Rhodium-catalyzed enantioselective hydrogenation of β-phthalimide acrylates to synthesis of β2-amino acids

Article abstract of DOI:10.1021/ol0612399

The enantioselective hydrogenation of β-phthalimide acrylates provides the corresponding chiral β²-amino acids in excellent enantiomeric excess catalyzed by Rh-monophosphorus.

Full text of DOI:10.1021/ol0612399

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3359-3362
Rhodium-Catalyzed Enantioselective
Hydrogenation of -Phthalimide
Acrylates to Synthesis of
Acids
â
â
2-Amino
Hanmin Huang, Xiongcai Liu, Jun Deng, Min Qiu, and Zhuo Zheng*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, People’s Republic of China
zhengz@dicp.ac.cn
Received May 21, 2006
ABSTRACT
The enantioselective hydrogenation of
â
-phthalimide acrylates provides the corresponding chiral
â
2-amino acids in excellent enantiomeric
excess catalyzed by Rh monophosphorus.
−
Chiral â2-amino acids (R-substituted â-amino acids) and their
derivatives are critical key structural elements in natural
products and pharmaceuticals.1 For example, compound 1
is a key intermediate in the synthesis of the cryptophycin-
1,2 which was first isolated from terrestrial Nostoc sp. ATCC
53789 by researchers at Merck and found to be very active
against fungi, especially strains of Cryptococcus,3 which
frequently infect immunodeficient persons suffering from
diseases, such as AIDS and cancer.
Michael addition,5 H-atom transfer reaction,6 C-H insertions
of carbenoids reaction,7 and rhodium enolate protonations,8
have been developed to make chiral â2-amino acids, straight-
forward hydrogenation of prochiral dehydro-precursors rep-
resents one of the simplest and efficient routes. However,
For these and other reasons, enantioselective synthesis of
â2-amino acids has attracted extensive interest. Although
several stoichiometric4 and catalytic methods, such as
(1) (a) Nussbaum, F. V.; Spiteller, P. â-Amino Acids in Nature. In
Highlights in Bioorganic Chemistry; Schmuck, C., Wennemers, H., Eds.;
Wiley-VCH: Weinheim, Germany, 2003; p 63. (b) Spiteller, P.; Nussbaum,
F. V. Biosynthesis of â-Amino Acids. In Highlights in Bioorganic
Chemistry; Schmuck, C., Wennemers, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2003; p 90.
Figure 1. Examples of chiral â2-amino acids and cryptophycin-1.
(2) (a) Subbaraju, G. V.; Golakoti, T.; Patterson, G. M. L.; Moore, R.
E. J. Nat. Prod. 1997, 60, 302. (b) Chaganty, S.; Heltzel, C.; Golakoti, T.;
Moore, R. E.; Yoshida, W. Y. J. Nat. Prod. 2004, 67, 1403.
(3) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.; Chartrain,
M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M. J.; Liesch, J. M.; Yudin,
K. J. Ind. Microbiol. 1990, 5, 113.
the only previous documented attempt at this asymmetric
hydrogenation, using Rh and Ru catalysts, gave poor to
moderate enantioselectivity.9 So, the search for an efficient
10.1021/ol0612399 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/28/2006

asymmetric hydrogenation catalytic system for the synthesis
of â2-amino acids is still a challenge. Herein, we report the
first highly enantioselective hydrogenation of â-phthalimide
acrylates for the synthesis of â2-amino acid derivatives using
the Rh-monophosphite catalytic system.
The basic strategy of our method involves asymmetric
hydrogenation of â-acrylates with a phthalimido-protected
â-amino group, which may satisfy the chelation requirement
between the metal and substrate.9a,10 The â-phthalimide
acrylates were readily prepared in good overall yields in three
steps from the commercially available inexpensive aldehydes,
acrylates, and phthalimide.11With these substrates in hand,
asymmetric hydrogenation of many functionalized olefins,12
was applied as catalysts in this hydrogenation reaction. The
particular catalyst was prepared in situ by mixing [Rh(COD)2]-
BF4 and the phosphorus ligands in the solvents. All the
hydrogenation reactions were carried out at room tempera-
ture, under 10 atm pressure of H2.
Some representative results are shown in Table 1. The first
attempt, using Rh/DuPhos as catalyst precursor, afforded the
Table 1. Enantioselective Hydrogenation of â-Phthalimide
Acrylates 2aa
entry
ligand
solvent
conv.%b
ee% (config.)c
1
2
3
4
5
6
7
4
4
5
6
7
8
9g
CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
>99
>99
>99
>99
>99
>99
>99
59.0 (R)
67.9 (R)
57.9 (S)
66.7 (R)
4.9 (R)
89.0 (S)
99.1 (R)
a Unless otherwise stated, reactions were performed on a 0.5 mmol scale
at room temperature for 12 h, P(H2) ) 10 atm, for the bidentate ligands
(4-7): 1 mol % of [Rh(COD)2]BF4 and 1.1 mol % of ligand. For the
monodentate ligands (8, 9): 1 mol % of [Rh(COD)2]BF4 and 2.2 mol % of
ligand. b Determined by GC. c Determined by chiral HPLC, and the absolute
configuration was determined by comparing the sign of specific rotation of
the corresponding amino acid.
Figure 2. Chiral phosphine ligands evaluated in the asymmetric
hydrogenations.
we initiated our hydrogenation reaction studies by screening
several known catalysts. The simple â-phthalimide acrylate
2a was chosen as a model substrate. A diverse array of chiral
phosphine/Rh complexes, which were very effective in
desired product 3a in quantitative conversion with moderate
enantioselectivity (59% ee, entry 1). Unfortunately, all efforts
to improve the enantiomeric excess value with this catalyst
failed. Further examination of a number of other typical
axially chiral and planarly chiral bisphosphine, such as
BINAP, BIPHEP, and Taniaphos, also gave unsatisfactory
enantioselectivity (less than 70%, Table 1, entries 3-5).
These results indicated that bidentate phosphine ligands used
here are not efficient for this reaction. Thus, we next turned
our attention to the use of the monodentate chiral phospho-
rus13 as ligands for this reaction. The result showed that good
enantioselectivity with quantitative conversion was obtained
when Monophos 8 was applied in this reaction. This finding
encouraged us to use our newly created P-O monophosphite
914 as ligands to try this enantioselective hydrogenation
reaction. As shown in entry 7, up to 99.1% ee with
quantitative conversion was obtained when Rh/9g was
employed in this reaction.
(4) For representative examples, see: (a) Evans, D. A.; Urpi, F.; Somers,
T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215. (b)
Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D. J. Org. Chem. 1991,
56, 2553. (c) Juaristi, E.; Quintana, D. Tetrahedron: Asymmetry 1992, 3,
723. (d) Juaristi, E.; Quintana, D.; Balderas, M.; Garc´ıa-Pe´rez, E.
Tetrahedron: Asymmetry 1996, 7, 2233. (e) Seebach, D.; Boog, A.;
Schweizer, W. B. Eur. J. Org. Chem. 1999, 335. (f) Nagula, G.; Huber, V.
J.; Lum, C.; Goodman, B. A. Org. Lett. 2000, 2, 3527. For review, see:
(g) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (h) Juaristi, E.; Lopez-
Ruiz, H. Curr. Med Chem. 1999, 6, 983.
(5) (a) Rimkus, A.; Sewald, N. Org. Lett. 2003, 5, 79. (b) Eilitz, U.;
Lessmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry
2003, 14, 189. (c) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2003, 125, 3700.
(6) Sibi, M. P.; Patil, K. Angew. Chem., Int. Ed. 2004, 43, 1235.
(7) Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002,
41, 2197.
(8) Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571.
(9) (a) Saylik, D.; Campi, E. M.; Donohue, A. C.; Jackson, W. R.;
Robinson, A. J. Tetrahedron: Asymmetry 2001, 12, 657. (b) Elaridi, J.;
Thaqi, A.; Prosser, A.; Jackson, W. R.; Robinson, A. J. Tetrahedron:
Asymmetry 2005, 16, 1309.
(12) (a) Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH: New
York, 2000. (b) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(13) For reviews on monophosphorus chiral ligands, see: (a) Jerphagnon,
T.; Renaud, J.-L.; Bruneau, C. Tetrahedron: Asymmetry 2004, 15, 2101.
(b) Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40, 1197.
(14) (a) Huang, H.; Zheng, Z.; Luo, H.; Bai, C.; Hu, X.; Chen, H. J.
Org. Chem. 2004, 69, 2355. (b) Huang, H.; Zheng, Z.; Luo, H.; Bai, C.;
Hu, X.; Chen, H. Org. Lett. 2003, 5, 4137.
(10) Examples of catalytic asymmetric hydrogenation using this strat-
egy: (a) Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004, 126,
1626. (b) Wang, C.; Sun, X.; Zhang, X. Angew. Chem., Int. Ed. 2005, 44,
4933. (c) Hu, A.; Lin, W. Org. Lett. 2005, 7, 455.
(11) For the synthesis of substrates and details on experimental conditions,
see the Supporting Information.
3360
Org. Lett., Vol. 8, No. 15, 2006

Encouraged by the results described above, we investigated
the effects of solvents, hydrogen pressure, and catalyst
precursors to determine the optimal conditions (Table 2). A
Table 3. Enantioselective Hydrogenation of â-Phthalimide
Acrylates 2a
Table 2. Enantioselective Hydrogenation of â-Phthalimide
Acrylates 2aa
entry
substrate (R1, R2)
P(H2) atm conv.%b ee% (config.)c
1
2
2a, (H, Et)
2b, (H, Me)
2a, (H, Et)
2c, (C6H5, Me)
2d, (p-ClC6H4, Me)
2e, (p-FC6H4, Me)
2f, (p-CF3C6H4, Me)
2g, (o-MeOC6H4, Me)
2h, (p-MeC6H4, Me)
10
10
10
85
85
85
85
85
85
85
85
>99
>99
>99
82
>95
>95
>95
87
99.1 (R)
98.3 (R)
97.7 (R)
92.0 (R)
86.4 (+)
95.9 (+)
94.6 (+)
85.4 (+)
76.0 (+)
55.4 (+)
49.5 (-)
3d
4e
5e
6e
7e
8e
9e
entry ligand solvent P(H2) atm conv.%b ee% (config.)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
9g
9g
9g
9g
9g
9g
9g
9g
9a
9b
9c
9d
9e
9f
CH3OH
i-PrOH
THF
10
10
10
10
10
20
30
40
10
10
10
10
10
10
74
83
88
22.5 (R)
22.5 (R)
41.1 (R)
22.3 (R)
99.1 (R)
99.1 (R)
98.8 (R)
98.1 (R)
98.9 (R)
98.3 (R)
98.3 (R)
99.1 (R)
97.7 (R)
98.3 (R)
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
86
73
60
91
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
10e 2i, (2-thienyl, Me)
11e 2j, (i-Pr, Me)
a Unless otherwise stated, reactions were performed on a 0.5 mmol scale
at room temperature for 12 h, 1 mol % of [Rh(COD)2]BF4, 2.2 mol % of
ligand 9. b Determined by GC or 1H NMR. c Enantiomeric excess values
were determined by chiral HPLC, and the absolute configuration was
determined by comparing the sign of specific rotation of the corresponding
amino acids. d [Rh(COD)2]BF4 (0.1 mol %), ligand 9g (0.22 mol %).
e [Rh(COD)2]BF4 (4 mol %), ligand 9g (8.8 mol %), 36 h.
a Unless otherwise stated, reactions were performed on a 0.5 mmol scale
at room temperature for 12 h, 1 mol % of [Rh(COD)2]BF4, 2.2 mol % of
ligand 9. b Determined by GC. c Determined by chiral HPLC, and the
absolute configuration was determined by comparing the sign of specific
rotation of the corresponding amino acid.
imide acrylates were hydrogenated to yield their correspond-
ing â2-amino acid precursors. In general, the enantioselec-
tivity in these experiments was high (Table 3, entries 1-8).
However, the conversion for the reaction was variable. For
the aromatic substituted substrates, it was found that the
presence of electron-withdrawing groups on the phenyl ring
of the substrate led to higher conversion and more favorable
enantiomeric excess values than did electron-donating groups
(Table 3, entries 5-7 vs entries 4, 8, and 9). The heteroaro-
matic and alkyl-substituted substrates (2i and 2j) also can
be hydrogenated with moderate enantioselectivity (Table 3,
entries 10 and 11).
The absolute configurations of the hydrogenation products
3a and 3c obtained with 9g as a chiral ligand were assigned
as R by converting them into their corresponding known
â2-amino acids4 by using standard reactions9 (Scheme 1).
Scheme 1 also shows an application of this methodology
for a potential efficient synthesis of the (R)-(-)-R-methyl-
dramatic solvent effect was observed when using Rh/9g com-
plexes as catalyst precursor (entries 1-5). Only CH2Cl2 is
most effective in terms of the conversion and enantioselec-
tivity. This agrees with our early results.14 Hydrogen pressure
had no dramatic effect on the activity and selectivity for this
substrate: slightly lower selectivity was observed when the
pressure increased from 10 to 40 atm (Table 2, entries 5-8).
To test the effect of structure of the chiral P-O ligands on
the enantioselectivity of the reaction, a set of ManniPhos
ligands with different -OR was employed. The best result
was observed when 9d and 9g were used as ligands.
Using the optimized catalyst precursor Rh/9g and condi-
tions optimized for the hydrogenation of 2a, we proceeded
to explore the scope and limitations of the methodology. As
shown in Table 3, the substrates (2a and 2b) without a
substituent in the â-position of the carbon-carbon double
bond can give full conversion and excellent enantioselectivity
(up to 99.1% ee) even in lower catalyst loading (Table 3,
entry 3, 0.1 mol % catalyst). Unfortunately, use of the same
reaction conditions for the hydrogenation of 2c, which
contains a phenyl group in the â-position of the carbon-
carbon double bond, failed to give more than 5% conversion
of starting material. However, up to 92% ee and 82%
conversion was observed when high hydrogen pressure (85
atm) and 4 mol % catalyst were employed (Table 3, entry
4). Under these conditions, a variety of substituted â-phthal-
Scheme 1. Highly Enantioselective and Practical Synthesis of
(R)-(-)-R-Methyl-â-alanine 1
Org. Lett., Vol. 8, No. 15, 2006
3361

â-alanine 1, which is a critical key building block for
synthesis of cryptophycin-1.2
Acknowledgment. Financial support from the National
Science Foundation of China (20472083) is gratefully
acknowledged. H.H. gratefully acknowledges Professor Hui-
lin Chen (DICP) for his encouragement and important
suggestions.
In summary, we have developed the first highly enantio-
selective method for the synthesis of â2-amino acids based
on the asymmetric hydrogenation of â-phthalimide acrylates.
Up to 99% ee has been achieved with an Rh-manniphos
catalyst. Efforts are underway in our laboratory to discover
further application of this catalyst and to identify other
catalyst systems that deliver improved activities and enan-
tioselectivities for this hydrogenation.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0612399
3362
Org. Lett., Vol. 8, No. 15, 2006