Insect pest control agents: Novel chiral butanoate esters (juvenogens)

Article abstract of DOI:10.1016/j.bmc.2007.06.043

During the investigation of ester derivatives (juvenogens, biochemically activated insect hormonogenic compounds) of biologically active alcohols with potential application in insect pest control, a need for availability of all existing stereoisomers of e

Full text of DOI:10.1016/j.bmc.2007.06.043

Bioorganic & Medicinal Chemistry 15 (2007) 6037–6042
Insect pest control agents: Novel chiral butanoate
esters (juvenogens)
Zdeneˇk Wimmer,a,* Alexandra J. F. D. M. Floro,b Marie Zarevu´cka,c
a
d
d
´
Martina Wimmerova, Guido Sello and Fulvia Orsini
aInstitute of Experimental Botany AS CR, Laboratory of Chemistry, Vı´denˇska´ 1083, 14220 Prague 4, Czech Republic
bUniversity of Algarve, School of Technology, Food Engineering, Campus da Penha, 8000-117 Faro, Portugal
cInstitute of Organic Chemistry and Biochemistry AS CR, Flemingovo na´meˇstı´ 2, 16610 Prague 6, Czech Republic
dUniversity of Milan, Via Venezian 21, 20133 Milan, Italy
Received 7 March 2007; revised 15 June 2007; accepted 22 June 2007
Available online 27 June 2007
Abstract—During the investigation of ester derivatives (juvenogens, biochemically activated insect hormonogenic compounds) of
biologically active alcohols with potential application in insect pest control, a need for availability of all existing stereoisomers
of ethyl N-{2-[4-(2-butanoyloxycyclohexyl)methyl]phenoxy}ethyl carbamate occurred. They were synthesized from their chiral pre-
cursors, the corresponding stereoisomers of 2-(4-methoxybenzyl)cyclohexyl butanoate, by removing their protecting group (methyl),
and by subsequent condensation of the aromatic hydroxyl moiety with ethyl N-(2-bromoethyl) carbamate. The requested enantio-
mers of 2-(4-methoxybenzyl)cyclohexyl butanoate were obtained by a Candida antarctica lipase-mediated transesterification and chi-
ral resolution of the respective racemic cis- and trans-isomers of 2-(4-methoxybenzyl)cyclohexanol either directly or after a
subsequent chemical esterification of the chiral precursor. In this synthesis, two convenient butanoic acid activating esters, vinyl but-
anoate and 2,2,2-trifluoroethyl butanoate, were employed, and the chiral precursors in the synthesis of the target molecules were
obtained in 41–48% yields (i.e., 82–96% conversion), and with enantiomeric purity ee = 96–98%, respectively. The enantiomeric pur-
ity of the products was determined by chiral HPLC analysis, and their absolute configuration was assigned on the basis of analyzing
the 1H and 19F NMR spectra of their diastereoisomeric Mosher acid (3,3,3-trifluoromethyl-2-methoxy-2-phenylpropanoic acid)
esters.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
these compounds, chemoenzymic approach was em-
ployed in this synthetic procedure.
Several years ago, a series of fatty acid esters derived
from
racemic
ethyl
N-{2-[4-(2-hydroxycyclo-
Enzymic reactions mediated by lipases (triacylglycerol
hydrolases, EC 3.1.1.3) in non-aqueous media, including
transesterification reactions, have received considerable
attention over the past decade.3 Enantiomerically pure
compounds of biological interest or convenient enantio-
merically pure synthons are usually easily available in
high yields.4 In our past and current projects, the li-
pase-mediated resolution of racemic 2-substituted cyclo-
alkanols, precursors of the insect juvenile hormone
bioanalogs, a series of insect pest management agents,
has been extensively studied.5 Among the lipases tested
to date, lipase B from Candida antarctica was able to
resolve both separated racemic isomers of 2-(4-meth-
oxybenzyl)cyclohexanol with almost quantitative
enantiomeric purity (ee > 99%) of the products, 2-(4-
methoxybenzyl)cyclohexyl acetates5, in the process of
transesterification. Therefore, this enzyme has been
hexyl)methyl]phenoxy}ethyl carbamate was synthesized
and subjected to a detailed laboratory screening tests
against the termite (Prorhinotermes simplex) and the
blowfly (Neobellieria bullata).1 Selected esters from that
series (butanoate and hexadecanoate esters) were subse-
quently subjected to the field trials against termites in
Australia.2 Butanoate esters seemed to receive priority
attention, and, therefore, their pure enantiomers were
requested for basic laboratory screening tests. To obtain
Keywords: Juvenogen; Enzymic transesterification; Enzymic resolu-
tion; Chiral ester; Enantiomer; Diastereoisomer.
*
Corresponding author. Tel.: +420 241 062 381; fax: +420 241 062
111; e-mail: wimmer@ueb.cas.cz
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.06.043

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Z. Wimmer et al. / Bioorg. Med. Chem. 15 (2007) 6037–6042
selected for this chemoenzymic synthesis, which choice
turned to be an advantageous decision.
of the target ethyl N-{2-[4-(2-butanoyloxycyclohexyl)
methyl]phenoxy}ethyl carbamate stereoisomers and (b)
to study the ways of enzymic resolution of the isomeric
racemates to get both the products and the remaining
substrates with as high as possible enantiomeric purity
and chemical yields.
The objective of the present study (Scheme 1) was (a) to
synthesize enantiopure butanoate esters of the studied
alcohols applicable as chiral synthons in the synthesis
OCH3
OCH3
OCH3
OCH3
OH
+
OH
OCOCH2CH2CH3
2a
OH
1a
3a
O
OH
NHCOOCH2CH3
OCOCH2CH2CH3
OCOCH2CH2CH3
OCOCH2CH2CH3
5a
4a
6a
O
NHCOOCH2CH3
OCOCH2CH2CH3
OCOCH2CH2CH3
8a
7a
OCH3
OCH3
OCH3
OCH3
OH
+
OH
OCOCH2CH2CH3
OH
1b
2b
3b
O
OH
NHCOOCH2CH3
OCOCH2CH2CH3
OCOCH2CH2CH3
OCOCH2CH2CH3
5b
4b
6b
O
NHCOOCH2CH3
OCOCH2CH2CH3
OCOCH2CH2CH3
8b
7b
Scheme 1. Lipase-mediated resolution of 1a and 1b.

Z. Wimmer et al. / Bioorg. Med. Chem. 15 (2007) 6037–6042
6039
2. Results and discussion
OCH3
OCH3
OCH3
OCH3
Using a chemoenzymic approach, the requested enanti-
omers of ethyl N-{2-[4-(2-butanoyloxycyclohexyl)
methyl]phenoxy}ethyl carbamate were synthesized. In
the introductory enzymic resolution of racemic sub-
strates 1a and 1b (Scheme 1), vinyl butanoate and
2,2,2-trifluoroethyl butanoate were employed as buta-
noic acid activating derivatives. Lipase B from C. ant-
arctica was employed for mediating enzymic
transesterification (Scheme 1). The course of the enzy-
mic process was monitored by TLC, and the reactions
were finally worked-up after 72 h of stirring in sealed
vials at 40 ꢁC. 2,2,2-Trifluoroethyl butanoate afforded
2a (cis-isomer) with high enantiomeric purity, and vinyl
butanoate represented good medium in preparation of
2b (trans-isomer). The opposite enantiomers of 2-(4-
methoxybenzyl)cyclohexanol (3a and 3b) remained un-
used by the lipase, but enantiomerically resolved, in
the reaction mixture (Table 1).
O
O
F3C
2c
Ph
OCH3
O
O
F3C
3c
Ph
OCH3
To assign the absolute configuration and the enantio-
meric purity of the products 2a, 2b, 3a, and 3b, chiral
HPLC analysis combined with 1H and 19F NMR spectra
analysis of diastereoisomeric esters 2c, 2d, 3c, and 3d de-
rived from the enantiomerically pure 3,3,3-trifluorom-
ethyl-2-methoxy-2-phenylpropanoic acid (Mosher acid;
MTPA) were used. Assigning of the absolute configura-
tion at the C(2) chiral center was based on the differ-
ences of the chemical shifts of the signals of both
hydrogen atoms of the CH2-Ar (benzyl) group in the
1H NMR spectra, and on the differences of the chemical
shift of the signal of the CF3 group in the 19F NMR
spectra.6 The obtained data were in agreement with
the earlier published data of similar compounds bearing
the identical key features of chirality.5 The HPLC anal-
ysis performed on a chiral Nucleodex-b-OH column re-
sulted in separation of the enantiomers present in the
analyzed samples of the alcohols, the major enantiomers
of which are described by the absolute configurations in
the formulae 2a, 2b, 3a, and 3b (Scheme 1). Esterifica-
tion of the chiral alcohols by the (S)-MTPCl (Mosher
acid chloride) afforded diastereoisomeric MTPA esters
(Fig. 1). The absolute configuration was assigned to
the compounds 2a, 2b, 3a, and 3b on the basis of analyz-
O
O
F3C
2d
Ph
OCH3
O
O
F3C
3d
Ph
OCH3
Figure 1. Structures of the (R)-MTPA ester derivatives of chiral
alcohols.
was introduced into the targeted chiral molecules using
their reaction with ethyl N-(2-bromoethyl) carbamate
under basic conditions in 2-butanone (Scheme 1).
1
19
ing the H and F NMR spectra5 of the MTPA esters
2c, 2d, 3c, and 3d (Table 2).
The NMR data of the products were determined on the
basis of both, 1D and 2D NMR experiments. The criti-
cal analysis of the 1D 1H NMR and 1H,1H-PFG-COSY
To get the target compounds, the following reaction
steps7 were applied: (a) the methyl group used as a pro-
tecting function for the aromatic hydroxyl was removed
under acidic conditions; and (b) the aliphatic side chain
1
spectra8 of pure enantiomers allowed assigning the H
Table 1. Results of the analysis of the enzymic resolution process
Substrate
Alkyl butanoate
Product (yield [%]a;
absolute configuration; ee [%])
Remaining substrate (yield [%]a;
absolute configuration; ee [%])
1a
1a
1b
1b
Vinyl
2a (43; (1S,2S); 80)
2a (47; (1S,2S); 97)
2b (48; (1S,2R); 98)
2b (42; (1S,2R); 84)
3a (44; (1R,2R); 79)
3a (46; (1R,2R); 96)
3b (46; (1R,2S); 96)
3b (41; (1R,2S); 81)
2,2,2-Trifluoroethyl
Vinyl
2,2,2-Trifluoroethyl
a Isolated yield, after chromatographic separation of the product and the resolved substrate.

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Z. Wimmer et al. / Bioorg. Med. Chem. 15 (2007) 6037–6042
Table 2. Selected 1H and 19F NMR parameters (signals and coupling constants) of 2c, 2d, 3c, and 3d
Ester of
the (R)-MTPA
Parameter
Product
(absolute configuration)
1H NMR
d (H-7b)
19F NMR
d (H-7a)
J (2,7a)
J (2,7b)
d (CF3)
2c
2d
3c
3d
2.25
2.07
2.33
2.17
2.45
2.70
2.52
2.89
8.1
9.8
8.2
9.9
6.8
3.1
6.7
3.2
ꢀ67.13
ꢀ67.44
ꢀ67.31
ꢀ67.55
2a (1S,2S)
2b (1S,2R)
3a (1R,2R)
3b (1R,2S)
chemical shifts and coupling constants. However, posi-
tions of the H signals of the cyclohexane cycle could
be extracted neither directly from the 1D NMR spectra
pulse program delivered by producer of the spectrome-
ter, for unambiguous assignment of both proton and
carbon signals in the spectra. IR spectra were recorded
in a solution (CCl4) on a Bruker IFS 88 instrument.
Mass spectra (FAB) were recorded on a VG analytical
70–250 SE mass spectrometer, ZAB-EQ (BEQQ config-
uration) at 70 eV. Preparative column chromatography
was performed on a silica gel type 60 (particle size
0.04–0.063 mm; Fluka, Switzerland). TLC was per-
formed on aluminum sheets precoated with silica gel
60 (Merck, Germany). Analytical HPLC was carried
out on a TSP (Thermoseparation Products, USA)
instrument equipped with a ConstaMetric 4100 Bio
pump and a SpectroMonitor 5000 UV DAD. The anal-
yses of the products were performed on a chiral Nucle-
odex b-OH column (150 · 4 mm; Macherey-Nagel,
Germany) using a methanol/water mixture (9:1, v/v) as
mobile phase at 0.3 mL minꢀ1. The eluate was moni-
tored at 220, 254, and 275 nm, and the UV spectra were
run from 200 to 300 nm. Optical rotations were mea-
sured on an Autopol IV polarimeter (Rudolph Research
Analytical, USA). Elemental analyses were performed
on a Perkin-Elmer 2400, series II CHNS/O analyzer
(USA).
1
nor from the 1H,1H-PFG-COSY spectra, and it was nec-
1
essary to estimate these values from the H,13C-PFG-
HSQC spectra8 using the knowledge of the 13C NMR
chemical shifts from the model compounds with similar
structure.9 The 2D 1H,13C-PFG-HSQC spectra were
used for unambiguous assignment of the 13C NMR
chemical shifts of the remaining carbon atoms.
Preliminary results of the biological screening tests on
the termite P. simplex demonstrate the juvenilizing effect
of the compounds 5a, 5b, 8a, and 8b. When the concen-
tration 0.5 mg mLꢀ1 of the active ingredient was used in
the force feeding test, 65–90% juvenilizing effect was ob-
served under mortality corresponding to the control
experiment. Methodology used for screening tests was
always normally used in these tests and described
earlier.1
3. Conclusion
The employed enzymic process represents a convenient
way of preparation of 2a and 3a using 2,2,2-trifluoroeth-
yl butanoate as butanoic acid activating derivative, and
of 2b and 3b using vinyl butanoate in high enantiomeric
purity (ee = 95–98%) and conversion (92–95%). The tar-
get chiral products 5a, 5b, 8a, and 8b were then prepared
by a sequence of the synthetic steps described in Section
2. The products 5a, 5b, 8a, and 8b have been submitted
to entomological screening tests, which will be published
separately after completing the tests on several unrelated
insect pest species.
4.2. Enzymic resolution of the racemic isomers of 2-(4-
methoxybenzyl)cyclohexanol 1a and 1b
The respective cis- or trans-isomer of 2-(4-methoxyben-
zyl)cyclohexanol (1a or 1b; 500 mg; 2.27 mmol) was dis-
solved in either vinyl butanoate or 2,2,2-trifluoroethyl
butanoate (10 mL) in a vial and non-immobilized pow-
dered lipase from C. antarctica (30 mg; 2.7 U mgꢀ1
)
was added. The vial was sealed by a screw stopcock
equipped with a Teflon-coated rubber seal, and the reac-
tion mixture was stirred at 40 ꢁC for 24 h. The enzyme
was filtered off, the solvent was evaporated, and the res-
idue separated by a column chromatography on silica
gel using light petroleum/diethyl ether mixture (10:1 to
5:1) as mobile phase. Chemical yields of the products
2a, 2b, 3a, and 3b are given in Table 1 in relation to
the alkyl butanoate used in the reaction.
4. Experimental
4.1. General
1
The H NMR and the 13C NMR spectra were recorded
on a Bruker AVANCE 500 spectrometer (in a FT mode)
at 500.1 MHz and 125.8 MHz, respectively, in CDCl3
1
Compound 2a: H NMR (CDCl3): 1.00 (t, J = 7.4 Hz,
1
using either tetramethylsilane (d = 0.0 for H NMR) or
3H), 1.20–1.27 (m, 1H), 1.35–1.42 (m, 1H), 1.40–1.52
(m, 2H), 1.45–1.53 (m, 2H), 1.67–1.72 (m, 1H), 1.71
(m, 1H), 1.72 (m, J = 7.5 Hz, 2H), 1.88–1.94 (m, 1H),
2.35 (t, J = 7.6 Hz, 2H), 2.39 (dd, J = 7.9, 13.7 Hz,
1H), 2.56 (dd, J = 7.8, 13.7 Hz, 1H), 3.78 (s, 3H), 4.92
(dt, J = 2.6, 2.6, 4.4 Hz, 1H), 6.81 (m, 2H), 7.01 (m,
2H); 13C NMR (CDCl3): 13.79 (q), 18.73 (t), 20.87 (t),
25.06 (t), 27.00 (t), 30.00 (t), 36.79 (t), 37.75 (t), 42.57
a solvent signal (CDCl3—d = 77.00 for 13C NMR) as
internal reference at a temperature of 303 K. The 19F
NMR spectra were recorded on a Varian UNITY 500
spectrometer at 470.3 MHz in deuteriochloroform using
hexafluorobenzene as external reference (d = ꢀ162.9).
The 2D NMR experiments (1H,1H-PFG-COSY and
1H,13C-PFG-HSQC) were performed using standard

Z. Wimmer et al. / Bioorg. Med. Chem. 15 (2007) 6037–6042
6041
(d), 55.22 (q), 71.84 (d), 113.72 (d), 129.89 (d), 132.53 (s),
157.83 (s), 173.17 (s); IR (CCl4): 3464 (w), 3033 (w),
1729 (s), 1612 (w), 1243 (s), 1176 (s), 1095 (m); FAB
had first to be saponified by heating to reflux with potas-
sium carbonate (150 mg) in a mixture of methanol
(20 mL) and water (5 mL) for 2 h. Methanol and water
were removed under reduced pressure, the residue was
applied onto a silica gel column and purified, affording
the pure products in the yields P95%, and subsequently
transformed into their MTPA esters 2c and 2d. The es-
ters 2c, 2d, 3c, and 3d (Fig. 1) were obtained in quanti-
tative yields. Their selected 1H and 19F NMR data,
which are important for assignment of the absolute con-
figuration of 2a, 2b, 3a, and 3b, are given in Table 2.
MS: (m/z) 291 [(M+H)]+; Calcd for C18H26O3 (290.39):
20
D
C, 74.44; H, 9.03. Found C, 74.40; H, 9.05; ½aꢁ +89
(c 0.035, CHCl3).
1
Compound 2b: H NMR (CDCl3): 0.95 (t, J = 7.4 Hz,
3H), 0.96 (m, 1H), 1.24–1.33 (m, 2H), 1.27–1.32 (m,
1H), 1.57–1.61 (m, 1H), 1.67 (m, J = 7.4 Hz, 2H),
1.67–1.74 (m, 3H), 1.97–2.02 (m, 1H), 2.20 (dd,
J = 9.3, 13.6 Hz, 1H), 2.26 (dt, J = 0.9, 7.4, 7.4 Hz,
2H), 2.84 (dd, J = 3.8, 13.6 Hz, 1H), 3.78 (s, 3H), 4.57
(dt, J = 4.5, 10.1, 10.1 Hz, 1H), 6.81 (m, 2H), 7.03 (m,
2H); 13C NMR (CDCl3): 13.70 (q), 18.60 (t), 24.53 (t),
25.09 (t), 29.92 (t), 31.88 (t), 36.63 (t), 37.83 (t), 43.89
(d), 55.23 (q), 76.52 (d), 113.60 (d), 130.06 (d), 132.32
(s), 157.79 (s), 173.39 (s); 5: IR (CCl4): 3464 (w), 3034
(w), 1728 (s), 1612 (w), 1243 (s), 1177 (s), 1101 (m),
1089 (m); FAB MS: (m/z) 291 [(M+H)]+; Calcd for
4.4. Synthesis of the butanoate esters 6a and 6b
A solution of the alcohols 3a or 3b (0.884 mmol) in ben-
zene (10 mL) and pyridine (0.4 mL) was cooled to 0 ꢁC
under vigorous stirring.
A
fatty acid chloride
(1.06 mmol) was added in one portion by a pipette,
and the mixture was stirred at 20 ꢁC for 2–6 h. The reac-
tion course was monitored by TLC. The mixture was
then poured onto a mixture of ice (20 mL) and hydro-
chloric acid (1 mL). The organic layer was extracted with
diethyl ether, and the extract was dried over sodium sul-
fate. After evaporation of the solvent under reduced
pressure, the crude residue was purified by column chro-
matography on silica gel. The products 6a and 6b were
obtained in 95% yields. Their analytical data were iden-
C18H26O3 (290.39): C, 74.44; H, 9.03. Found C, 74.47;
20
D
H, 9.01; ½aꢁ +124 (c 0.046, CHCl3).
1
Compound 3a: H NMR (CDCl3): 1.18–1.25 (m, 1H),
1.34–1.44 (m, 2H), 1.42–1.48 (m, 2H), 1.54–1.62 (m,
1H), 1.64–1.70 (m, 2H), 1.73–1.79 (m, 1H), 2.48 (dd,
J = 7.6, 13.6 Hz, 1H), 2.66 (dd, J = 7.6, 13.6 Hz, 1H),
3.78 (s, w = 11, 1H), 3.79 (s, 3H), 6.82 (m, 2H), 7.10
(m, 2H); 13C NMR (CDCl3): 20.34 (t), 25.31 (t), 26.37
(t), 33.27 (t), 37.75 (t), 43.67 (d), 55.23 (q), 68.51 (d),
113.66 (d), 129.95 (d), 133.01 (s), 157.75 (s); IR (CCl4):
3631 (w), 3501 (w), 3064 (w), 3032 (w), 2934 (s), 2835
(m), 1176 (s), 1041 (s), 974 (m); FAB MS: (m/z) 220
tical with those recorded for 2a and 2b with the exception
20
D
of the optical rotation data: 6a: ½aꢁ ꢀ87 (c 0.040,
20
CHCl3); 6b: ½aꢁ ꢀ120 (c 0.037, CHCl3).
D
4.5. Synthesis of the compounds 5a, 5b, 8a, and 8b
([M]+). Calcd for C14H20O2 (220.30): C, 76.32; H, 9.15.
(a) A solution of the respective 2a, 2b, 6a or 6b (100 mg,
0.4 mmol) in a benzene/ethanol (1:1) mixture (5 mL) was
heated to 40 ꢁC in the presence of concentrated hydro-
bromic acid (0.1 mL) for 12 h. Solvents were evapo-
rated, and the residue was partitioned between water
and ether layer. The organic extract was dried over so-
dium sulfate, and the crude residues (4a, 4b, 7a, and
7b) obtained after removal of the solvent were directly
used in the following reaction step.
20
D
Found: C, 76.28; H, 9.13; ½aꢁ ꢀ33 (c 0.036, CHCl3).
1
Compound 3b: H NMR (CDCl3): 0.90 (ddt, J = 3.5,
11.5, 11.5, 16.5 Hz, 1H), 1.09 (dtt, J = 3.5, 3.5, 11.7,
11.7, 15.0 Hz, 1H), 1.19–1.29 (m, 2H) 1.46 (m, 1H),
1.56–1.60 (m, 1H), 1.64 (ddt, J = 2.0, 3.5, 3.5, 16.5 Hz,
1H), 1.68–1.73 (m, 1H), 1.95–2.00 (m, 1H), 2.33 (dd,
J = 9.0, 13.5 Hz, 1H), 3.07 (dd, J = 4.1, 13.5 Hz, 1H),
3.28 (dt, J = 4.3, 9.9, 9.9 Hz, 1H), 3.79 (s, 3H), 6.82 (m,
2H), 7.10 (m, 2H); 13C NMR (CDCl3): 24.88 (t), 25.43
(t), 30.00 (t), 35.77 (t), 38.07 (d), 47.08 (t), 55.22 (q),
74.51 (d), 113.61 (d), 130.25 (d), 132.67 (s), 157.76 (s);
IR (CCl4): 3624 (w), 3604 (w), 3064 (w), 3033 (w), 2835
(m), 1177 (m), 1042 (s), 1025 (m); FAB MS: (m/z) 220
(b) Dry powdered potassium carbonate (1 g) and ethyl
N-(2-bromoethyl)carbamate (1 g, 5.0 mmol) were added
to a solution of the respective chiral 4a, 4b, 7a, and 7b
(0.2 mmol) in 2-butanone (15 mL). The mixture was re-
fluxed for 12 h, cooled, filtered, and the solid material
was washed with diethyl ether (30 mL). The filtrate
was washed with water (10 mL) and dried over magne-
sium sulfate. After filtration, the solvents were removed
under reduced pressure, and the residues were purified
by column chromatography on silica gel, yielding the
target products 5a (90%), 5b (91%), 8a (93%), and 8b
(92%).
([M]+). Calcd for C14H20O2 (220.30): C, 76.32; H, 9.15.
20
D
Found: C, 76.36; H, 9.16; ½aꢁ +22 (c 0.043, CHCl3).
4.3. Synthesis of 3,3,3-trifluoro-2-methoxy-2-phenylprop-
anoic acid esters 2c, 2d, 3c, and 3d
A general procedure used for the synthesis of the (R)-
MTPA (3,3,3-trifluoro-2-methoxy-2-phenylpropanoic
acid; Mosher’s acid) esters on a milligram scale starting
from the (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropa-
noyl chloride (MTPCl, Mosher’s chloride) was already
described in details.5,10 While the chiral alcohols 3a
and 3b could be directly transformed into their MTPA
esters 3c and 3d, their enantiomers corresponding to
their butanoate esters 2a and 2b (104.6 mg; 0.36 mmol)
Compound 5a/8a: 1H NMR (CDCl3): 1.00 (t,
J = 7.4 Hz, 3H), 1.20–1.51 (m, 8H), 1.24 (t, J = 7.2 Hz,
3H), 1.72 (m, 2H), 1.91 (m, 1H), 2.35 (t, J = 7.5 Hz,
2H), 2.39 (dd, J = 8.2, 13.6 Hz, 1H), 2.55 (dd, J = 6.9,
13.6 Hz, 1H), 3.57 (bq, J = 5.3 Hz, 2H), 4.00 (t,
J = 5.3 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 4.91 (dt,
J = 2.6, 2.6, 4.4 Hz, 1H), 5.11 (bt, J = 5.3 Hz, 1H),

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Z. Wimmer et al. / Bioorg. Med. Chem. 15 (2007) 6037–6042
6.79 (m, 2H), 7.00 (m, 2H). 13C NMR (CDCl3): 13.78
(q), 14.61 (q), 18.72 (t), 20.86 (t), 25.05 (t), 26.99 (t),
29.99 (t), 36.78 (t), 37.74 (t), 40.52 (t), 42.55 (d), 60.91
(t), 66.99 (t), 71.77 (d), 114.30 (d), 129.97 (d), 133.06
(s), 156.64 (s), 156.74 (s), 173.13 (s). IR (CCl4): 3464
(w), 3033 (w), 1729 (s), 1612 (w), 1585 (w), 1510(s),
1243 (s), 1176 (s), 1095 (m) cmꢀ1. FAB MS (m/z) 392
([M+H]+, 35), 304 (21), 231 (8), 154 (9), 137 (9), 116
(100), 107 (21), 88 (42), 71 (13). Calcd for C22H33NO5
References and notes
ˇ
1. Wimmer, Z.; Saman, D.; Kuldova, J.; Hrdy, I.; Bennet-
´
tova, B. Bioorg. Med. Chem. 2002, 10, 1305–1312.
´
´
2. Hrdy´, I.; Kuldova, J.; Wimmer, Z.; Lenz, M.; Gleeson, P.
´
V. Laboratory and Field Trials with Juvenogens as
Potential Termite Control Agents. XXII International
Congress of Entomology, Abstracts on CD-ROM. Bris-
bane (Australia), 2004.
3. (a) Klibanov, A. M. Nature 2001, 409, 241–246; (b)
Kontogianni, A.; Skouridou, V.; Sereti, V.; Stamatis, H.;
Kolisis, F. N. Eur. J. Lipid Sci. Technol. 2001, 103, 655–
660; (c) Buchholz, K.; Kasche, V.; Bornscheurer, U. T.
Enzymes in Organic Chemistry. In Biocatalysts and
Enzyme Technology; Buchholz, K., Kasche, V., Born-
scheurer, U. T., Eds.; Wiley-VCH: Weinheim, 2005; pp
109–170.
4. (a) Patel, R. N. Enzyme Microb. Technol. 2002, 31, 804–
826; (b) Skouridou, V.; Chrysina, E. D.; Stamatis, H.;
Oikonomakos, N. G.; Kolisis, F. N. J. Mol. Catal. B:
Enzym. 2004, 29, 9–12.
(391.49): C, 67.49; H, 8.50; N, 3.58. Found: C, 67.52;
20
D
H, 8.47; N, 3.61; Compound 5a: ½aꢁ +80 (c 0.031,
20
CHCl3); Compound 8a: ½aꢁ ꢀ79 (c 0.027, CHCl3).
D
Compound 5b/8b: 1H NMR (CDCl3): 0.96 (t,
J = 7.4 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.26–1.78 (m,
10 H), 2.00 (m, 1H), 2.19 (dd, J = 9.3, 13.6 Hz, 1H),
2.27 (t, J = 7.5 Hz, 2H), 2.84 (dd, J = 3.8, 13.6 Hz,
1H), 3.57 (bq, J = 5.3 Hz, 2H), 4.00 (t, J = 5.3 Hz,
2H), 4.12 (q, J = 7.2 Hz, 2H), 4.56 (dt, J = 4.4, 10.1,
10.1 Hz, 1H), 5.12 (bt, J = 5.3 Hz, 1H), 6.80(m, 2H),
7.03 (m, 2H). 13C NMR (CDCl3): 13.70 (q), 14.61 (q),
18.60 (t), 24.52 (t), 25.09 (t), 29.91 (t), 31.87 (t), 36.64
(t), 37.84 (t), 40.56 (t), 43.89 (d), 60.92 (t), 67.05 (t),
76.48 (d), 114.25 (d), 130.16 (d), 132.90 (s), 156.66 (s),
156.75 (s), 173.35 (s). IR (CCl4): 3464 (w), 3034 (w),
1728 (s), 1612 (w), 1585 (w), 1509 (s), 1243 (s), 1177
(s), 1101 (m), 1089 (m) cmꢀ1. FAB MS (m/z) 392
([M+1]+, 17), 320 (6), 304 (11), 222 (6), 133 (6), 116
(100), 107 (37), 88 (45), 71 (13). Calcd for C22H33NO5
5. (a) Wimmer, Z. Tetrahedron 1992, 48, 8431–8436; (b)
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Wimmer, Z.; Zarevu´cka, M.; Rejzek, M.; Saman, D.;
Zhao, Q.; Legoy, M.-D. Helv. Chim. Acta 1997, 80, 818–
831; (c) Brunet, C.; Zarevu´cka, M.; Wimmer, Z.; Legoy,
M.-D. Enzyme Microb. Technol. 2002, 31, 609–614; (d)
Wimmer, Z.; Skouridou, V.; Zarevu´cka, M.; Saman, D.;
Kolisis, F. N. Tetrahedron: Asymmetry 2004, 15, 3911–
3917.
ˇ
6. Rinaldi, P. L. Prog. Nucl. Magn. Reson. Spectrosc. 1982,
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A.; van Zijl, C. M. J. Magn. Reson. 1991, 93, 423–429; (b)
Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W.
Magn. Reson. Chem. 1993, 31, 287–292.
(391.49): C, 67.49; H, 8.50; N, 3.58. Found: C, 67.45;
20
D
H, 8.47; N, 3.55; Compound 5b: ½aꢁ +109 (c 0.033,
20
CHCl3); 8b: ½aꢁ ꢀ105 (c 0.036, CHCl3).
D
ˇ
9. Rejzek, M.; Wimmer, Z.; Zarevu´cka, M.; Saman, D.;
Acknowledgments
ˇ
Pavlık, M.; Rıcankova, M. Tetrahedron: Asymmetry 1994,
´
5, 1501–1512.
´ˇ´
´
This investigation was supported by the Grant 203/05/
2146 (Czech Science Foundation). A. Floro thanks the
Socrates scholarship for financial support of her study
visit to the Czech Republic. The authors thank Acad-
emy of Sciences of the Czech Republic and Italian
CNR for a mobility grant (2004–2006).
10. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543–2549; (b) Dale, J. A.; Mosher, H. S. J. Org.
Chem. 1970, 35, 4002–4003; (c) Dale, J. A.; Mosher, H. S.
J. Am. Chem. Soc. 1973, 95, 512–519; (d) Sullivan, G. R.;
Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143–
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