Asymmetric reductive alkylation of alanylproline by the ethyl esters of 4-substituted 2-oxobutenoic acids

Article abstract of DOI:10.1023/B:COHC.0000018334.85109.3f

A method was developed for the synthesis of N-[1-(S)-(ethoxycarbonyl)-3- phenylpropyl]alanylproline (enalapril) by reductive alkylation of alanylproline with ethyl 2-oxo-4-phenylbutenoate under the conditions of hydrogenation in the presence of palladium black and 1.6%Pd/C. The yield of enalapril amounted to 65%. With the ethyl ester of the α-oxo acid the diastereoselectivity of formation of the S,S,S-diastereomer was higher than with the saturated synthon. It is assumed that with ethyl 2-oxo-4-phenylbutenoate as synthon a conformationally restricted surface complex is formed between the unsaturated synthon and the active centers of the catalyst. During reductive alkylation of alanylproline by ethyl 2-oxo-4-(2-thienyl)butenoate poisoning of the catalyst occurs.

Full text of DOI:10.1023/B:COHC.0000018334.85109.3f

Chemistry of Heterocyclic Compounds, Vol. 39, No. 12, 2003
ASYMMETRIC REDUCTIVE ALKYLATION
OF ALANYLPROLINE BY THE ETHYL ESTERS
OF 4-SUBSTITUTED 2-OXOBUTENOIC ACIDS
V. Slavinska, Dz. Sile, G. I. Chipens, Yu. Balodis, G. Rozenthal,
K. Venteris, and E. Lukevics
A method was developed for the synthesis of N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]alanylproline
(enalapril) by reductive alkylation of alanylproline with ethyl 2-oxo-4-phenylbutenoate under the
conditions of hydrogenation in the presence of palladium black and 1.6% Pd/C. The yield of enalapril
amounted to 65%. With the ethyl ester of the α-oxo acid the diastereoselectivity of formation of the
S,S,S-diastereomer was higher than with the saturated synthon. It is assumed that with ethyl 2-oxo-4-
phenylbutenoate as synthon a conformationally restricted surface complex is formed between the
unsaturated synthon and the active centers of the catalyst. During reductive alkylation of alanylproline
by ethyl 2-oxo-4-(2-thienyl)butenoate poisoning of the catalyst occurs.
Keywords: alanylproline, angiotensin-converting enzyme inhibitors, palladium black, 4-substituted
ethyl 2-oxobutenoates, asymmetric reductive alkylation.
Inhibitors of angiotensin-converting enzyme – enalapril and its analogs – are highly effective
antihypertensive preparations and agents for the treatment of heart failure, glaucoma, and other diseases [1, 2].
Numerous methods have been proposed for the synthesis of these compounds. One method for the
synthesis of enalapril is the condensation of alanylproline with 4-substituted ethyl 2-oxobutyrates with
NaB(CN)H
reducing agents.
Only the (S,S,S)-diastereomer of N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]alanylproline, which is
more active than the (R,S,S)-diastereomer, is used in medicine. If the reductive alkylation of alanylproline by
3
and molecular hydrogen in the presence of hydrogenation catalysts (Ni, Pd black, Pd/C, Ir, etc.) as
ethyl 2-oxo-4-phenylbutyrate is conducted in the presence of NaB(CN)H as condensing agent or in the presence
3
of Pd black, both stereomers are formed in equal amounts, (S,S,S):(R,S,S) ~ 1:1 [3]. During the reductive
alkylation of alanylproline by ethyl 2-oxo-4-phenylbutyrate under the conditions of hydrogenation at Pd/C (5
and 10% Pd/C) or IrO the ratio of the diastereomers is better, (S,S,S):(R,S,S) = 1.5:1 [3, 4]. In industry Raney
2
nickel is used as catalyst. High diastereoselectivity in the formation of the (S,S,S)-diastereomer was achieved
when potassium fluoride, acetic acid, and other additions were used [3, 5].
_
*
______
Dedicated to highly respected Academician Janis Stradins with feelings of gratitude for his consent and support
for research on peptide chemistry and catalysis.
_________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga, LV-1006; e-mail: dzsile@osi.lv. Translated from Khimiya
_
Geterotsiklicheskikh Soedinenii, No. 12, pp. 1794-1799, December, 2003. Original article submitted
October 25, 2003.
0
009-3122/03/3912-1579$25.00©2003 Plenum Publishing Corporation
1579

We showed for the first time that industrial 1.6% Pd/C catalyst (with a low Pd content) can be used
successively in the synthesis of enalapril after previous activation. The ratio of diastereomers is
(
S,S,S):(R,S,S) ~ 1.5:1 [5], and the product yields are comparable with the results obtained with 10% Pd/C [1].
We assumed that the stereoselectivity of the process could be increased substantially if the structure of
the agent for alkylation of the alanylproline was varied. Using appropriate methods for the production of the
4
-substituted 2-oxobutenoic acid derivatives [6-9], we realized the reductive alkylation of alanylproline with the
unsaturated synthon ethyl 2-oxo-4-phenylbutenoate in the presence of palladium black. Alkylation was realized
in reactions of the conjugated type (Scheme 1).
Scheme 1
OH
CO Et
Pd, H2
mol. sieves
2
H
O
O
CO Et
2
CO Et
2
First independent reaction
Ala-Pro
OH
H
H
CO Et
2
+
CO Et
2
Ala-Pro
Second reaction, the rate of which depends
on the rate of the first reaction
Hydrogenation of the salts and ethyl esters of 4-substituted 2-oxobutenoic acids (the first reaction)
R = phenyl, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl) at palladium and nickel catalysts was described
(
in [10-13].
The derivatives of 4-substituted 2-oxobutenoic acids are hydrogenated by a parallel-consecutive reaction
scheme with the formation of the named oxo and hydroxy compounds. The selectivity in the formation of the
oxo compounds is increased if palladium catalysts and the salts of the respective 4-substituted 2-oxobutenoic
acids are used. The selectivity in formation of the respective oxo compounds decreases in the following order,
depending on the structure of the initial compound: 4-(2-thienyl)- > 4-(2-furyl)- > 4-phenyl- > 4-(3-pyridyl)- >
4
-(4-pyridyl)-2-oxobutyric acid (Na salt).
During the synthesis of enalapril and its analogs by conjugated hydrogenation of the unsaturated ethyl
esters of 4-substituted 2-oxobutenoic acids and condensation of the saturated oxo compound with alanylproline
it is possible to expect more complete utilization of the saturated keto compound. The rate of transformation of
the keto compound into the respective hydroxy compound in the consecutive reaction and the rate of the
transformations of the keto compound into the bimolecular condensation products, established during the
hydrogenation of the esters of the unsaturated α-keto acids, decrease [14]. In addition, there is no need to isolate
the saturated ester of the α-keto acid from the hydrogenation product (in the case where the synthon is obtained
by hydrogenation of the respective unsaturated compound).
The two reactions have the same main side product – the ethyl ester of the respective saturated hydroxy
compound, and the retardation of the second reaction by the side products of the first reaction is therefore
unlikely to be increased.
1
580

During the synthesis of enalapril by reductive alkylation of alanylproline by ethyl 2-oxo-4-
phenylbutenoate under optimum conditions (room temperature, ratio of alanylproline to ethyl 2-oxo-4-
phenylbutenoate 1:(1.5-2.5), ratio of Pd black to alanylproline ~ 1:1, in absolute ethanol in the presence of
molecular sieves) the average yield of enalapril is 50-65%. During the synthesis a significant increase in the
diastereoselectivity of formation of the (S,S,S)-diastereomer was observed. In the investigated region of reaction
conditions (S,S,S):(R,S,S) = (2.3-3.1):1.
During the synthesis of enalapril according to the conjugated scheme it can be supposed that the
reaction takes place at other active centers of the catalyst with other degrees of surface coverage with the
reagents. It is possible that the orientation of the individual structural elements on the surface of the catalyst and
the structure of the complexes change under these conditions, leading to some change in the diastereoselectivity
of the reaction.
It is not, however, possible to exclude the probability that the unsaturated oxo ester will condense with
the alanylproline to form a conformationally restricted complex according to Scheme 2.
This would give rise to attack by the adsorbed hydrogen at the C atom of the enamine group and the
formation of the (S,S,S)-diastereomer. There are, however, no published data on the relative reactivity of
saturated and unsaturated keto esters with alanylproline in the presence of palladium catalysts.
Scheme 2
H
H
O
Pd
Ala-Pro
Pd
O
CO Et
2
H
CO Et
2
H
trans-isomer
Me
H
Pd
N
C
H
CON
CO H
2
H
CO Et
2
Me
Pd
H
N
C
H
CON
CON
CO H
2
H
CO Et
2
Me
CO Et
2
H
C
H
N
H
CO H
2
S,S,S-diastereomer
We realized the reductive alkylation of alanylproline with sodium 2-oxo-4-phenylbutenoate and the
corresponding saturated compound using NaBH
4
and NaB(CN)H [15]. Under the conditions of condensation
3
the saturated oxo compound is characterized by higher reactivity than its unsaturated analog. When the latter
was used, the unsaturated analog of enalapril was obtained.
1
581

It is possible that the saturated and the unsaturated oxo esters both participate in the reductive alkylation
of alanylproline by the unsaturated oxo ester at the palladium catalyst.
We also studied the synthesis of the enalapril analog containing a 2-thienyl radical by the reductive
alkylation of alanylproline with ethyl 2-oxo-4-(2-thienyl)butenoate in the presence of palladium black. This
reaction also takes place asymmetrically. Here, however, strong poisoning of the catalyst by the sulfur-
containing compounds is observed, and it is not therefore advisable to obtain the above-mentioned analog by
this method.
Thus, the ethyl esters of the respective unsaturated 4-substituted 2-oxobutenoic acids can be used as
synthons for the synthesis of enalapril and, probably, its analogs if the palladium catalyst is not poisoned by the
unsaturated oxo compound or its transformation products.
EXPERIMENTAL
Ethyl 2-oxo-4-phenyl- and 2-oxo-4-(2-thienyl)butenoates were synthesized by the method in [7, 16].
Ethyl 2-oxo-4-phenylbutenoate was determined by chromatography on a Varian 3700 chromatograph
with a flame-ionization detector, a 2000 × 2 mm column, 5% of OV-17 sorbent on Chromosorb WHP
(
8077/100 mesh), helium, programmed temperature 80 → 240°C.
Ala-Pro and N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]alanylproline were determined by HPLC on a
Du Pont 850 chromatograph on a column measuring 4.6 × 150 mm, filled with Zorbax C . The mobile phase
was acetonitrile; 0.1 M KH
TLC (n-BuOH–Py–AcOH–H
8
2
PO
4
·H
3
PO , pH 2.5, λ 215-230 nm. The condensation reaction was monitored by
4
2
O = 15:10:3:6).
Reductive Alkylation of Alanylproline by Ethyl 2-Oxo-4-phenylbutenoate. Anhydrous ethanol
13 ml) and palladium black (~0.2 g, from a suspension in anhydrous ethanol) were added to a flask provided
(
with a magnetic stirrer and a tube for the delivery of hydrogen, where Ala-Pro·HCl (2.00 g, 0.898 mmol),
triethylamine (0.13 ml), calcined 4A molecular sieves (1.44 g), and ethyl 2-oxo-4-phenylbutenoate (0.91 g,
4
.34 mmol, purity 97%) were placed. The mixture was hydrogenated with molecular hydrogen at room
temperature for 44 h. In the course of the reaction (~20 h) a fresh portion of the catalyst (0.1 g) and ethyl 2-oxo-
4
-phenylbutenoate (0.25 g) were added to the reaction mixture.
At the end of the reaction the catalyst and the molecular sieves were filtered off and washed with
anhydrous ethanol (20 × 4 ml). The ethanol solution was combined with the filtrate and evaporated.
1
0% sodium chloride solution (40 ml) was added to the residue, and the pH was brought to 8-9 with a saturated
solution of potassium carbonate. The alkaline solution was extracted with ethyl acetate (20 × 3 ml). The
aqueous solution was then acidified with 1 M phosphoric acid (pH 4-5) and extracted with ethyl acetate
(
20 × 5 ml). The ethyl acetate solution, obtained by extraction from the acidic solution, was dried by stirring for
4
5 min with sodium sulfate. The sodium sulfate was filtered off and washed with ethyl acetate. The ethyl acetate
solution was evaporated. We obtained 3.25 g of the unpurified product, which contained 2.20 g of the
(
S,S,S)-diastereomer of enalapril. The yield at the condensation stage was 65%. The obtained precipitate was
dissolved in 10 ml of hot acetonitrile, 6.7 g of maleic acid dissolved in 3 ml of hot acetonitrile was added, and
the mixture was left overnight at +10°C. The precipitate was washed with 8 ml of acetonitrile. We obtained
2
.3 g of enalapril maleate; mp 142-143°C (mp 143-144°C [1]). The NMR spectra of the enalapril maleate agreed
with published data [1].
The work was financed by the Latvian Science Council (grant No. 203).
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