Synthesis and application of chiral monoesters derived from cyclohex-4-ene-1,2-dicarboxylic acid and bicyclo[2.2.1]-hept-5-ene-2,3- dicarboxylic acid

Article abstract of DOI:10.1134/S1070428008120051

Optically active alkyl and cycloalkyl hydrogen cyclohex-4-ene-1,2- and bicyclo[2.2.1]hept-5-ene- 2,3-dicarboxylates were synthesized by asymmetric Diels-Alder reactions in the presence of chiral catalyst. The cycloadducts were found to possess antimicrobi

Full text of DOI:10.1134/S1070428008120051

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1756–1759. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © E.G. Mamedov, A.G. Gasanov, I.G. Ayubov, R.Z. Babaeva, Kh.I. Gasanov, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 12, pp. 1782–1785.
Synthesis and Application of Chiral Monoesters Derived
from Cyclohex-4-ene-1,2-dicarboxylic Acid and Bicyclo[2.2.1]-
hept-5-ene-2,3-dicarboxylic Acid
E. G. Mamedov, A. G. Gasanov, I. G. Ayubov, R. Z. Babaeva, and Kh. I. Gasanov
Institute of Petrochemical Processes, National Academy of Sciences of Azerbaidjan,
pr. Khodzhaly 30, Baku, 1025 Azerbaidjan
e-mail: eldar_mamedbeyli@mail.ru
Received July 10, 2007
Abstract—Optically active alkyl and cycloalkyl hydrogen cyclohex-4-ene-1,2- and bicyclo[2.2.1]hept-5-ene-
2,3-dicarboxylates were synthesized by asymmetric Diels–Alder reactions in the presence of chiral catalyst.
The cycloadducts were found to possess antimicrobial activity.
DOI: 10.1134/S1070428008120051
Cyclohexene- and bicyclo[2.2.1]hept-5-ene-2,3-di-
carboxylic acid esters are widely used in various fields
of chemistry [1]. In particular, these compounds were
proposed as plasticizers, stabilizers, and fragrant sub-
stances. Derivatives of the cyclohexene and nor-
bornene series are components of many medical agents
[2–4]. For example, we synthesized cyclohexene- and
norbornenedicarboxylic monoesters which showed
antimicrobial activity toward various microorganisms
[5–7]. However, natural and synthetic drugs are often
effective only as the corresponding optically active
isomers [8].
di(menthyloxy)aluminum [AlCl(OMent)2, II], which
were prepared from L-menthol according to the proce-
dure described in [9]. The reactions were carried out in
the temperature ranges from –40 to –10°C for buta-
1,3-diene and from –40 to 20°C for cyclopentadiene
using different amounts of catalysts I and II in organic
solvents (methylene chloride, benzene, toluene); the
reaction time was 0.5 h.
We examined the effects of different factors, such
as temperature, catalyst, solvent, and molar ratio cata-
lyst–dienophile on the chemical and optical yields of
the cycloaddition products. The results for the reac-
tions of cyclopentadiene with dienophiles IIIb and IIIf
are given in table. It is seen that the optical yields of
norbornenedicarboxylic acid monoesters Vb and Vf
strongly depend on the temperature. The optical yield
increases as the temperature decreases, while the
Therefore, in the present work we synthesized
chiral cyclohexene- and norbornenedicarboxylic acid
monoesters (Scheme 1) by asymmetric Diels–Alder
reaction in the presence of chiral catalysts, dichloro-
(menthyloxy)aluminum (AlCl2OMenth, I) and chloro-
Scheme 1.
COOH
COOR
COOH
CH2
CH2
Catalyst, solvent
+
COOR
IIIa–IIIf
IVa–IVf
COOH
Catalyst, solvent
+
IIIa–IIIf
COOR
Va–Vf
R = Pr (a), i-Pr (b), Bu (c), i-Bu (d), t-Bu (e), cyclo-C6H11 (f).
1756

SYNTHESIS AND APPLICATION OF CHIRAL MONOESTERS
Reaction of cyclopentadiene with dienophiles IIIb and IIIf
1757
Dienophile Tempera-
Molar ratio
catalyst–dienophile
Optical yield, [α]D20 (EtOH),
Solvent
CH2Cl2
Catalyst
Yield, %
no.
ture, °C
%
35
45
50
45
45
44
deg
IIIb
–20
000.25:1
I
85
84
84
91
89
88
+24.8
+31.9
+35.3
+31.9
+31.9
+30.8
–10
–40
IIIf
–10
0.0125:1
Toluene
CH2Cl2
II
–10
–10
chemical yield decreases insignificantly. The catalyst,
solvent, and molar ratio catalyst–dienophile weakly
affect the optical yield. The yields of the other prod-
ucts were 83–91%, the optical yield of compounds
IVa–IVf attained 44%, and the optical yield of Va–Ve
reached 49%.
tive isomers turned out to be more active against vari-
ous microorganisms; therefore, these compounds may
be recommended for use as antiseptics.
EXPERIMENTAL
The IR spectra were recorded on a UR-20 instru-
ment in the range from 400 to 4000 cm–1; samples
were examined as thin films or KBr pellets. The
1H NMR spectra were obtained on a Jeol FT-80A spec-
trometer (80 MHz) using ethanol-d6 as solvent and
D2O as reference. The optical rotations were measured
on a Perkin–Elmer 141 polarimeter.
The product structure was confirmed by the data of
1
elemental analysis and IR and H NMR spectra. The
1H NMR spectra contained signals at δ 11.6 (COOH),
5.85–6.0 (HC=CH), 2.6–2.9 (1-H, 4-H in Va–Vf), and
1.15–1.4 ppm (CH2).
The optical yields of compounds IVa–IVf and Va–
Vf were determined by comparing their experimental
specific optical rotations with the maximal optical
rotations reported in [10, 11]. Their relative configura-
tions were established by correlating the signs of op-
tical rotation with those of structurally similar com-
pounds with known configuration [10, 11]: (1S,2S) for
cyclohexenedicarboxylic acid monoesters (+)-IVa–
(+)-IVf and (2S,3S) for bicyclo[2.2.1]hept-5-ene-2,3-
dicarboxylic acid monoesters (+)-Va–(+)-Vf.
Chiral monoesters IVa–IVf and Va–Vf (general
procedure). A solution of 0.1 mol of dienophile IIIa–
IIIf in 20 ml of methylene chloride was cooled to
–40°C, 12.5 mmol of catalyst I or II in 10 ml of meth-
ylene chloride, toluene, or chlorobenzene was added,
and a solution of 0.1 mol of buta-1,3-diene or cyclo-
80
Compounds IVa–IVf and Va–Vf were tested for
antimicrobial activity against some microorganisms,
including Staphylococcus aureus, Pseudomonas
aeruginosa, Escherichia coli, anthracoid, and yeasts of
the Candida series, by the serial dilution technique
[12, 13]. We also compared the antimicrobial activity
of chiral norbornenedicarboxylic acid monoesters with
the activity of their racemic analogs prepared as
described in [12, 13] and some reference antimicrobial
agents widely used in medical practice (ethanol,
Rivanol, phenol, Nitrofurazone). Figure shows the
results of these studies using compound Vb and etha-
nol as examples. It is seen that the chiral compound
exhibits higher antimicrobial activity than its racemic
analog and control (ethanol). Analogous results were
obtained for other compounds IV and V: optically ac-
3
60
2
40
1
20
0
0.0
0.02
0.04
0.06
0.08
0.10
Concentration, % (aqueous solution)
Antimicrobial activity of (1) optically active monoester
(2S,3S)-(+)-Vb, (2), racemic monoester Vb, and (3) ethanol
(control) against S. aureus.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

MAMEDOV et al.
1758
pentadiene in 10 ml of the same solvent was added
dropwise at a required temperature (see table). The
mixture was stirred for 0.5 h, treated with dilute
hydrochloric acid, washed with water, and dried over
magnesium sulfate. The solvent was distilled off, and
the residue was recrystallized from isooctane.
142°C (from isooctane). IR spectrum, ν, cm–1: 1730
(C=O), 1600 (C=C), 1300 (C–O). H NMR spectrum,
δ, ppm: 0.9 m (3H, CH3), 1.15–1.4 s (2H, CH2), 6.0 m
(2H, CH=CH), 12.0 s (1H, COOH). Found, %: C 64.17;
H 6.96. C12H16O4. Calculated, %: C 64.29; H 7.14.
1
Isopropyl hydrogen (2S,3S)-bicyclo[2.2.1]hept-5-
ene-2,3-dicarboxylate (Vb). Yield 83%, mp 138–
139°C (from isooctane). IR spectrum, ν, cm–1: 1730
Propyl hydrogen (1S,2S)-cyclohex-4-ene-1,2-di-
carboxylate (IVa). Yield 85%, mp 95–69°C (from
isooctane). IR spectrum, ν, cm–1: 1725 (C=O), 1612
1
(C=O), 1612 (C=C), 1300 (C–O). H NMR spectrum,
1
(C=C), 1290 (C–O). H NMR spectrum, δ, ppm:
δ, ppm: 0.9 s (6H, CH3), 6.2 m (2H, CH=CH), 11.9 s
(1H, COOH). Found, %: C 63.92; H 7.36. C12H16O4.
Calculated, %: C 64.29; H 7.14.
5.85 m (2H, CH=CH), 11.6 s (1H, COOH). Found, %:
C 62.84; H 7.02. C11H16O4. Calculated, %: C 62.26;
H 7.55.
Butyl hydrogen (2S,3S)-bicyclo[2.2.1]hept-5-ene-
2,3-dicarboxylate (Vc). Yield 90%, mp 135–137°C
(from isooctane). IR spectrum, ν, cm–1: 1730 (C=O),
Isopropyl hydrogen (1S,2S)-cyclohex-4-ene-1,2-
dicarboxylate (IVb). Yield 85%, mp 91–92°C (from
isooctane). IR spectrum, ν, cm–1: 1730 (C=O), 1610
1
1630 (C=C), 1290 (C–O). H NMR spectrum, δ, ppm:
1
0.9 s (3H, CH3), 6.0 m (2H, CH=CH), 11.9 s (1H,
COOH). Found, %: C 65.10; H 7.10. C13H18O4. Calcu-
lated, %: C 65.54; H 7.56.
(C=C), 1290 (C–O). H NMR spectrum, δ, ppm: 4.2 s
(1H, CHO), 5.85 m (2H, CH=CH), 11.6 s (1H,
COOH). Found, %: C 61.85; H 8.11. C11H16O4. Calcu-
lated, %: C 62.26; H 7.55.
Isobutyl hydrogen (2S,3S)-bicyclo[2.2.1]hept-5-
ene-2,3-dicarboxylate (Vd). Yield 85%, mp 138–
139°C (from isooctane). IR spectrum, ν, cm–1: 1735
Butyl hydrogen (1S,2S)-cyclohex-4-ene-1,2-di-
carboxylate (IVc). Yield 91%, mp 120°C (from iso-
octane). IR spectrum, ν, cm–1: 1730 (C=O), 1630
1
(C=O), 1630 (C=C), 1290 (C–O). H NMR spectrum,
1
δ, ppm: 1.0 d (6H, CH3), 6.0 m (2H, CH=CH), 12.0 s
(1H, COOH). Found, %: C 65.34; H 7.98. C13H18O4.
Calculated, %: C 65.54; H 7.56.
(C=C), 1290 (C–O). H NMR spectrum, δ, ppm: 0.9 d
(3H, CH3), 5.90 m (2H, CH=CH), 11.8 s (1H, COOH).
Found, %: C 63.15; H 7.35. C12H18O4. Calculated, %:
C 63.71; H 7.96.
tert-Butyl hydrogen (2S,3S)-bicyclo[2.2.1]hept-5-
ene-2,3-dicarboxylate (Ve). Yield 83%, mp 142–
143°C (from isooctane). IR spectrum, ν, cm–1: 1750
Isobutyl hydrogen (1S,2S)-cyclohex-4-ene-1,2-di-
carboxylate (IVd). Yield 84%, mp 116–117°C (from
isooctane). IR spectrum, ν, cm–1: 1725 (C=O), 1630
1
(C=O), 1630 (C=C), 1290 (C–O). H NMR spectrum,
1
(C=C), 1295 (C–O). H NMR spectrum, δ, ppm:
δ, ppm: 1.0 t (9H, CH3), 6.0 m (2H, CH=CH), 12.0 s
(1H, COOH). Found, %: C 66.71; H 6.82. C13H18O4.
Calculated, %: C 65.54; H 7.56.
1.0 d.d (6H, CH3), 5.95 m (2H, CH=CH), 11.4 s (1H,
COOH). Found, %: C 64.26; H 7.42. C12H18O4. Cal-
culated, %: C 63.71; H 7.96.
Cyclohexyl hydrogen (2S,3S)-bicyclo[2.2.1]hept-
5-ene-2,3-dicarboxylate (Vf). Yield 86%, mp 115°C
(from isooctane). IR spectrum, ν, cm–1: 1730 (C=O),
tert-Butyl hydrogen (1S,2S)-cyclohex-4-ene-1,2-
dicarboxylate (IVe). Yield 83%, mp 108°C (from
isooctane). IR spectrum, ν, cm–1: 1730 (C=O), 1610
1
1635 (C=C), 1300 (C–O). H NMR spectrum, δ, ppm:
1
(C=C), 1295 (C–O). H NMR spectrum, δ, ppm:
6.0 m (2H, CH=CH), 12.0 s (1H, COOH). Found, %:
C 68.18; H 7.57. C15H20O4. Calculated, %: C 68.01;
H 7.12.
5.95 m (2H, CH=CH), 11.9 s (1H, COOH). Found, %:
C 63.51; H 7.97. C12H18O4. Calculated, %: C 63.71;
H 7.96.
REFERENCES
Cyclohexyl hydrogen (1S,2S)-cyclohex-4-ene-1,2-
dicarboxylate (IVf). Yield 86%, mp 85–87°C (from
isooctane). IR spectrum, ν, cm–1: 1730 (C=O), 1620
(C=C), 1290 (C–O). 1H NMR spectrum, δ, ppm: 6.1 m
(2H, CH=CH), 11.5 s (1H, COOH). Found, %: C 66.12;
H 8.26. C14H20O4. Calculated, %: C 66.66; H 7.94.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

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