Lactones with the p-Menthane System
J. Agric. Food Chem., Vol. 52, No. 6, 2004 1631
anisotropic displacement parameters. Hydrogen atoms were included
from geometry of molecules and ∆F maps. They were refined with
isotropic displacement parameters. Crystallographic data for the
structure reported in this paper (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre. Copies
of this information may be obtained free of charge from the Director,
CCDC, 12 UNION Road, Cambridge 1EZ. UK (fax, +44-1223-
336033; e-mail, deposit@ccdc.cam.ac.uk).
feeding deterency of p-menthanolides, synthesized by us earlier
from optically pure isomers of perillyl alcohol and limonene
(16), showed their quite good activity toward selected insect
storage pests (Sitophilus granarius L., Tribolium confusum Duv.,
and Trogoderma granarium Ev.) (17). Some of them possess
interesting fragrances (18). Their odoriferous properties and
biological activity are influenced by the configuration of the
chiral centers.
In search for new, biologically active monoterpenoid com-
pounds, we have synthesized enantiomeric pairs of esters and
lactones from (R)-(+)- and (S)-(-)-pulegone (10a and 10b).
Here we present the synthesis of enantiomeric pairs of new
compounds with the p-menthane system possessing interesting
odoriferous properties. The chemical synthesis of optically pure
compounds plays an important role in the development of new
drugs, agrochemicals, food additives, flavors and fragrances. It
is well established that chiral discrimination is of primary
importance in odor perception and drug disposition (19-22).
Odor Evaluation. Odoriferous characteristic was done by a group
of perfumers from Technical University of Ło´dz´ under the direction
of Prof. J. Go´ra. The odor evaluation was performed for ethanolic
solutions of samples (10%) with the use of a strip blotter.
Synthesis and Separation of Compounds. cis-(1R, 5R)-(-)-Pulegol
(11a). A suspension of NaBH4 (0.4 g, 10.57 mmol) in EtOH (21 mL)
was added dropwise to an ice-cooled solution of pulegone (R)-(+)-
10a (1.5 g, 9.85 mmol) in MeOH (18 mL) and water (3.6 mL). Stirring
was continued for 2 h at room temperature. When the reaction was
completed (TLC, hexane/acetone 20:1), the mixture was poured into
brine, and the product was extracted with hexane. The combined extracts
were washed with water and dried over anhydrous MgSO4. The solvent
was evaporated in vacuo, and the crude product (1R, 5R)-(-)-11a (1.51
g; according to the GC analysis, 96% purity) was used for the next
EXPERIMENTAL SECTION
25
step without further purification: [R]D ) -105.2° (c ) 1.9, EtOH);
Reagents. (R)-(+)-pulegone, (S)-(-)-pulegone, triethyl orthoacetate,
tributyltin hydride, 1,8-diazabicyclo[5.4.0]undec-7-ene were purchased
from Aldrich and Fluka.
mp ) 30-31 °C (lit. (23): [R]D ) -104°, EtOH:H2O 95:5; mp )
1
29-30 °C). H NMR (acetone-d6): 1.07 (d, J ) 6.8 Hz, 3H, CH3-5),
1.33-1.42 (m, 1H, H-5), 1.49-1.58 (m, 2H, CH2-group), 1.62 and
1.74 (two s, 6H, (CH3)2Cd), 1.66-1.72 (m, 2H, CH2-group), 2.11 and
2.34 (two m, 2H, CH2-group), 3.25 (br. s, 1H, -OH), 4.58 (m, 1H, H
- 1). IR (nujol): 3300 (br. s, OH), 1340 and 1272 (s, C-OH), 1116
(s, OH).
General Procedures. Analytical TLC. Analytical TLC was per-
formed on silica gel (Kieselgel 60 F254, Merck) with mixtures of hexane,
acetone, and diethyl ether in various ratios as developing systems.
Compounds were detected by spraying the plates with 1% Ce(SO4)2/
2% H3(P(Mo3O10)4) in 10% H2SO4, followed by heating to 120 °C.
Column Chromatography. Column chromatography was carried out
on silica gel (Kieselgel 60, 40-63 µm, 230-400 mesh, Merck) with
mixtures of hexane, acetone, and diethyl ether in various ratios as
eluents.
GC Analyses. GC Analyses were performed with a Varian CP-3380
instrument, using the following capillary columns: HP-1 (cross-linked
methyl siloxane), 25-m × 0.32-mm × 0.52-µm; HP-5 (cross-linked
5% phenyl methyl siloxane), 25-m × 0.32-mm × 0.52-µm (injector
temp 250 °C, detector temp 300 °C (FID), carrier gas H2); and CP-
Cyclodextrin-â-2,3,6-m-19, 25-m × 0.25-mm × 0.25-µm (injector temp
150 °C, detector temp 200 °C (FID), carrier gas H2).
Temperature Programs. 11a and 11b: 5 min at 180 °C, raised to
300 °C at 30 °C/min and held 1 min; retention times, 4.069 for 11a
and 4.084 for 11b (HP-5). 12a and b and 13a and b: 5 min at 120 °C,
raised to 300 °C at 30 °C/min and held 1 min; retention times, 5.128
for 12a, 5.130 for 12b, 4.805 for 13a, and 4.812 for 13b (HP-1). 14a
and b, 15a and b and 16: 5 min at 280 °C, raised to 300 °C at 30
°C/min and held 1 min; retention times, 4.404 for 14a, 4.398 for 14b,
2.939 for 15a, 2.921 for 15b, and 2.614 for 16 (HP-5).
1H NMR Spectra. 1H NMR Spectra were recorded in CDCl3 or
acetone-d6 solutions on a Bruker Avance DRX 300 (300 MHz)
spectrometer with TMS as internal standard.
cis-(1S,5S)-(+)-Pulegol (11b). In the same manner as described for
the preparation of (1R, 5R)-(-)-11a, pulegone (S)-(-)-10b (1 g, 6.57
mmol) yielded the crude cis-pulegol (1S, 5S)-(+)-11b (0.95 g; according
25
to the GC analysis, 97% purity): [R]D ) +103.8° (c ) 1.6, EtOH).
1
Its IR and H NMR spectra were identical to those of (1R, 5R)-(-)-
11a.
Ethyl (4R)-(+)-3-Methyl-3-(4-methyl-1-cyclohexen-1-yl)butanoate
(12a). A mixture of the crude cis-pulegol (1R, 5R)-(-)-11a (1.51 g,
9.79 mmol), triethyl orthoacetate (15 mL, 80 mmol) and catalytic
amount of propionic acid (1 drop) was heated at 138 °C for 8 h under
the conditions for distillative removal of ethyl alcohol. When the
reaction was completed (GC, TLC), the mixture was concentrated in
vacuo to remove unreacted orthoacetate. The residue was chromato-
graphed on silica gel. Elution with hexane/diethyl ether (80:1) gave
25
the pure ester (4R)-(+)-12a (1.89 g, 86% yield): [R]D ) +44.1° (c
1
) 5.63, acetone); nD20) 1.4630. H NMR (CDCl3): 0.91 (d, J ) 6.1
Hz, 3H, CH3-4), 1.10 and 1.13 (two s, 6H, (CH3)2C<), 1.20 (t, J ) 7.1
Hz, 3H, -OCH2CH3), 1.44-1.66 (m, 4H, CH2-groups), 1.96-2.10 (m,
3H, CH2-group and H - 4), 2.29 and 2.32 (AB system, J ) 13.2 Hz,
2H, CH2 - 2), 4.04 (q, J ) 7.1 Hz, 2H, -OCH2CH3), 5.41 (m, 1H,
H-2). IR (film): 1748 (s, CdO), 1392 and 1372 (s, (CH3)2C<), 1232
and 1120 (s, C-O-C).
Ethyl (4S)-(-)-3-Methyl-3-(4-methyl-1-cyclohexen-1-yl)butanoate
(12b). According to the procedure described for the preparation of (4R)-
IR Spectra. IR spectra were taken for liquid films on a Specord M80
infrared spectrophotometer (Carl Zeiss Jena).
(+)-12a, the crude cis-pulegol (1S, 5S)-(+)-11b (1.6 g, 10.37 mmol)
Melting Points. Melting points (uncorrected) were determined using
a Boetius apparatus.
25
yielded the unsaturated ester (4S)-(-)-12b (1.95 g, 84%): [R]D
)
-44.4° (c ) 3.87, acetone). Its IR and NMR spectra were identical to
those of (4R)-(+)-12a.
Optical Rotations. Optical rotations were measured with an Autopol
IV automatic polarimeter (Rudolph) in acetone or ethyl alcohol as the
solvent with the concentrations denoted in grams per 100 mL.
X-ray Crystal Analysis. X-ray data were collected at low temper-
ature using an Oxford Cryosystem device on a Kuma KM4CCD κ-axis
diffractometer with graphite-monochromated MoKR radiation (λ )
0.71073 Å). The crystal was positioned at 65 mm from the CCD camera.
Frames (n ) 612) were measured at 0.75° intervals with a counting
time of 20 s. The data were corrected for Lorentz and polarization
effects. No absorption correction was applied. Data reduction and
analysis were carried out with the Oxford Diffraction programs. The
structure was solved by direct methods (program SHELXS-97) and
refined by the full-matrix least-squares method on all F2 data using
the SHELXL-97 programs. Non-hydrogen atoms were refined with
(4R)-(+)-3-Methyl-3-(4-methyl-1-cyclohexen-1-yl)butanoic Acid (13a).
The unsaturated ester (4R)-(+)-12a (0.95 g, 4.23 mmol) was refluxed
for 3 h in 2.5% KOH/EtOH solution (13 mL). After cooling and
evaporating the solvent, the residual solid was dissolved in water and
washed with diethyl ether to remove organic impurities. The water layer
was acidified with 0.1 M HCl solution, and the product was extracted
with diethyl ether. The combined ethereal solution was washed with
brine, dried (MgSO4), and evaporated in vacuo to give the crude acid
(4R)-(+)-13a (0.81 g, 98% yield): [R]D27 ) +47.8° (c ) 5.9, acetone);
20
1
nD ) 1.4710. H NMR (CDCl3): 0.91 (d, J ) 6.2 Hz, 3H, CH3-4),
1.13 and 1.15 (two s, 6H, (CH3)2C<), 1.53-1.72 (m, 4H, CH2-groups),
2.00-2.15 (m, 3H, CH2-group and H-4), 2.33 and 2.35 (AB system, J