Hydrolysis of cyclopropane derivatives of aspartic and adipic acids

Article abstract of DOI:10.1023/A:1015301513947

Hydrolysis of substituted cyclopropane amino acids was performed. Free and partially substituted Z and E isomers of cyclopropane analogs of aspartic and adipic acids were obtained.

Full text of DOI:10.1023/A:1015301513947

Russian Journal of General Chemistry, Vol. 72, No. 1, 2002, pp. 86 90. Translated from Zhurnal Obshchei Khimii, Vol. 72, No. 1, 2002,
pp. 93 97.
Original Russian Text Copyright
2002 by Anisimova, Berkova, Deiko.
Hydrolysis of Cyclopropane Derivatives
of Aspartic and Adipic Acids
N. A. Anisimova, G. A. Berkova, and L. I. Deiko
Mountain Altai State University, Mountain Altai, Russia
Gertsen State Pedagogical University, St. Petersburg, Russia
Received July 20, 1998
Abstract Hydrolysis of substituted cyclopropane amino acids was performed. Free and partially substituted
Z and E isomers of cyclopropane analogs of aspartic and adipic acids were obtained.
The intensive recent development of the chemistry
of cyclopropane amino acids is associated with their
HCl,
H2O
R
CO2Me
NHAc
I, II
R
CO2H
NH2 HCl
III, IV
wide natural occurrence and diverse physiological
activity [1, 2]. The interest of synthetic chemists and
pharmacologists has been attracted to neuroreceptors
activated by L-glutamic and aspartic acids which are
known as exciting amino acids. These acids strongly
affect neurons of the central nervous system of
mammals and neuromuscular synapses of insects
[3, 4]. For studies on glutamate receptors of interest
are rigid structural analogs of exciting amino acids,
containing a three-carbon ring [5, 6]. In this connec-
tion the search for effective exciting amino acids and
their antagonists among cyclopropane amino acids is a
topical problem, since in this series one can reveal
both new drugs and selective insecticides.
R = H (I, III), Ph (II, IV).
Cyclopropanedicarboxylic amino acids, cyclic
analogs of glutamic and aspartic acids, are of parti-
cular interest for assessment of the effect of the con-
formation of exciting amino acids on receptor activity.
In [6, 10, 11], only cyclic analogs of glutamic acid
could be obtained. Attempted preparation of the
cyclopropane analog of aspartic acid failed [7]. Using
stereohomogeneous isomers of dimethyl ester of
1-(acetylamino)cyclopropane-1,2-dicarboxylic
acid
It is known that hydrolysis of precursors of cyclo-
propane amino acids involves some difficulties and is
not infrequently accompanied by cleavage of the three-
membered ring or elimination of functional groups.
The yield of free cyclopropane amino acids in the
hydrolysis is much affected by the number and posi-
tions of ring substituents [7].
(Z-V and E-VI), as well as milder hydrolysis condi-
tions allowed us to preserve the three-membered ring
and to isolate for the first time and identify its hydro-
chlorides. It was shown that hydrochloric acid hydro-
lysis of substituted isomers V and VI is not unidirec-
tional. Thus, hydrolysis of ester Z-V gives rise to
2-oxoglutaric acid (VII) (yield 60%) and hydrochlo-
ride Z-VIII (yield 8%). Isomer E-VI under the
same conditions gives primarily a more stable an-
hydride hydrochloride IX and hydrochloride E-X in
yields of 60 and 6%, respectively.
Thus, the authors of [8, 9] could hydrolyze esters
of cyclopropane N-(acetyl)amino acids I and II under
rigid conditions (6 N HCl, boiling, 6 h) with preserva-
tion of the three-membered ring to obtain 1-amino-
cyclopropanecarboxylic acid hydrochloride (III) in an
yield of 70%. Phenyl substituion in the three-
membered ring reduces the yield of hydrochloride IV
to 50% as a result of partial ring cleavage and forma-
tion of unsaturated hydrolysis products [9]. We used
Consecutive elimination of the C- and N-protective
groups allowed the yield of hydrochloride Z-VIII to
be raised to 15%. Studies on the behavior of esters V
and VI under base hydrolysis conditions showed that
treatment of the latter with an equimolar amount of
milder conditions of acid hydrolysis (3 N HCl, boiling, 1 N aqueous sodium hydroxide results in formation of
15 20 min) for esters I and II and thus improved the
yields of hydrochlorides III and IV to 90 and 70%,
respectively.
N-substituted disodium salts Z-XI and E-XII. Acidi-
fication of these salts to pH 5 6 gives rise to N-sub-
stituted 1-aminocyclopropane-1,2-dicarboxylic acid Z-
1070-3632/02/7201-0086$27.00 2002 MAIK Nauka/Interperiodica

HYDROLYSIS OF CYCLOPROPANE DERIVATIVES
XIII and its anhydride XIV. On further acidification isomer E-VI under similar conditions.
87
to pH 2 and heating, an acyclic reaction product VII
and hydrochloride Z-VIII are formed; anhydride
hydrochloride IX is a single hydrolysis product of
Hydrochloride Z-XV was obtained by alkylation of
hydrochloride Z-VIII with diazomethane.
HA
MeO2C
CO2Me
HX NHAc
HB
V, VI
Silica gel L 100/250
CO2Na
NHAc
CO2Me
NHAc
NaO2C
MeO2C
CO2Me
H
CO2Na
NHAc
H
OH, H2O
OH, H2O
H
H
NHAc
MeO2C
NaO2C
Z-XI
Z-V
E-VI
E-XII
3 N HCl
O
2 N HCl
3 N HCl
2 N HCl
HO2C (CH2)2 C CO2H
V
+
O
C
O
O
C
O
O
O
C
H
C
CO2H
H
2.5 N HCl
CO2H
NHAc
H
2.5 N HCl
NHAc
NH2 HCl
H
NH2 HCl
HO2C
HO2C
Z-XIII
VIII
IX
XIV
CH2N2
+
CO2H
HO2C
H
CO2Me
H
NH2 HCl
NH2 HCl
XV
MeO2C
X
Hydrolysis of 2-(acetylamino)-2-(methoxycarbo-
nyl)-3-(2-methoxycarbonylcyclopropyl)propanoic acid
(XVI) involves no three-membered ring cleavage.
The structures of the first prepared compounds,
amino acids VIII, X, and XIX, their derivatives IX,
XIII XV, and XVIII, and salts XI, XII, and XVII,
were established from a comparison with specially
prepared model compounds III and IV [8, 9, 12]. The
mutual arrangement of substituents in the cyclopro-
Base hydrolysis of ester XVI occurs at room
temperature and yields trisodium salt XVII whose
acidification in the cold makes possible preservation
of the three carboxy groups and isolation of 2-(acetyl-
amino)-2-carboxy-3-(2-carboxycyclopropyl)propanoic
acid (XVIII) (yield 90%). Subsequent acidification of
the latter with 3 N HCl (boiling, 30 min) gives
2-amino-3-(2-carboxycyclopropyl)propanoic acid
hydrochloride (XIX) (yield 90%). It should be noted
that acidification of trisodium salt XVII under heating
(boiling, 1 h), as would be expected, results in removal
of one of the COOH group and decreases the yield of
hydrochloride XIX to 60%.
1
pane analogs of aspartic acid was revealed by H
1
NMR spectroscopy (Table 1). The H NMR spectra of
cyclopropanes characteristically display upfield ring
proton signals. The 2-COOH substituent in the ring
affects the chemical shifts of the HA and HB ring
protons in different isomers. In the Z isomer it shifts
downfield the HA signal and in the E isomer, the HB
signal. In the three-spin ABX system of ring protons,
the geminal JAB constant has the lowest value, which
is characteristic of three-membered rings [13, 14]. The
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 1 2002

88
ANISIMOVA et al.
CO2Me
CH2 C CO2Me
MeO2C
NHAc
XVI
OH, H2O
CO2Na
CH2 C CO2Na
NaO2C
CO2H
NHAc
XVII
H+, H2O
3 N HCl
CH2 CH CO2H
NH2 HCl
CH2 C CO2H
NHAc
HO2C
HO2C
XVIII
XIX
greater of the two vicinal constants relates to cis
orientation of the protons (JAB in the Z isomer and
JBX in the E isomer).
Salt XVII and hydrochloride XIX presumably have
E arrangement of substituents with respect to the ring
plane. However, a more exact configurational assess-
ment could not be performed because of the overlap
of signals of vicinal ring protons and the methylene
group of the substituent (Table 2).
Experimental evidence for the stereochemical
assessment of the molecules is provided by the fact
that anhydrides are formed exclusively from the E
isomers. The spectral characteristics of ring protons
of anhydrides IX and XIV are fully consistent with
the fixed E configuration of the molecule.
Thus, we showed that hydrolysis of amino acids of
the cyclopropane series under mild conditions with
consecutive elimination of the C- and N-protective
Table 1. Yields, 1H NMR spectra, and elemental analyses of compounds VIII XV
1H NMR spectrum (D2O), , ppm; J, Hz
HA HB HX
Found, %
Calculated, %
Comp. Yield,
Formula
no.
%
NH NHAc J
J
JBX
C
H
N
C
H
N
AB AX
Z-VIII
IX
15
60
6
2.00 m 2.06 m 3.09 m 8.00 s
(1H) (1H) (1H) (2H)
2.01 m 1.83 m 2.98 m 7.50 s
(1H) (1H) (1H) (2H)
2.18 m 2.00 m 2.32 m 8.20 s
(1H) (1H) (1H) (2H)
4.5 9.5 8.0 33.05 4.41 7.60 C5H8ClNO4 33.06 4.41 7.71
33.06 4.50 7.69
4.5 7.5 9.5 36.90 3.69 8.36 C5H6ClNO3 36.70 3.67 8.56
36.95 3.72 8.42
4.5 7.5 9.5 33.05 4.45 7.63 C5H8ClNO4 33.06 4.41 7.71
33.08 4.50 7.70
X
Z-XI
E-XII
70
70
60
60
90
1.85 m 1.96 m 2.66 m 8.00 s 2.00 s 4.5 9.5 7.0 36.50 2.85 5.89 C7H7NNa2O5 36.36 3.03 6.06
(1H) (1H) (1H) (1H) (3H) 36.52 2.95 5.99
2.17 m 1.86 m 2.45 m 8.10 s 1.99 s 5.0 7.5 10.0 36.42 2.90 5.90 C7H7NNa2O5 36.36 3.03 6.06
(1H) (1H) (1H) (1H) (3H) 36.52 3.00 6.04
1.38 m 1.46 m 2.43 m 8.80 s 2.00 s 4.5 8.5 7.0 44.90 4.81 7.50 C7H9NO5
(1H) (1H) (1H) (1H) (3H) 44.92 4.82 7.51
1.99 m 1.87 m 2.96 m 7.90 s 2.00 s 4.5 7.0 8.0 50.00 4.15 7.99 C7H7NO4
(1H) (1H) (1H) (1H) (3H) 50.11 4.20 8.00
Z-
44.92 4.81 7.49
49.70 4.14 8.28
XIIIa
XIVa
Z-XVb
2.00 m 2.32 m 2.61 m 7.36 s 3.63 s 4.5 9.5 7.5 39.90 5.75 6.58 C7H12ClNO4 40.10 5.73 6.68
(1H)
(1H)
(1H)
(2H) (6H)c
40.00 5.80 6.68
a
1
b
1
c
The H NMR spectrum was measured in DMSO.
The H NMR spectrum was measured in CDCl .
2CO Me.
2
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 1 2002

HYDROLYSIS OF CYCLOPROPANE DERIVATIVES
89
Table 2. Yields, melting points, 1H NMR spectra, and elemental analyses of compounds XVII XIX
1H NMR spectrum (D2O), , ppm
Found, %
Calculated, %
Comp. Yield,
mp,
C
Formula
no.
XVII
XVIII
XIX
%
CH2
(ring)
CH
(ring)
substituent
C
H
N
C
H
N
90
Oil
1.46 m, 2.13 m, 1.71 s (3H, NHAc), 36.80 3.00 4.08 C10H10NNa3O7 36.92 3.00 4.31
1.97 m 3.05 m 3.35 m (2H, CH2) 36.90 3.1 4.10
(2H)
(1H)
90 128 130 1.44 m, 2.10 m, 2.35 s (3H, NHAc), 45.99 5.01 5.39 C10H13NO7
1.63 m 2.55 m 3.09 m (2H, CH2) 46.10 5.02 5.40
46.33 5.02 5.41
(2H)
83 85 1.20 m, 2.00 m, 3.09 m (CH2CH) 40.11 5.79 6.71 C7H12ClNO4
1.44 m 2.55 m 40.16 5.80 6.72
(2H) (1H)
(1H)
90
40.10 5.73 6.68
groups allows preparation in high yields of hydro-
chlorides III and IV (containing one COOH group)
and acid XIX, where one of the COOH groups and 220 C [9, 18]). H NMR spectrum (D2O), , ppm:
1.80 m, 1.91 m (ring protons). Compound IV: yield
1.28 g (70%), mp 217 219 C (from water) (mp 219
1
the three membered ring are intervened by a me- 1.48 m and 1.80 m (2H, ring CH2), 1.34 m (1H, CH),
thylene unit.
7.76 m (5H, Ph).
A possible reason for the low yields with esters V
and VI is that the two deprotected COOH groups
attached directly to the ring increase strain in the
system. As a result, with Z-V, the three-membered
ring is cleaved, while with E-VI, a more stable an-
hydride IX is formed.
Hydrochlorides VIII X. A solution of 2 g of
compound V or VI in 30 ml of 3 N hydrochloric acid
was heated under reflux for 10 20 min. The reaction
mixture was allowed to stand for 6 h and then neutra-
lized with 3 N aqueous sodium hydroxide to pH 8 9.
The solvent was removed by distillation, and the dry
residue was washed with acetone (3 50 ml). The
extracts were evaporated, and the oily residue was
subjected to chromatography. Hydrochloride Z-VIII:
yield 0.14 g (8%), eluent acetone. Compound X: yield
0.1 g, mp 187 190 S. Compound IX: yield 0.91 g,
mp 160 163 C, eluent methanol.
EXPERIMENTAL
1
The H NMR spectra were measured on a Tesla
VS-470 instrument (working frequency 80 MHz) in
D2O, DMSO, and CDCl3; internal reference HMDS.
Column chromatography was performed on Silica
gel L 100/250 (Chemapol); the Rf values were deter-
mined on Silufol-254 plates, eluent hexane acetone,
3:2.
The residue after washing with acetone was re-
crystallized from water to obtain 1.01 g of oxoglutaric
acid VII.
Sodium 1-(acetylamino)cyclopropane-1,2-dicar-
boxylates (Z-XI and E-XII) and sodium 2-(acetyl-
amino)-2-carboxy-3-(2-carboxycyclopropyl)pro-
panoate (XVII). A solution of 2 g of compound V,
VI, or XVI in 30 ml of 1 N aqueous sodium hydr-
oxide was allowed to stand at 22 C for 10 h. The re-
action mixture was evaporated to dryness, the crystal-
line residue was washed witrh diethyl ether (3
50 ml), the ether extracts were combined, evaporated,
and recrystallized from water to isolate salts Z-XI, E-
XII, and XVII. Compound Z-XI: yield 1.5 g, mp
228 230 C (decomp.). Compound E-XII: yield 1.49 g,
mp 210 212 C (decomp.). Compound XVII: yield
1.96 g.
Cyclopropane amino acid derivatives I, II, V, VI,
and XVI were prepared by the procedured described
in [8, 9, 15 17].
1-Aminocyclopropanecarboxylic acid hydro-
chloride (III) and 1-amino-2-phenylcyclopro-
panecarboxylic acid hydrochloride (IV) were pre-
pared by a modified procedure [8, 9, 18]. A solution
of ester I or II in 30 ml of 3 N hydrochloric acid was
heated under reflux for 15 20 min, after which the
water was removed by distillation, and the crystals
that precipitated were washed with diethyl ether. The
ether extracts were evaporated. Compound III: yield
1.58 g (90%), mp 223 225 C (from water) (mp 229
230 C [9]). 1H NMR spectrum (D2O), , ppm:
1-(Acetylamino)cyclopropane-1,2-dicarboxylic
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 1 2002

90
ANISIMOVA et al.
acid (Z-XIII) and 1-(acetylamino)cyclopropane-1,2-
dicarboxylic anhydride (XIV), and 2-(acetylami-
no)-2-carboxy-3-(2-carboxycyclopropyl)propanoic
acid (XVIII). A solution of 1.5 g of salt XI, XII, and
XVII in 30 ml of water was acidified with 2 N hyd-
rochloric acid to pH 5 6 and then evaporated to
dryness. The residue was recrystallized. Isomer Z-
VIII: yield 0.7 g, mp 113 115 C (from aqueous
acetone). Anhydride XIV: yield 0.63 g, mp 118
120 C (from water). Compound XVIII: yield 1.05 g.
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then neutralized with 3 N aqueous sodium hydroxide
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crystallized from water to obtain 1.2 g (60%) of oxo-
glutaric acid VII, mp 95 97 C (mixed sample with
commercial sample shows no melting point depres-
sion). Compound IX: yield 0.75 g, mp 161 163 C
(from water). Compound XIX: yield 0.91 g, oil, Rf
0.65.
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Dimethyl 1-aminocyclopropane-1,2-dicarboxy-
late hydrochloride (XV). Ethereal diazomethane,
10 ml, was added dropwise to a stirred solution of
0.5 g of hydrochloride VIII in 10 ml of acetone. The
reaction mixture was allowed to stand for 24 h at
22 C. The solvent was removed by distillation, and
the oily residue was subjected to column chromato-
graphy (eluent chloroform) to obtain 0.52 g of hydro-
chloride XV as a yellow oil, Rf 0.70, n2D0 1.4650.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 1 2002