Highly enantioselective Cu-catalyzed conjugate addition-elimination of activated ally lie acetates with glycine derivatives

Article abstract of DOI:10.1021/ol900439h

The reaction of a glycinate Schiff base with the activated alkyl- and aryl-substituted allylic acetates afforded 4-alkylidenylglutamic acid derivatives in high yields and high enantioselectivities by using Cu/P,N-FcPhox as the catalyst.

Full text of DOI:10.1021/ol900439h

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2073-2075
Highly Enantioselective Cu-Catalyzed
Conjugate Addition-Elimination of
Activated Allylic Acetates with Glycine
Derivatives
Chun-Gen Chen,† Xue-Long Hou,*,† and Lin Pu*,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Finglin Road, Shanghai 200032, P. R. China, and
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904
xlhou@mail.sioc.ac.cn; lp6n@Virginia.edu
Received March 3, 2009
ABSTRACT
The reaction of a glycinate Schiff base with the activated alkyl- and aryl-substituted allylic acetates afforded 4-alkylidenylglutamic acid derivatives
in high yields and high enantioselectivities by using Cu/P,N-FcPhox as the catalyst.
Glycinate benzophenone Schiff bases have been widely
used as glycine anion equivalents in the alkylations, the
Michael reactions, the Mannich reactions, and the aldol
reactions to afford many different types of R-amino acid
derivatives.1,2 In many cases, phase-transfer catalysts and
some other organic small molecules have been used as the
catalysts.2a-k Although chiral transition-metal complexes
have been recognized as efficient catalysts in asymmetric
catalysis,3 only a limited number of examples were reported
to use such complexes in the asymmetric transformation of
the glycine derivatives.2l-p,4 The utility of transition-metal
catalysts in these reactions remains to be explored further.
On the other hand, 4-substituted glutamate analogues such
as 4-substituted alkylidene glutamic acids are a class of
amino acids having high biological activities.5 Many efforts
have been focused on their synthesis by using the optically
active glycine Schiff bases and pyroglutamate.6 Recently,
Ramachandran realized the enantioselective synthesis of
4-substituted alkylidene glutamic acid derivatives under PTC
catalytic conditions.7 However, there are some limitations
regarding the scope of the substrates as well as the enanti-
oselectivities in some cases. The asymmetric catalytic version
of effective syntheses of 4-alkylidenyl glutamic acids still
remains to be explored. As a program aimed at the synthesis
and applications of chiral ligands in asymmetric catalysis,
we studied the use of glycine derivatives in asymmetric
reactions.8 Further studies revealed that CuI/P,N-ferrocene
ligands are effective catalysts in the tandem conjugate
addition-elimination reaction of a glycine Schiff base with
allylic acetates, providing the 4-alkylidenyl glutamic acid
† Shanghai Institute of Organic Chemistry.
‡ University of Virginia.
(1) For reviews of the synthesis of R-amino acid derivatives, see: (a)
O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506–517. (b) Na´jera, C.;
Sansano, J. M. Chem. ReV. 2007, 107, 4584–4671. (c) Hashimoto, T.;
Maruoka, K. Chem. ReV. 2007, 107, 5656–5682
.
10.1021/ol900439h CCC: $40.75
Published on Web 04/09/2009
 2009 American Chemical Society

derivatives in high yield and enantioselectivity. In this paper,
we disclose our preliminary results.
to be a better solvent than CH2Cl2, Et2O and toluene in terms
of enantioselectivities (Table 1, entries 8-10). The ee could
be enhanced to 92% at -30 °C (Table 1, entry 11).
The tandem conjugate addition-elimination reactions of
various substituted active allylic acetates9 with the ben-
zophenone imine of the glycine tert-butyl ester 1 were studied
under the optimized conditions, and the results are sum-
marized in Table 2. The reaction was general regardless of
Initially, the reaction of the benzophenone imine of the
glycine tert-butyl ester 1 with the allylic acetate 2a was
examined in the presence of ligand 3a/CuClO4 and K2CO3
(eq 1). The desired 4-alkylidenyl glutamic acid derivative
4a was obtained in 95% yield and with 86% ee. Encouraged
by this result, a series of the P,N-ferrocenyl ligands bearing
various aryl groups on the P atom and substituents R on the
oxazoline ring were examined under the conditions of eq 1
(Table 1).
Table 2. Asymmetric Alkylation of 1 Using the Cu/Ligand 3da
entry
R
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
p-NO2C6H4 (2a)
Ph (2b)
91
85
96
92
92
99
98
88
96
94
97
85
92
94
90
83
90
91
92
98
92
92
98
93
p-FC6H4 (2c)
p-ClC6H4 (2d)
p-BrC6H4 (2e)
m-ClC6H4 (2f)
p-MeC6H4 (2g)
2-thienyl (2h)
2-furanyl (2i)
Et (2j)
9
10d
11d
12d
Table 1. Optimization of the Cu-Catalyzed Asymmetric
Alkylation of the Glycine Derivative 1a
i-Pr (2k)
phenylethyl (2l)
entry
ligand
solvent
yieldb (%)
eec (%)
a Molar ratio of glycine ester 1/allylic acetate 2/CuClO4/ligand 3d/K2CO3
) 1:1:0.1:0.11:4, concentration (0.1 M). b Isolated yields. c Determined by
HPLC. d Run at room temperature.
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3d
3d
3d
3d
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
Et2O
toluene
THF
95
97
90
95
97
82
94
95
89
91
91
86
77
86
91
8
72
90
85
90
85
92
the substitutions of the allylic acetates. The yields were high,
and the ee values ranged from 83% to 98%. Phenyl and para-
and meta-substituted aromatic allylic acetates gave the
corresponding products in high yields and with good to
excellent enantioselectiveties (Table 2, entries 1-7). High
ee values were also obtained when the heterocyclic allylic
acetates were used (Table 2, entries 8 and 9). For aliphatic
9
10
11d
a Molar ratio of glycine ester 1/allylic acetate 2/CuClO4/ligand/K2CO3
) 1:1:0.1:0.11:4, concentration (0.1 M). b Isolated yields. c Determined by
HPLC. d The reaction was carried at -30 °C.
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It was found that varying the substituent on the P atom to
3,5-ditrifluoromethylphenyl (3b) or 4-methoxylphenyl (3c)
led to the product with either a decreased enantioselectivity
or a similar result (Table 1, entries 2 and 3). A better result
was obtained with ligand 3d, which had a tert-butyl group
on the oxazoline ring and phenyl groups on the P atom: the
corresponding product was formed in 95% yield and with
91% ee (Table 1, entry 4). Varying the substituent on the
oxazoline ring to a phenyl group led to the product with much
decreased enantioselectivity (Table 1, entry 5). When ligand
3f was employed, the product was obtained in 82% yield
and with 72% ee (Table 1, entry 6). The more bulky ligand
3g slightly decreased the enantioselectivity to 90% ee (Table
1, entry 7). The solvent effect was also studied. THF proved
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Org. Lett., Vol. 11, No. 10, 2009

allylic acetates, the reaction was sluggish and could not reach
complete conversion at -30 °C. However, we were pleased
to find that the reactions proceeded smoothly at room
temperature with good yields and excellent enantioselectivi-
ties (Table 2, entries 10-12).
and 86% ee) were achieved. For the benzyl-substituted
iminoester 5b, the product was obtained in 63% yield and
23% ee (eq 2).12
Furthermore, the CuI/P,N-ferrocene ligand 3d was applied
to the asymmetric reaction of R-substituted iminoester 5,10
with the allylic acetate 611 to construct a quaternary carbon
center. For the aldimine Schiff base 5a, derived from alanine
methyl ester, good yield and enantioselectivity (70% yield
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It seems that the reaction proceeds in the addition-
elimination way7 as no product was given when the glycine
tert-butyl ester 1 reacted with CH2dCHCH2OAc under the
above reaction conditions.
In summary, we have reported a general and practical
method for the preparation of 4-alkylidenyl glutamic acid
derivatives with high yield and enantioselectivity by using
a Cu/P,N-ferrocene catalyst. Further studies of the catalyst
and its application are in progress.
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Acknowledgment. Financial support from the National
Natural Science Foundation of China (20532050, 20672130,
20821002), the Major Basic Research Development Program
(2006CB806100), Chinese Academy of Sciences, and Sci-
ence and Technology Commission of Shanghai Municipality
is acknowledged.
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Supporting Information Available: Detailed experimen-
1
tal procedures, H and 13C NMR data, and HPLC spectra
for 4 and 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
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OL900439H
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(11) Allylic acetate 2a was also tried, but a complicated mixture of
products was afforded after hydrolysis perhaps caused by the reactivity of
the methyl ester and the PhCHdN- groups.
(12) The ee value was obtained by HPLC analysis of 7.
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