An efficient synthesis of γ-amino β-ketoester by cross-Claisen condensation with α-amino acid derivatives

Article abstract of DOI:10.1016/S0040-4039(03)00464-7

Cross-ester condensation between N-protected amino acid ester and the lithium enolate prepared from alkyl acetate gave the corresponding β-ketoester in high yield without the formation of the tertiary alcohol that is commonly seen as by-product. This inte

Full text of DOI:10.1016/S0040-4039(03)00464-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3163–3166
An efficient synthesis of g-amino b-ketoester by cross-Claisen
condensation with a-amino acid derivatives
Yutaka Honda, Satoshi Katayama, Mitsuhiko Kojima, Takayuki Suzuki and Kunisuke Izawa*
AminoScience Laboratories, Ajinomoto Co., Inc., Suzuki-cho, Kawasaki-ku, Kawasaki-shi 210-8681, Japan
Received 11 January 2003; revised 18 February 2003; accepted 20 February 2003
Abstract—Cross-ester condensation between N-protected amino acid ester and the lithium enolate prepared from alkyl acetate
gave the corresponding b-ketoester in high yield without the formation of the tertiary alcohol that is commonly seen as
by-product. This interesting reaction is applicable to the amino acid derivatives with suitable N-protecting groups, which can help
to stabilize the reaction intermediates. © 2003 Elsevier Science Ltd. All rights reserved.
b-Ketoesters have for many years been widely used as
versatile synthetic intermediates. The conversion of
amino acids to their corresponding ketoesters, which
can be used as chiral building blocks for various phar-
maceutical intermediates, is an important technology.
approach that has most commonly been adopted has
been to convert amino acid derivatives to their corre-
sponding b-ketoesters by the nucleophilic addition of
an enolate formed from alkyl acetate or a malonic acid
half-ester to an activated carboxylic acid.5 However,
most of the methods used to activate carboxylic acids,
e.g. mixed anhydride, acid chloride, activated ester,
Weinreb amide, etc. have been reported to give only
moderate yields.6 While N-protected N-carboxy anhy-
dride (NCA) is a reactive electrophile, it is not stable
enough for widespread use.7 Under such conditions,
carbonyl imidazolide has often been efficiently applied
and for many years it has been thought to be the only
promising procedure for preparing b-ketoesters.8,9
Rapid condensation with activated imidazolide can
provide efficient conversion while avoiding the risk of
racemization. In some reports, b-ketoesters have been
formed using imidazolide which was prepared by means
of the saponification of the corresponding alkyl ester
even though cross-ester condensation could be expected
to furnish the shortest path. Hoffman and Tao reported
that the reaction with most N,N-dibenzyl amino acid
methyl esters required several hours at a high tempera-
Claisen condensation is a well-known method for the
general synthesis of b-ketoesters. However, there have
been very few reports of cross-condensation between
different esters, and yields have mostly been quite
low.1,2 This is probably due to the presence of signifi-
cant side reactions, such as self-condensation and the
formation of tertiary alcohols. Successful results have
been obtained in this reaction using hydroxyl esters as
an electrophile with a large excess of base.3 There have
also been other examples with certain esters with strong
electron-withdrawing groups adjacent to the carbonyl
group such as alkyl fluoroalkanoate, and with methyl
esters of g-amino acid derivatives, but these have exhib-
ited only moderate yields of at most 60%.4 Ohta et al.
overcame this problem by adding lithium alkoxide as
an extra base to control the formation of tertiary
alcohols.1 Rather than cross-ester condensation, the
Scheme 1. Condensation reaction with N,N-dibenzyl L-phenylalanine benzyl ester.
Keywords: amino acid; g-amino b-ketoester; Claisen condensation; cross-ester condensation; lithium enolate.
* Corresponding author. Tel.: +81-44-245-5066; fax: +81-44-211-7610; e-mail: kunisuke izawa@ajinomoto.com
–
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00464-7

3164
Y. Honda et al. / Tetrahedron Letters 44 (2003) 3163–3166
ture to reach completion, and were accompanied by
partial racemization.8 It should also be noted that the
use of imidazolide is rather expensive in an industrial
setting. Therefore, we considered that the conversion of
an amino acid to a b-ketoester using inexpensive and
readily available intermediates would be an important
technology for the pharmaceutical industry. We recently
reported the synthesis of N-Cbz-a-aminoalkyl a%-
halomethylketone in which cross-Claisen condensation
was used as the key reaction.10 This interesting result
prompted us to investigate the cross-Claisen condensa-
tion of amino acid derivatives. We therefore studied the
further application of this reaction as a general method
for synthesizing b-ketoesters with various protecting
groups other than Cbz, to determine its scope and
limitations.
the lithium in enolate 2a can contribute to internal
chelation with nitrogen to form 7a, unaffected by the
concentration of lithium ion (entries 1 and 4). On the
other hand, the reaction with 1b would be accompanied
by the elimination of lithium since the N-methoxycar-
bonyl N-methylamino group of 1b is a weaker Lewis
base (Path B). In another possible path to establish
selective condensation without the formation of a ter-
tiary alcohol, lithium benzyloxide is not spontaneously
eliminated from 7a until the reaction mixture is
quenched with acid (Path C). Path A is preferable
because at least two equivalents of 2 were needed to
complete the reaction (entries 2 and 3).
Application to other N-protected amino acid derivatives
are also shown (Scheme 4, Table 2). N-Carbobenzyloxy
L
-phenylalanine methyl ester 2b reacted with tert-butyl
N,N-Dibenzyl
can be obtained by a one-step reaction from
L
-phenylalanine benzyl ester 1a,11 which
-Phe, was
lithioacetate 2 to give b-ketoester 3b quantitatively
(entry 1). Lithium enolate prepared from a primary alkyl
ester such as ethyl acetate as well as tert-butyl ester
similarly gave a good result (entry 2). Although lithium
hexamethyldisilazide also effectively gave the enolate at
a high temperature, lithium tert-butoxide did not
(entries 3 and 4). The examples in Table 2 show that this
cross-ester condensation has a wide range of applica-
tions (entries 5–8). In the case of Claisen condensation
to N-alkoxycarbonyl-protected amino acid ester, the
negative charge of the nitrogen atom formed near the
carbonyl group probably completely prevented the
approach of the carbanion, as Ohta et al. previously
noted in the reaction to the hydroxyl ester.1 The reaction
to Cbz-Cys(Ph)-OMe gave a considerable amount of
tertiary alcohol, even though the desired ketoester was
obtained as the major product (entry 8).
L
reacted with tert-butyl lithioacetate prepared from tert-
butyl acetate 2 and lithium diisopropylamide in tetra-
hydrofuran at −50°C (Scheme 1, Table 1);12 the reaction
selectively gave the corresponding b-ketoester 3a with-
out racemization (entry 1). The application of Claisen
condensation to 1a is an unusual example to avoid the
formation of a tertiary alcohol, which is a common
problem in cross-ester condensation. In contrast, con-
densation with N-methoxycarbonyl N-methyl derivative
1b13 gave a mixture of the desired b-ketoester and
tertiary alcohol (entry 5) (Scheme 2). The unexpected
success with 1a could be due to the stabilized intermedi-
ate 8a, obtained by the chelation of lithium with a
dibenzylamino group14 (Scheme 3, Path A). Regardless
of the mechanism of this addition, the results show that
Table 1. Preparation of b-ketoester via cross-Claisen condensation between N-protected
tert-butyl acetate
L-phenylalanine benzyl ester and
Entry
Ester 1
Enolate 2
Temperature
Methodb
Product HPLC peak ratioc 3/6
Yieldd
t-BuOAc (equiv.)
Base (equiv.)
(1), (2)a (°C)
3e (%)
1
2
3
4
5
1a
1a
1a
1a
1b
3.3
3.0
1.0
3.3
3.3
LDA (2.9)
LDA (2.0)
LDA (1.0)
LDA (2.9)
LDA (2.9)
−45, −48
−45, −50
−45, −50
−45, −50
−45, −50
A
A
A
B
\99/1
\99/1
\99/1
\99/1
54/46
90
84
30
94
44
A
a Enolates were prepared at temperature (1), and condensation reactions were then carried out at temperature (2). The figure shows the maximum
internal temperature during addition and reaction.
b Method A: The ester was added dropwise to the enolate. Method B: The enolate was added dropwise to the ester.
c The ratio of ‘ketoester/tertiary alcohol’ was indicated by peak area% (UV at 210 nm) in HPLC (Inertsil ODS-2, 0.03 M KH2PO4 aqueous buffer
solution/acetonitrile).
d Ketoesters (3a,b) were isolated by preparative TLC.
e The optical purity of each compound was higher than 98% ee, as determined by chiral HPLC (Chiralcel OD-H, n-hexane/ethanol) at 210 nm.
Scheme 2. Condensation reaction with N-methoxycarbonyl N-methyl L-phenylalanine benzyl ester.

Y. Honda et al. / Tetrahedron Letters 44 (2003) 3163–3166
3165
Scheme 3. Supposed mechanism of the reactions.
Scheme 4. Condensation reaction with N-protected amino acid methyl ester.
Table 2. Cross-Claisen condensation reaction between N-alkoxycarbonylamino acid methyl ester and acetic acid ester
Entry
Ester
Enolate
Temperature
Product HPLC peak
Yield (%)c
ratiob 3 (5)/6
Rf
Pg
R
Ester (equiv.)
Base (equiv.)
(1), (2)a (°C)
1
2
3
4
5
6
7
8
9
1c
1c
1c
1c
1d
1e
1f
1g
1h
1i
Bn
Bn
Bn
Bn
i-Pr
i-Bu
4-OH-Bn
PhSCH2-
Bn
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
H
H
H
H
H
H
H
H
H
Me
2 (4.0)
4 (4.0)
2 (4.0)
2 (4.0)
2 (4.0)
2 (4.0)
2 (4.0)
2 (3.7)
2 (4.0)
2 (4.0)
LDA (3.5)
LDA (4.0)
LHMDS (3.5)
LiOBu-t (3.5)
LDA (3.6)
LDA (3.6)
LDA (3.6)
LDA (3.6)
LDA (3.5)
LDA (3.5)
−45, −50
−50, −50
−25, −25
−20, −20
−50, −55
−50, −55
−50, −55
−65, −70
−45, −50
−50, −55
\99/1
\99/1
\99/1
\99/1
\99/1
\99/1
\99/1
96/4
3c
5c
3c
3c
3d
3e
3f
3g
3h
3i
97
89
87
Trace
89
98
65
87
85
\99/1
41/59
10
Bn
29
a Enolates were prepared at temperature (1), and condensation reactions were then carried out at temperature (2). (Cf. footnote to Table 1).
b The ratio of ‘ketoester/tertiary alcohol’ was indicated by peak area% in HPLC. (Cf. footnote to Table 1).
c Ketoesters (3c-i, 5c) were isolate by preparative TLC.
In conclusion, the efficient application of cross-Claisen
condensation between N-protected a-amino acid ester
and alkyl acetate was achieved. This is an interesting
reaction since an intermediate stabilized by the contri-
bution of an amino functional group could overcome
The participation of sulfur in the enolate may make the
reaction less selective. In the absence of a carbamate
anion, where acidic hydrogen is substituted by an alkyl
group, a tertiary alcohol was obtained as the major
product (entries 9 and 10).

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Y. Honda et al. / Tetrahedron Letters 44 (2003) 3163–3166
the common problem of cross-ester condensation. This
reaction may be useful as a versatile method for synthe-
sizing g-amino b-ketoesters.
9. (a) Hoffman, R. V.; Tao, J. Tetrahedron 1997, 53, 7119–
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Acknowledgements
We thank Dr. Tomoyuki Onishi for his helpful
discussion.
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1
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