, S. M.; Thurnheer, U.; Villani, F. J., Jr.; Walker, D. G. Org.
Process Res. DeV. 2001, 5, 23. (b) Hoekstra, W. J.; Maryanoff, B. E.;
Damiano, B. P.; Andrade-Gordon, P.; Cohen, J. H.; Costanzo, M. J.;
Haertlein, B. J.; Hecker, L. R.; Hulshizer, B. L.; Kauffman, J. A.; Keane,
P.; McComsey, D. F.; Mitchell, J. A.; Scott, L.; Shah, R. D.; Yabut, S. C.
J. Med. Chem. 1999, 42, 5254. (c) Zhong, H. M.; Cohen, J. H.; Abdel-
10
11
99
100
a Absolute configurations were determined to be R by comparing the
optical rotations with reported values. Reactions were carried out under 20
psi of H2 in solvent at room temperature for 24 h. Substrate/[Rh(Tang-
Phos)nbd]SbF6 ) 200:1. The ees were determined by chiral GC using a
chiralselect 1000 column.
4160
Org. Lett., Vol. 4, No. 23, 2002

(less than 100 turnovers). We found that the Rh-TangPhos
system is very efficient for this type of substrate. As shown
in Table 2 (entries 7-15), good to excellent ees (74.3-
98.5%) have been obtained for a series of â-aryl â-(acyl-
amino)acrylates. While no major electronic effect was
observed for para-substituted â-aryl â-(acylamino)acrylates,
electron-rich substrates gave slightly higher ees (entries 12
and 13). For ortho-substituted â-aryl â-(acylamino)acrylates,
lower enantioselectivities were observed (entries 14 and 15).
To further demonstrate the catalytic efficiency of the Rh-
TangPhos system for hydrogenation of â-(acylamino)-
acrylates, 4l was subjected to hydrogenation in THF under
20 psi of H2 in the presence of 0.1 mol % [Rh(TangPhos)-
nbd]SbF6. The product (S)-5l was obtained in 100% yield
and in 98.5% ee (TON ) 1000), with no deterioration of
enantioselectivity.
In conclusion, an efficient catalytic system for rhodium-
catalyzed asymmetric hydrogenation of â-(acylamino)acry-
lates has been developed. With TangPhos as the chiral ligand,
high enantioselectivities (up to 99.6%) and turnover numbers
have been obtained in the hydrogenation of E/Z isomeric
mixtures of both â-alkyl and â-aryl â-(acylamino)acrylates.
Under these conditions, a variety of chiral â-alkyl and â-aryl
â-amino acids can be efficiently synthesized. Since the
substrates are easy to prepare according to known pro-
cedures,4c,9 the Rh-TangPhos system provides an efficient
and practical way for making chiral â-amino acid derivatives.
Table 2. Hydrogenation of â-Alkyl or â-Aryl
â-(Acylamino)acrylates with the Rh-TangPhos System
entrya
R1
R2
geometryc
eeb (%)
configuration
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me
Me
Me
Et
n-Pr
i-Bu
Et ((E)-4a )
Et ((Z)-4a )
i-Pr (4b)
Me (4c)
Et (4d )
Me (4e)
Me (4f)
Me (4g)
Me (4h )
Me (4i)
E
Z
E
E
E
E
E/Z
E/Z
E/Z
E/Z
E/Z
E/Z
E/Z
E/Z
E/Z
99.5 (5a )
97.3 (5a )
99.3 (5b)
99.6 (5c)
99.6 (5d )
98.5 (5e)
93.8 (5f)
95.0 (5g)
92.3 (5h )
95.1 (5i)
94.0 (5j)
98.5d (5k )
98.5 (5l)
74.3 (5m )
83.1 (5n )
R
R
R
R
R
R
S
S
S
S
S
S
S
S
S
Ph
p-F-Ph
p-Cl-Ph
p-Br-Ph
p-Me-Ph
p-MeO-Ph Me (4k )
p-BnO-Ph Me (4l)
Me (4j)
o-Me-Ph
o-MeO-Ph Me (4n )
Me (4m )
a Reactions were carried out under 20 psi of H2 in THF at room
temperature for 24 h. Substrate/[Rh(TangPhos)nbd]SbF6 ) 200:1. Absolute
configurations were determined by comparing the optical rotations with
reported values. b The ee (%) values were determined by chiral GC using
a Chiralselect 1000 column. c For E/Z ratios of E/Z mixtures, see refs 4c
and 8. d The ee was determined by chiral HPLC using an (s,s)-whelk-01
column.
Acknowledgment. This work was supported by grants
from the National Institutes of Health.
achieved for their syntheses through asymmetric hydrogena-
tion. Previous reports showed only moderate ees with Rh-
DuPhos,4c Rh-BICP,4c and Ru-BINAP3 systems. We
recently developed a Ru-o-BINAPO system for the hydro-
genation of â-aryl â-(acylamino)acrylates.9 Although excel-
lent ees were obtained, the catalytic efficiencies were low
Supporting Information Available: X-ray structure of
1, experimental procedure for hydrogenation, and analytical
data of new substrates and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Magid, A. F.; Kenney, B. D.; Maryanoff, C. A.; Shah, R. D.; Villani, F. J.,
Jr.; Zhang, F.; Zhang, X. Tetrahedron Lett. 1999, 40, 7721. (d) Shankar,
B. B.; Kirkup, M. P.; McCombie, S. W.; Clader, J. W.; Ganguly, A. K.
Tetrahedron Lett. 1996, 37, 4095. (e) Burnett, D. A.; Caplen, M. A.; Davis,
H. R., Jr.; Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 59, 1733.
OL026935X
(9) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem.
Soc. 2002, 124, 4952.
Org. Lett., Vol. 4, No. 23, 2002
4161