Efficient rhodium-catalyzed asymmetric hydrogenation for the synthesis of a new class of N-aryl β-amino acid derivatives

Article abstract of DOI:10.1021/ol0523897

(Chemical Equation Presented) N-Aryl β-amino esters were obtained by asymmetric hydrogenation of a new class of N-aryl β-enamino esters. High conversions and up to 96.3% ee values were achieved with a Rh-TangPhos catalyst.

Full text of DOI:10.1021/ol0523897

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5343-5345
Efficient Rhodium-Catalyzed Asymmetric
Hydrogenation for the Synthesis of a
New Class of N-Aryl
Derivatives
â-Amino Acid
Qian Dai, Weiran Yang, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity, 104 Chemistry Building,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received October 3, 2005
ABSTRACT
N-Aryl
â-amino esters were obtained by asymmetric hydrogenation of a new class of N-aryl â-enamino esters. High conversions and up to
96.3% ee values were achieved with a Rh-TangPhos catalyst.
Enantiomerically pure â-amino acids and their derivatives
are very important chiral building blocks for the synthesis
of â-peptides, â-lactams, and many important biologically
active compounds.1 Among the stoichiometric and catalytic
methods for â-amino acids synthesis, asymmetric hydrogena-
tion is one of the most atom economic and efficient
approaches.2 Most of the current approaches require an acyl
protecting group on the nitrogen of the unsaturated â-amino
acids as a chelating group to achieve high reactivities and
enantioselectivities.3 A major drawback to these approaches
is the difficulty of introducing and removing this protecting
group, which limits their potential applications.4 N-Aryl
â-amino acid derivatives are key structural elements of many
natural products and drug intermediates.5,6 We envision that
the most efficient way to prepare such compounds is to
perform asymmetric hydrogenation of N-aryl â-enamino
esters (Figure 1). For examples, the most efficient way to
introduce a phenyl group on drug CGP-68730A is the
enantioselective hydrogenation of N-aryl â-enamine (Figure
1, route a). It is very difficult to couple two pieces, which
contain phenyl moiety and amine moiety respectively,
together as shown below (Figure 1, route b). Although the
aryl group can be introduced by the transition metal-catalyzed
amination reaction (Figure 1, route d), the more direct method
is to prepare N-aryl â-enamine and perform asymmetric
hydrogenation (Figure 1, route c). To the best of our
(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) Ma, J.
Angew. Chem., Int. Ed. 2003, 42, 4290.
(2) (a) Dumas, F.; Mezrhab, B.; d’Angelo, J.; Riche, C.; Chiaroni, A. J.
Org. Chem. 1996, 61, 2293. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. J.
Am. Chem. Soc. 1998, 120, 431. (c) Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 12. (d) Zhou, Y.; Tang, W.; Wang, W.; Li, W.; Zhang, X.
J. Am. Chem. Soc. 2002, 124, 4952. (e) Tang, W.; Wang, W.; Chi, Y.;
Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509. (f) Tang, W.; Wu, S.;
Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570. (g) You, J.; Drexler, H.;
Zhang, S.; Fischer, C.; Heller, D. Angew. Chem., Int. Ed. 2003, 42, 913.
(3) (a) Halpern, J. Science 1982, 217, 401. (b) Lubell, W. D.; Kitamura,
M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543.
(4) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084.
(5) For previous examples of asymmetric hydrogenation of electron-rich
N-alkyl and N,N-dialkyl enamines, see: (a) Lee, N. E.; Buchwald, S. L. J.
Am. Chem. Soc. 1994, 116, 5985. (b) Tararov, V. I.; Kadyrov, R.; Riermeier,
T. H.; Holz, J.; Bo¨rner, A. Tetrahedron Lett. 2000, 41, 2351.
(6) (a) Pozza, M. F.; Zimmermann, K.; Bischoff, S.; Lingenhohl, K. Prog.
Neuro-Psychopharmacol. Biol. Psychiatry 2000, 24, 647. (b) Zhi, L.; Tegley,
C. M.; Marschke, K. B.; Jones, T. K. Bioorg. Med. Chem. Lett. 1999, 1009.
10.1021/ol0523897 CCC: $30.25
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Published on Web 10/18/2005

To explore the asymmetric hydrogenation reaction, sub-
strate 1a was employed in the screening of reaction condi-
tions with several ligand systems (Figure 3). Surprisingly,
Figure 3. Structure of ligands for asymmetric hydrogenation.
poor enantioselectivity (31.9% ee) was obtained for a
JosiPhos ligand (Table 1, entry 1), which was effective for
Figure 1. Examples of drug candidates and potential substrates
for hydrogenation.
Table 1. Asymmetric Hydrogenation of Substrate 1a
knowledge, only the Merck group reported the synthesis of
â-amino acids via asymmetric hydrogenation of unprotected
enamines.7 There have been no reports on the asymmetric
hydrogenation of N-aryl â-enamine. Herein, we report a
highly enantioselective hydrogenation of N-aryl â-enamino
esters by using rhodium complexes with the electron-
donating bisphosphines developed in our lab (e.g. TangPhos,8a
DuanPhos,8b and Binapine2e).
T, P(H2), conv,b ee,c
entry catalysta solvent °C
atm
%
%
configd
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3d
3d
3d
3d
3d
3e
3f
TFE
50
6
6
6
6
6
6
6
30
95
6
100
67
52
95
77
100
67
83
75
78
58
31.9
76.7
47.9
76.1
94.6
90.9
92.9
77.7
72.9
69.6
50.1
(-)
(+)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(+)
A family of enamines has been prepared from â-keto esters
MeOH 50
MeOH 50
MeOH 50
CH2Cl2 50
TFE
TFE
TFE
TFE
TFE
TFE
and aniline derivatives (Figure 2).9 These compounds are
50
rt
rt
rt
50
50
10
11
6
a 3a: (R)-(S)-JosiPhos/[Rh(cod)Cl]2. 3b: [Rh(S)-C3-TunePhos(cod)]BF4.
3c: [Rh(R,R)-Et-DuPhos(cod)]BF4. 3d: [Rh(S,S,R,R)TangPhos(nbd)]SbF6.
3e: [Rh(RP,SC)DuanPhos(nbd)]SbF6. 3f: [Rh(S)-Binapine(cod)]BF4. b As-
sayed by NMR. c Assayed by chiral HPLC. d Absolute configurations were
not determined.
hydrogenation of unprotected â-enamine.7 While chiral biaryl
bisphosphine (S)-C3-TunePhos11 offered moderate conversion
Figure 2. Structure of substrates 1 and 2.
(8) (a) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612. (b)
Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646.
(9) Brandt, C. A.; Silva, A. C.; Pancote, C. G.; Brito, C. L.; Solveira,
M. Synthesis 2004, 10, 1557.
obtained exclusively as (Z)-isomers according to literature
procedures.9,10
(10) Xie, W.; Fang, J.; Li, J.; Wang, P. G. Tetrahedron 1999, 55, 12929.
(11) (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem.
2000, 65, 6223. (b) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003,
125, 9570.
(7) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang,
F.; Sun, Y.; Armstrong, J. D., III.; Grabowski, E. J. J.; Tillyer, R. D.;
Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918.
5344
Org. Lett., Vol. 7, No. 23, 2005

and enantioselectivity (Table 1, entry 2), higher conversion
was achieved with a more electron-donating trialkyl-bisphos-
phine TangPhos (Table 1, entry 4). (R,R)-Et-DuPhos was
also tested, which gave only 47.9% ee and 52% conversion
(Table 1, entry 3). We also screened several solvents for the
reaction (Table 1, entries 4-6). TFE (2,2,2-trifluoroethanol)
was found to be the optimal solvent for achieving both high
conversions and ee values (Table 1, entry 6). Interestingly,
we also found that there is a strong pressure effect for this
reaction (Table 1, entries 7-9). Increasing reaction pressure
led to the decrease of the enantioselectivities. Compared with
the results achieved by TangPhos (Table 1, entry 6), lower
conversions and ee values were obtained with DuanPhos
(Table 1, entry 10) and Binapine (Table 1, entry 11).
Table 2. Asymmetric Hydrogenation of Substrates 1a-ia and
2a-eb
entry
substrate
conv,c %
ee,d
%
confige
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
100
100
100
100
48
100
83
78
90.9
(-)
(-)
(+)
(+)
(+)
(-)
(-)
Rf
(-)
(-)
(-)
(+)
(-)
(+)
94.8
94.9
89.7
78.9
96.3
96.1
93.8
95.7
92.3
91.1
95.3
89.7
79.3
Using the optimized reaction condition for hydrogenation
of 1a (Table 1, entry 6), we next examined a variety of N-aryl
â-alkyl enamino esters (Table 2, entries 2-9). Over 90% ee
values were obtained for most of the substrates. Increasing
the steric hindrance of the R1 group resulted in a decrease
of ee (Table 2, entry 4). Low conversion and enantioselec-
tivity were observed for substrate 1e, which has an electron-
withdrawing group (Table 2, entry 5). While the reaction
condition (Table 1, entry 6) was good for hydrogenation of
N-aryl â-alkyl enamines, only 90.9% ee and low conversion
(30%) were obtained when N-aryl â-aryl enamine 2b was
used. To address the reactivity issue, we increased the
reaction temperature to 80 °C and complete conversion and
91.1% ee were achieved (Table 2, entry 11). For hydrogena-
tion of N-aryl â-aryl enamines 2 (Table 2, entries 10-14),
introduction of an electron-withdrawing group on the â-aryl
group resulted in higher enantioselectivity (Table 2, entry
12). Substrates with ortho-substituted electron-donating
â-aryl groups led to much lower ee values and reactivities
(Table 2, entries 13 and 14).
88
100
100
100
100
67
a Reaction conditions: 1 mol % of 3d, 50 °C, 6 atm of H2, 18 h.
b Reaction conditions: 1 mol % of 3d, 80 °C, 6 atm of H2, 24 h. c Assayed
by NMR. d Assayed by chiral HPLC. e Absolute configurations were not
determined. f Absolute configuration was determined by comparison of the
sign of the optical rotation with the reported data (see the Supporting
Information).
useful for the preparation of a number of chiral drug
intermediates. Further investigation will be reported in due
course.
Acknowledgment. This work was supported by the
National Institutes of Health.
Supporting Information Available: General procedure
for the synthesis of N-aryl â-enamino esters and their
hydrogenations and physical characterization data for sub-
strates and hydrogenation products. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a highly efficient
method for the synthesis of a new class of N-aryl substituted
â-amino acid derivatives. The reaction is highly substrate
dependent. Introduction of a highly electron-donating trialkyl
phosphine ligand TangPhos is critical for achieving high
conversion and enantioselectivity. This method is potentially
OL0523897
Org. Lett., Vol. 7, No. 23, 2005
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