Origin of enantiomeric selectivity in the aryloxyphenoxypropionic acid class of herbicidal acetyl coenzyme A carboxylase (ACCase) inhibitors.

Article abstract of DOI:10.1021/jf0116395

Molecular modeling was used to propose an "active conformation" for the R-2-phenoxypropionic acid portion of the aryloxyphenoxypropionic acid series of herbicidal acetyl CoA carboxylase (ACCase) inhibitors. This candidate active conformation is a low-energy conformer with the R-methyl distal to the phenoxy fragment, stabilized by the generalized anomeric effect around the propionate ether bond; the inactive S-enantiomer has difficulty accessing this conformation due to steric interaction of the S-methyl with the o-hydrogen of the phenyl. This candidate conformation was challenged by preparation of a series of novel rigid analogues. ACCase inhibition data suggest that the systems which contain a fused five-membered, but not a six-membered, ring present the necessary pharmacophore to the active site of ACCase, confirming the active conformation hypothesis and demonstrating that the precise placement of the carboxylate relative to the phenyl group is more critical than the placement of the methyl.

Full text of DOI:10.1021/jf0116395

4554 J. Agric. Food Chem. 2002, 50, 4554−4566
Origin of Enantiomeric Selectivity in the
Aryloxyphenoxypropionic Acid Class of Herbicidal Acetyl
Coenzyme A Carboxylase (ACCase) Inhibitors
JAMES A. TURNER* AND DANIEL J. PERNICH
Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, Indiana 46268-1054
Molecular modeling was used to propose an “active conformation” for the R-2-phenoxypropionic acid
portion of the aryloxyphenoxypropionic acid series of herbicidal acetyl CoA carboxylase (ACCase)
inhibitors. This candidate active conformation is a low-energy conformer with the R-methyl distal to
the phenoxy fragment, stabilized by the generalized anomeric effect around the propionate ether
bond; the inactive S-enantiomer has difficulty accessing this conformation due to steric interaction of
the S-methyl with the o-hydrogen of the phenyl. This candidate conformation was challenged by
preparation of a series of novel rigid analogues. ACCase inhibition data suggest that the systems
which contain a fused five-membered, but not a six-membered, ring present the necessary
pharmacophore to the active site of ACCase, confirming the active conformation hypothesis and
demonstrating that the precise placement of the carboxylate relative to the phenyl group is more
critical than the placement of the methyl.
KEYWORDS: Herbicide; aryloxyphenoxypropionic acids; conformational analysis; acetyl coenzyme A
carboxylase; ACCase inhibitor
INTRODUCTION
The aryloxyphenoxypropionic acids (1) are an important class
of very potent herbicides (1). These materials possess an
unusual, yet practically advantageous, attributestheir herbicidal
activity is expressed against a single family of plants, namely,
the Gramineae or grass family. In practical terms this means
that herbicides from this class can be used to control grasses,
generally considered the world’s most significant family of
weedy plants, in any dicotyledonous crop without concern of
potential crop injury. The herbicidal activity of the aryloxyphe-
noxypropionic acids results from inhibition of acetyl coenzyme
A carboxylase (ACCase), the enzyme responsible for catalysis
of the first committed step in de novo fatty acid biosynthesis
(2-4). It has recently been shown that most plant families
contain two types of ACCase, a herbicide-sensitive eukaryote
form and an insensitive prokaryote form (5). The selectivity of
aryloxyphenoxypropionic acids apparently results from the
absence of the insensitive form of ACCase in grasses.
Some typical commercial herbicides from the aryloxyphe-
noxypropionic acid area of chemistry include (Figure 1)
diclofop (1), which is primarily used for control of grass weeds
in cereal crops, and the much more potent, broad-spectrum
graminicides, haloxyfop (2) and quizalifop (3). Despite the
apparent diversity in the heterocyclic portion of these three
herbicides, bioactivity in this series is limited by rather strict
structural requirements on the aryl group and its associated
Figure 1. Representative aryloxyphenoxypropionic acid herbicides: di-
clofop (1); haloxyfop (2); quizalifop (3).
substituents. For example, the optimal substituent is different
depending upon the nature of the heterocycle itself. In the
monocyclic series (Ar ) benzene or pyridine), a substituent is
required at the position para to the ether linkage and activity is
maximized with larger halogens or pseudo-halogens (such as
an iodine or trifluoromethyl group) at this position (6). In the
bicyclic series (such as the quinoxaline shown here), analogues
with an unsubstituted heterocycle are phytotoxic but the activity
is greatly enhanced by the presence of a small halogen (chlorine
or fluorine) at the 6-position of the heterocycle (7). In contrast
to the aryl portion of the molecule, substitution on the benzene
ring of the phenoxypropionic acid fragment invariably results
in a decrease in bioactivity. Only the R-enantiomers of the
aryloxyphenoxypropionic acids are herbicidal (8-10).
An understanding of the nature of the interaction of the known
aryloxyphenoxypropionic acids with ACCase is desirable for
efforts directed toward discovery of novel classes of potentially
* Author to whom correspondence should be addressed [telephone (317)
337-3155; fax (317) 337-3215; e-mail jaturner@dow.com].
10.1021/jf0116395 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/26/2002

Enantiomeric Selectivity of Aryloxyphenoxypropionic Acids
J. Agric. Food Chem., Vol. 50, No. 16, 2002 4555
12 as a light-colored gum: 1H NMR δ 8.27 (br, 1H), 8.00 (d, J ) 2
Hz, 1H), 6.77 (d, J ) 9 Hz, 1H), 6.55 (d, J ) 3 Hz, 1H), 6.49 (dd,
J ) 3, 9 Hz, 1H).
Methyl 5-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-1,3-
benzodioxole-2-carboxylate (7a). A mixture of 11.30 g (37 mmol) of
catechol 12, 125 mL of 2-propanol, and 21.96 g (160 mmol) of
powdered anhydrous K2CO3 was stirred under N2 while 4.77 g (37
mmol) of dichloroacetic acid was added dropwise (gas evolution). The
resulting mixture was warmed at reflux for 24 h. The thick mixture
was cooled, and an additional 4.77 g (37 mmol) of dichloroacetic acid
was added and then stirred at reflux for an additional 48 h. After cooling,
the mixture was poured into 400 mL of water and made acidic by the
addition of 6 M HCl. The dark mixture was extracted with two portions
of ether, and the combined organic layers were extracted with two
portions of saturated NaHCO3. The aqueous layers were combined,
made acidic by the addition of 6 M HCl, and then extracted with two
portions of ether. The organic layers were combined, washed with water,
dried over MgSO4, and evaporated to leave 12 g of crude product as a
dark semisolid.
The crude material prepared above was stirred with 100 mL of
benzene, and 15 mL of thionyl chloride was added. The resulting
mixture was stirred at reflux for 4 h (gas evolution), cooled, and
evaporated to dryness. Toluene (25 mL) was added and the mixture
again evaporated to dryness. The resulting dark oil was dissolved in
100 mL of CH2Cl2 and cooled in an ice bath while 2.56 g (80 mmol)
of methanol and 6.32 g (80 mmol) of pyridine were added dropwise.
The resulting mixture was stirred at ambient temperature for 2 h and
then poured into 1 M HCl and extracted with two portions of ether.
The combined organic layers were washed with 1 M HCl and saturated
NaHCO3, dried over Na2SO4, and evaporated to dryness. The dark
residue was purified by preparative scale HPLC, eluting with 9:1
hexane/ethyl acetate to give an oily fraction, which was further purified
by bulb-to-bulb distillation (130-140 °C bath temperature, 0.07
mmHg). This gave 4.58 g (45%) of 7a as a pale yellow oil, which
solidified on standing: mp 84-87 °C; 1H NMR δ 8.28 (br, 1H), 7.95
(d, J ) 2 Hz, 1H), 6.90 (d, J ) 8 Hz, 1H), 6.74 (d, J ) 3 Hz, 1H),
6.67 (dd, J ) 3, 8 Hz, 1H), 6.39 (s, 1H), 3.88 (s, 3H). Anal. Calcd for
C15H9ClF3NO5: C, 47.95; H, 2.41; N, 3.73. Found: C, 47.61; H, 2.60;
N, 3.63.
5-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-1,3-benzodiox-
ole-2-carboxylic Acid (7). A solution of 1.88 g (5 mmol) of ester 7a
in 5 mL of THF was stirred under N2 while a solution of 2.2 g (5.5
mmol) of 10% aqueous NaOH was added. The resulting solution was
stirred at ambient temperature for 30 min, poured into water, and made
acidic by the slow addition of 1 M HCl. The resulting oily mixture
was stirred until crystals formed and the solid removed by filtration,
washed with water, and dried to give 1.80 g of 7 as colorless crystals:
mp 157-160 °C; 1H NMR δ 8.28 (br d, 1H), 7.97 (d, J ) 2 Hz, 1H),
6.88 (d, J ) 8 Hz, 1H), 6.72 (d, J ) 3 Hz, 1H), 6.67 (dd, J ) 3, 8 Hz,
1H), 6.34 (s, 1H). An analytical sample was obtained by recrystallization
from toluene/methylcyclohexane. Anal. Calcd for C14H7ClF3NO5: C,
46.49; H, 1.95; N, 3.87. Found: C, 46.14; H, 2.36; N, 3.78.
6-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2-phenyl-4H-
1,3,2-benzodioxaborinin (15). A mixture of 28.95 g (100 mmol) of
14, 14.64 g (110 mmol) of phenylboronic acid, 3.70 g (50 mmol) of
propanoic acid, 2 g of paraformaldehyde, and 200 mL of benzene was
warmed at reflux using a Dean-Stark trap to separate water formed
during the reaction. Additional paraformaldehyde was added in ∼2 g
portions at 1 h intervals until a total of 16 g (500 mmol) of
paraformaldehyde had been added. The resulting mixture was stirred
for an additional 3 h at reflux, cooled, poured into water, and extracted
with two portions of ether. The combined organic layers were washed
with saturated Na2CO3, dried over MgSO4, and evaporated to dryness.
The residue was recrystallized from hexane to give 23.27 g (57%) of
15 as nearly colorless crystals: mp 108-110 °C; 1H NMR δ 8.28 (br
d, 1H), 7.99 (m, 2H), 7.97 (d, J ) 2 Hz, 1H), 7.46 (m, 3H), 7.16 (d,
J ) 9 Hz, 1H), 7.05 (dd, J ) 3, 9 Hz, 1H), 6.95 (d, J ) 3 Hz, 1H),
5.35 (s, 2H). Anal. Calcd for C19H12BClF3NO3: C, 56.26; H, 2.98; N,
3.45. Found: C, 56.06; H, 3.10; N, 3.38.
Figure 2. Model for interaction of the aryloxyphenoxypropionic acids with
ACCase.
more potent and selective herbicides. A simple model for the
interaction of the aryloxyphenoxypropionic acids with the
enzyme ACCase can be derived from structure-activity rela-
tionships such as those described above (Figure 2). Thus, there
appear to be two important domains on the enzyme, a lipophilic
region and an anion-binding region, which are responsible for
recognition of the substrate. For this information to be of value
in the design of new classes of ACCase inhibitors, there is a
need to understand the relative orientation of these two domains
in three-dimensional space. This is a complex problem in this
series because there is the potential for complete freedom of
rotation around each of the four ether bonds. In this study we
have attempted to define the “active conformation” of the
phenoxypropionic acid portion of the aryloxyphenoxypropionic
acids, using a combination of molecular modeling and targeted
synthesis. In addition, we provide a proposal for the origin of
the enzymatic enantioselectivity in this series of ACCase
inhibitors.
MATERIALS AND METHODS
Melting points were determined on a Thomas-Hoover capillary
melting point apparatus and are uncorrected. Proton NMR spectra were
recorded in CDCl3 (unless otherwise noted) at 200 MHz by using a
Varian XL-200 spectrometer. Chemical shifts are reported in parts per
million (δ) downfield from internal tetramethylsilane. Normal phase
preparative chromatography was performed with a Waters PrepSystem
500A liquid chromatograph. Most reagents were obtained from Aldrich
Chemical Co. (Milwaukee, WI) and were used as received.
2-[5-(1,3-Benzodioxolyl)oxy]-3-chloro-5-(trifluoromethyl)pyri-
dine (11). A mixture of 45.5 g (0.33 mol) of 3,4-methylenedioxyphenol,
45.5 g (0.33 mol) of powdered anhydrous K2CO3, 59.3 g (0.30 mol) of
fluoropyridine 10, and 200 mL of DMSO was stirred under N2 at
ambient temperature for a period of 4 h. The resulting mixture was
poured into water and extracted with two portions of ether. The
combined organic layers were washed with 5% aqueous NaOH and
water, dried over MgSO4, and evaporated to dryness. The residual oil
was crystallized from hexane to give 72.99 g (77%) of tan crystalline
11: mp 62-65 °C; 1H NMR δ 8.28 (br, 1H), 7.96 (d, J ) 2 Hz, 1H),
6.83 (d, J ) 8 Hz, 1H), 6.68 (d, J ) 2 Hz, 1H), 6.62 (dd, J ) 2, 8 Hz,
1H), 6.02 (s, 2H). Anal. Calcd for C13H7ClF3NO3: C, 49.15; H, 2.22;
N, 4.41. Found: C, 49.16; H, 2.26; N, 4.29.
4-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]benzene-1,2-
diol (12). A solution prepared from 15.88 g (50 mmol) of 11, 21.9 g
(105 mmol) of PCl5, and 200 mL of CH2Cl2 was warmed at reflux for
a period of 3 days. The resulting mixture was cooled, cautiously poured
over ice, and stirred at ambient temperature for 1 h. The mixture was
diluted with ether and the aqueous layer separated and again washed
with ether. The combined organic layers were washed with water, dried
over MgSO4, and evaporated to leave a gummy residue.
The material prepared above was dissolved in 100 mL of THF, and
a solution prepared from 11.5 g (175 mmol) of KOH in 100 mL of
water was added. The dark mixture was stirred under N2 at ambient
temperature for 1 h, diluted with water, and washed with ether (discard).
The aqueous phase was then made acidic with 6 M HCl and the
resulting mixture extracted with three portions of ether. The combined
organic layers were washed with water, dried over MgSO4, and
evaporated to dryness. The dark residue was purified by preparative
scale HPLC, eluting with 3:2 hexane/acetone to give 11.8 g (78%) of
4-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2-(hydroxy-
methyl)phenol (13). A solution of 4.06 g (10 mmol) of boronate 15 in

4556 J. Agric. Food Chem., Vol. 50, No. 16, 2002
Turner and Pernich
10 mL of THF was cooled in an ice bath, and 10 mL of 30% H2O2
was added dropwise. The mixture was then stirred at ambient
temperature for 2 h and poured into water. The excess oxidant was
quenched by cautious addition of NaHSO3, and the mixture then
extracted with two portions of ether. The combined organic layers were
washed with aqueous NaHSO3, dried over MgSO4, and evaporated to
dryness. The resulting solid was recrystallized from toluene/hexane to
were evaporated to dryness, and the solid residue was recrystallized
from hexane to give 42.7 g (86%) of colorless crystalline 17: mp 58-
1
59.5 °C; H NMR δ 8.28 (br, 1H), 7.96 (d, J ) 2 Hz, 1H), 7.10 (d, J
) 8 Hz, 2H), 6.96 (d, J ) 8 Hz, 2H), 6.06 (ddt, J ) 18, 10, 5.3 Hz,
1H), 5.43 (ddt, J ) 18, 1.5, 1.5 Hz, 1H), 5.30 (ddt, J ) 10, 1.5, 1.5
Hz, 1H), 4.55 (dt, J ) 5.3, 1.5 Hz, 2H). Anal. Calcd for C15H11ClF3-
NO2: C, 54.64; H, 3.36; N, 4.25. Found: C, 54.36; H, 3.39; N, 4.21.
1
give 2.63 g (82%) of 13 as colorless crystals: mp 136-138 °C; H
4-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2-(prop-2-enyl)-
phenol (18). Allyl ether 17 (39.5 g, 0.12 mol) was warmed under N2
at 210-215 °C for a period of 2 h. The resulting oil was cooled and
crystallized from hexane to give 33.4 g (84%) of 18 as tan crystals:
NMR δ 8.24 (br d, 1H), 7.98 (d, J ) 2 Hz, 1H), 7.55 (br, 1H), 6.98
(dd, J ) 3, 9 Hz, 1H), 6.88 (m, 2H), 4.80 (s, 2H). Anal. Calcd for
C13H9ClF3NO3: C, 48.84; H, 2.84; N, 4.38. Found: C, 48.71; H, 2.95;
N, 4.54.
1
mp 93-95 °C; H NMR δ 8.28 (br, 1H), 7.96 (d, J ) 2 Hz, 1H),
Methyl 6-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-4H-1,3-
benzodioxine-2-carboxylate (8a). An oven-dried round-bottom flask
was flushed with N2 and charged with 60 mL of dioxane, 0.39 g (1.5
mmol) of 18-crown-6, and 4.40 g (110 mmol) of 60% NaH/oil
dispersion. The mixture was stirred under N2 while a solution of 5.81
g (45 mmol) of dichloroacetic acid in 20 mL of dioxane was added
dropwise over a period of 1 h. A solution of 9.6 g (30 mmol) of diol
13 in 30 mL of dioxane was added dropwise to the very thick mixture.
Upon completion of addition the reaction mixture was stirred at 80 °C
for 3 h and cooled, and then water was cautiously added. The mixture
was poured into 5% aqueous NaOH and washed with two portions of
ether. The ether layers were combined and extracted with 5% aqueous
NaOH, and the combined base layers were then made acidic with 6 M
HCl. The mixture was extracted with two portions of ether, and the
combined ether layers were washed twice with water, dried over MgSO4
and evaporated to leave 9.0 g of a light yellow semisolid.
6.75-6.95 (m, 3H), 6.00 (ddt, J ) 9, 18, 6 Hz, 1H), 5.22 (m, 1H),
5.14 (m, 1H), 3.40 (br d, J ) 6 Hz, 2H). Anal. Calcd for C15H11ClF3-
NO2: C, 54.64; H, 3.36; N, 4.25. Found: C, 54.64; H, 3.43; N, 4.18.
[5-((3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)-2,3-dihydro-
1-benzofuran-2-yl]methanol (20). A solution of 30.66 g (93 mmol)
of phenol 18 in 150 mL of CH2Cl2 was cooled in an ice bath, and
21.99 g (102 mmol) of 80% 3-chloroperoxybenzoic acid was added in
portions. The resulting mixture was stirred at room temperature for 6
h, and the precipitated solids were removed by filtration. The filtrates
were poured into a mixture of saturated aqueous NaHSO3 and 400 mL
of ether, and the organic layer was separated and washed twice with
saturated aqueous NaHCO3 and water, dried over MgSO4, and
evaporated to leave an oil.
The material prepared above was dissolved in 100 mL of toluene,
and 0.20 g of p-toluenesulfonic acid was added. The solution was stirred
at reflux for 6 h, an additional 0.20 g of p-toluenesulfonic acid then
added, and reflux continued for an additional 6 h. The solution was
cooled, poured onto a short column of silica gel, and eluted with 3:2
hexane/acetone. The filtrates were evaporated, and the residue was
crystallized from hexane to give 26.4 g (82%) of nearly colorless
The crude material prepared above was stirred with 100 mL of
benzene, and 10 mL of thionyl chloride was added. The resulting
mixture was stirred at reflux for 3 h (gas evolution), cooled, and
evaporated to dryness. Toluene (50 mL) was added and the mixture
again evaporated to dryness. The resulting oil was dissolved in 100
mL of CH2Cl2 and cooled in an ice bath while a solution of 10 mL of
methanol, 10 mL of pyridine, and 20 mL of CH2Cl2 was added
dropwise. The resulting mixture was allowed to warm to ambient
temperature, poured into 1 M HCl, and extracted with two portions of
ether. The combined organic layers were washed with 1 M HCl, dried
over MgSO4, and evaporated to dryness. The residue was purified by
preparative scale HPLC, eluting with 9:1 hexane/acetone, and the
resulting solid was recrystallized from hexane/acetone to give 3.53 g
1
crystalline 20: mp 82-85 °C; H NMR δ 8.28 (br, 1H), 7.95 (d, J )
2 Hz, 1H), 6.85-6.98 (m, 2H), 6.70 (d, J ) 8 Hz, 1H), 4.97 (m, 1H),
3.87 (dd, J ) 6, 14 Hz, 1H), 3.74 (dd, J ) 4, 14 Hz, 1H), 3.28 (dd, J
) 9, 18 Hz, 1H), 3.06 (dd, J ) 6, 18 Hz, 1H). Anal. Calcd for C15H11-
ClF3NO3: C, 52.11; H, 3.21; N, 4.05. Found: C, 52.10; H, 3.48; N,
3.91.
Methyl 5-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2,3-di-
hydro-1-benzofuran-2-carboxylate (6a). A solution of 10.37 g (30
mmol) of alcohol 20 and 100 mL of acetone was cooled in an ice bath
while excess Jones reagent was added in 1 mL portions. The resulting
mixture was stirred at room temperature overnight and then diluted
with saturated aqueous NaHSO3, poured into water, and extracted with
three portions of ether. The combined organic layers were extracted
with three portions of 10% aqueous NaOH. The aqueous layers were
combined and made acidic with 6 M HCl, and the resulting mixture
was extracted with three portions of ether. The ether layers were washed
with water, dried over MgSO4, and evaporated to leave a dark gum.
1
(30%) of 8a as colorless crystals: mp 96-97 °C; H δ NMR δ 8.26
(br, 1H), 7.96 (d, J ) 2 Hz, 1H), 7.03 (m, 2H), 6.83 (br, 1H), 5.51 (s,
1H), 5.09 (d, J ) 15 Hz, 1H), 4.98 (d, J ) 15 Hz, 1H), 3.90 (s, 3H).
Anal. Calcd for C16H11ClF3NO5: C, 49.31; H, 2.85; N, 3.59. Found:
C, 49.12; H, 2.90; N, 3.50.
6-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-4H-1,3-benzo-
dioxine-2-carboxylic Acid (8). A solution of 1.17 g (3 mmol) of 8a
in 5 mL of THF was stirred under N2 while a solution of 1.44 g (3.6
mmol) of 10% aqueous NaOH was added. The resulting solution was
stirred at ambient temperature for 2 h, poured into water, and made
acidic by the slow addition of 1 M HCl. The resulting oily mixture
was extracted with two portions of ether, and the combined organic
layers washed with water, dried over Na2SO4, and evaporated to dryness.
The resulting solid was recrystallized from toluene/methylcyclohexane
The material prepared above was dissolved in 100 mL of methanol,
10 drops of 12 M HCl added, and the solution warmed at reflux for 6
h. The methanol was removed on the rotovap and the residue filtered
through a short column of silica gel, eluting with CH2Cl2. The filtrates
were evaporated, and the residue was crystallized from hexane to give
1.87 g (17%) of 6a as pale yellow crystals: mp 103-104 °C; 1H NMR
δ 8.27 (br, 1H), 7.96 (d, J ) 2 Hz, 1H), 6.98 (br s, 1H), 6.93 (br s,
2H), 5.27 (dd, J ) 8, 12 Hz, 1H), 3.82 (s, 3H), 3.60 (dd, J ) 12, 16
Hz, 1H), 3.42 (dd, J ) 8, 16 Hz, 1H). Anal. Calcd for C16H11ClF3NO4:
C, 51.42; H, 2.97; N, 3.75. Found: C, 51.41; H, 2.98; N, 3.65.
1
to give 0.90 g (80%) of 8 as colorless crystals: mp 165-167 °C; H
NMR δ 8.25 (br, 1H), 7.96 (d, J ) 2 Hz, 1H), 7.02 (m, 2H), 6.82 (br,
1H), 5.50 (s, 1H), 5.05 (d, J ) 16 Hz, 1H), 4.98 (d, J ) 16 Hz, 1H).
Anal. Calcd for C15H9ClF3NO5: C, 47.95; H, 2.41; N, 3.73. Found:
C, 48.01; H, 2.50; N, 3.65.
3-Chloro-2-[4-(prop-2-enyloxy)phenoxy]-5-(trifluoromethyl)py-
ridine (17). A mixture of 43.43 g (0.15 mol) of phenol 14, 22.77 g
(0.165 mol) of powdered anhydrous K2CO3, and 85 mL of DMF was
warmed under N2 to 60 °C. A solution of 19.97 g (0.165 mol) of allyl
bromide in 10 mL of DMF was then added at a rate sufficient to
maintain the reaction temperature at 70 °C. The mixture was stirred at
70 °C for an additional 30 min and then cooled and poured into water.
The mixture was extracted with two portions of ether, and the combined
organic layers were washed with 2% aqueous NaOH and water, dried
over MgSO4, and evaporated to dryness. The residue was taken up in
CH2Cl2 and filtered through a short column of silica gel. The filtrates
3-Chloro-2-[4-(2-methylprop-2-enyloxy)phenoxy]-5-(trifluoro-
methyl)pyridine (17a). A mixture of 24.61 g (85 mmol) of phenol
14, 12.90 g (93.5 mmol) of powdered anhydrous K2CO3, 8.46 g (93.5
mmol) of 3-chloro-2-methylpropene, and 50 mL of DMSO was warmed
with an oil bath at 80-85 °C for a period of 4 h. The mixture was
cooled, poured into water, and extracted with three portions of ether.
The combined organic layers were washed with 5% aqueous NaOH
and water, dried over MgSO4, and evaporated to dryness. The residual
oil was distilled in a Kugelrohr apparatus (125 °C bath temperature,
0.15 mmHg) to give 27.55 g (94%) of 17a as a colorless oil, which
was contaminated with minor byproducts: 1H NMR δ 8.28 (br, 1H),

Enantiomeric Selectivity of Aryloxyphenoxypropionic Acids
J. Agric. Food Chem., Vol. 50, No. 16, 2002 4557
7.96 (d, J ) 2 Hz, 1H), 7.08 (m, 2H), 6.96 (m, 2H), 5.12 (br s, 1H),
5.00 (br s, 2H), 4.44 (s, 2H), 1.87 (s, 3H).
acetonitrile was warmed at reflux for 2 h. The mixture was cooled,
poured into water, made acidic with 6 M HCl, and extracted with two
portions of ether. The combined organic layers were washed four times
with water, dried over MgSO4, and evaporated to dryness. The residual
red oil was taken up in boiling methylcyclohexane, allowed to cool,
and filtered from the precipitated solids. The solids were washed with
additional methylcyclohexane and the combined filtrates evaporated
to dryness. The residue was taken up in boiling hexane, treated with
charcoal, filtered while hot through Celite, and allowed to cool to give
4-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2-(2-methylprop-
2-enyl)phenol (18a). A solution of 24.04 g (70 mmol) of 17a and 45
mL of diethylaniline was warmed at 210-215 °C for a period of 3.5
h. The solution was cooled, diluted with ether, and washed three times
with cold 1 M HCl, saturated aqueous NaHCO3 and water, dried over
MgSO4, and evaporated to dryness. The residual dark oil was purified
by preparative scale HPLC, eluting with 10:1 hexane/acetone. After
removal of solvent, the residue was crystallized from hexane to give
1
21.47 g (65%) of 23 as colorless crystals: mp 89-91 °C; H NMR δ
1
12.52 (s, 1H), 8.32 (br d, 1H), 8.01 (d, J ) 2 Hz, 1H), 7.81 (d, J ) 10
Hz, 1H), 6.78 (d, J ) 2 Hz, 1H), 6.72 (dd, J ) 2, 10 Hz, 1H), 2.62 (s,
3H). Anal. Calcd for C14H9ClF3NO3: C, 50.69; H, 2.74; N, 4.22.
Found: C, 50.65; H, 2.77; N, 4.22.
16.21 g (73%) of 18a as colorless crystals: mp 77-80 °C; H NMR
δ 8.29 (br, 1H), 7.97 (d, J ) 2 Hz, 1H), 6.82-7.00 (m, 3H), 5.27 (s,
1H), 4.94 (br s, 1H), 4.87 (br s, 1H), 3.37 (s, 2H), 1.76 (s, 3H). Anal.
Calcd for C16H13ClF3NO2: C, 55.91; H, 3.81; N, 4.08. Found: C, 55.87;
H, 3.76; N, 3.95.
1-[4-((3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)-2-(2-oxira-
nylmethoxy)phenyl]ethanone (24). A solution prepared from 3.32 g
(10 mmol) of phenol 23, 2.78 g (30 mmol) of epichlorohydrin, and 20
mL of ethanol was warmed under N2 at reflux. A solution prepared
from 0.69 g (10.5 mmol) of KOH, 2 mL of water, and 5 mL of ethanol
was added dropwise over 30 min. The resulting mixture was stirred at
reflux for 1.5 h, cooled, poured into water, and extracted with two
portions of ether. The combined organic layers were washed with 5%
aqueous NaOH, dried over MgSO4, and evaporated to dryness. The
residual solid was purified by preparative scale HPLC, eluting with
17:3 hexane/acetone. After removal of solvent, the residual material
was crystallized from hexane/acetone to give 2.26 g (58%) of 24 as
colorless crystals: mp 128-130 °C; 1H NMR δ 8.28 (br, 1H), 8.00 (d,
J ) 2 Hz, 1H), 7.88 (d, J ) 8 Hz, 1H), 6.82 (m, 2H), 4.37 (dd, J ) 4,
12 Hz, 1H), 3.98 (dd, J ) 6, 12 Hz, 1H), 3.40 (m, 1H), 2.94 (t, J ) 4
Hz, 1H), 2.76 (dd, J ) 2, 4 Hz, 1H), 2.68 (s, 3H). Anal. Calcd for
C17H13ClF3NO4: C, 52.66; H, 3.38; N, 3.61. Found: C, 52.53; H, 3.48;
N, 3.61.
[5-((3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)-2,3-dihydro-
2-methyl-1-benzofuran-2-yl]methanol (20a). A solution of 15.12 g
(44 mmol) of phenol 18a in 100 mL of CH2Cl2 was cooled in an ice
bath, and 7.94 g (46 mmol) of 80% 3-chloroperoxybenzoic acid was
added in portions. This mixture was stirred at 5 °C for 5 h and the
resulting precipitate removed by filtration. The filtrates were diluted
with ether, washed sequentially with saturated aqueous NaHSO3, three
portions of saturated aqueous NaHCO3, and water, dried over MgSO4,
and evaporated to dryness to leave an oil.
The material prepared above was dissolved in 50 mL of CH2Cl2,
0.20 g of p-toluenesulfonic acid was added, and the resulting solution
was stirred at ambient temperature for 2 days. The solution was then
washed with saturated aqueous NaHCO3, dried over Na2SO4, and
evaporated to dryness. The residual oil was purified by preparative scale
HPLC, eluting with 17:3 hexane/acetone. After removal of solvent,
the residual solid was crystallized from hexane to give 10.98 g (69%)
1
of 20a as colorless crystals: mp 103-105 °C; H NMR (CDCl3 +
D2O) δ 8.27 (br, 1H), 7.95 (d, J ) 2 Hz, 1H), 6.85-6.98 (m, 2H),
6.76 (d, J ) 8 Hz, 1H), 3.69 (d, J ) 16 Hz, 1H), 3.63 (d, J ) 16 Hz,
1H), 3.29 (d, J ) 16 Hz, 1H), 2.93 (d, J ) 16 Hz, 1H), 1.47 (s, 3H).
Anal. Calcd for C16H13ClF3NO3: C, 53.42; H, 3.64; N, 3.89. Found:
C, 53.57; H, 3.75; N, 3.70.
4-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2-(2-oxiranyl-
methoxy)phenyl Acetate (25). A solution of 13.18 g (34 mmol) of
acetophenone 24, 8.32 g (41 mmol) of 85% 3-chloroperoxybenzoic
acid, and 150 mL of CHCl3 was warmed at reflux for 24 h. The mixture
was cooled, and an additional 1.0 g (5 mmol) of MCPBA was added;
the mixture was then stirred at reflux for an additional 8 h. The mixture
was cooled and filtered, washing the solids with CH2Cl2. The combined
filtrates were washed with two portions of saturated NaHSO3 and two
portions of saturated NaHCO3, dried over MgSO4, and evaporated to
dryness. The residual oily solid was purified by preparative scale HPLC,
eluting with 17:3 hexane/acetone. The resulting solid was recrystallized
from hexane to give 9.27 g (68%) of 25 as colorless needles: mp 88-
90 °C; 1H NMR δ 8.26 (br, 1H), 7.98 (d, J ) 2 Hz, 1H), 7.09 (d, J )
8.5 Hz, 1H), 6.78 (dd, J ) 2.5, 8.5 Hz, 1H), 6.83 (d, J ) 2.5 Hz, 1H),
4.23 (dd, J ) 3, 11 Hz, 1H), 3.95 (dd, J ) 5.5, 11 Hz, 1H), 3.31 (m,
1H), 2.86 (t, J ) 5 Hz, 1H), 2.70 (dd, J ) 3, 5 Hz, 1H), 2.32 (s, 3H).
Anal. Calcd for C17H13ClF3NO5: C, 50.57; H, 3.25; N, 3.47. Found:
C, 50.30; H, 3.24; N, 3.39.
[6-((3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)-2,3-dihydro-
1,4-benzodioxin-2-yl]methanol (26). A mixture of 7.67 g (19 mmol)
of acetate 25, 8.40 g (21 mmol) of 10% aqueous NaOH, and 25 mL of
THF was stirred under N2 at ambient temperature for 2 days. The
mixture was neutralized with 1 M HCl and extracted with two portions
of ether. The combined organic layers were washed with water and
two portions of 2% NaOH, dried over MgSO4, and evaporated to
dryness to give 5.88 g (86%) of 26 as a colorless solid. A sample was
recrystallized from hexane to give colorless crystalline 26: mp 84-86
°C; 1H NMR δ 8.28 (br, 1H), 7.95 (d, J ) 2 Hz, 1H), 6.94 (d, J ) 8.5
Hz, 1H), 6.73 (d, J ) 3 Hz, 1H), 6.66 (dd, J ) 3, 8.5 Hz, 1H), 3.79-
4.38 (m, 5H). Anal. Calcd for C15H11ClF3NO4: C, 49.81; H, 3.07; N,
3.87. Found: C, 49.69; H, 3.07; N, 3.78.
Methyl 5-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2,3-di-
hydro-2-methyl-1-benzofuran-2-carboxylate (16a). A solution of 7.19
g (20 mmol) of alcohol 20a in 100 mL of acetone was cooled in an ice
bath, and 10 mL of Jones reagent was added in portions. The mixture
was allowed to warm to room temperature, excess Jones reagent added,
and the mixture stirred at room temperature for 2 days. Aqueous
NaHSO3 was added, and the resulting mixture was poured into water
and extracted with three portions of ether. The combined organic layers
were washed with water and evaporated to dryness. The residue was
partitioned between petroleum ether and Claisen’s alkali and the
aqueous layer separated, made acidic with 6 M HCl, and extracted twice
with ether. The combined ether layers were washed with water, dried
over MgSO4, and evaporated to dryness to leave a dark gum.
The material prepared above was dissolved in 75 mL of benzene,
and 3.0 g (25.2 mmol) of thionyl chloride and 3 drops of DMF were
added. The resulting solution was stirred at reflux for 3 h, cooled, and
evaporated. Toluene (25 mL) was added and the solution again
evaporated to dryness. The residue was dissolved in 15 mL of CH2Cl2
and added to a solution prepared from 0.80 g (25 mmol) of methanol,
2.53 g (25 mmol) of triethylamine, and 25 mL of CH2Cl2. The mixture
was stirred at ambient temperature for 2 h, poured into water, and
extracted with two portions of ether. The combined organic layers were
washed with two portions of 5% aqueous NaOH and once with water,
dried over MgSO4, and evaporated to dryness. The residue was purified
by preparative scale HPLC, eluting with 92:8 hexane/acetone. Removal
of solvent left 0.91 g (9.4%) of 16a as a pale yellow gum: 1H NMR
δ 8.26 (br, 1H), 7.94 (d, J ) 2 Hz, 1H), 6.83-6.96 (m, 3H), 3.80 (s,
3H), 3.68 (d, J ) 16 Hz, 1H), 3.17 (d, J ) 16 Hz, 1H), 1.73 (s, 3H).
Anal. Calcd for C17H13ClF3NO4: C, 52.66; H, 3.38; N, 3.61. Found:
C, 52.52; H, 3.44; N, 3.59.
6-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2,3-dihydro-
1,4-benzodioxine-2-carboxylic Acid (9). A mixture of 10.0 g of
KMnO4, 3.5 g of KOH, and 5.0 g of CuSO4‚5 H2O was ground together
with a mortar and pestle to give a dark, pasty material. The paste was
suspended in 75 mL of CH2Cl2, 3.07 g (8.5 mmol) of alcohol 26 added,
and the resulting mixture stirred rapidly at ambient temperature
overnight. The mixture was cooled in an ice bath, and 50 mL of
saturated aqueous NaHSO3 was slowly added. The mixture was stirred
1-[4-((3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)-2-hydroxy-
phenyl]ethanone (23). A mixture of 16.72 g (110 mmol) of 2′,4′-
dihydroxyacetophenone, 14.49 g (105 mmol) of powdered anhydrous
K2CO3, 19.95 g (100 mol) of fluoropyridine 10, and 150 mL of

4558 J. Agric. Food Chem., Vol. 50, No. 16, 2002
Turner and Pernich
for 10 min, made acidic with 6 M HCl, and then extracted with three
portions of ether. The combined organic layers were washed with two
portions of saturated NH4Cl, dried over Na2SO4, and evaporated to
dryness. The residual solid was recrystallized from toluene/hexane to
give 2.00 g (63%) of 9 as colorless crystals: mp 176-177 °C; 1H NMR
(CH3COCH3-d6) δ 8.38 (d, J ) 2 Hz, 1H), 8.28 (d, J ) 2 Hz, 1H),
7.00 (d, J ) 10 Hz, 1H), 6.75 (m, 2H), 5.45 (dd, J ) 3.5, 4 Hz, 1H),
4.53 (dd, J ) 4, 12 Hz, 1H), 4.39 (dd, J ) 3.5, 12 Hz, 1H). Anal.
Calcd for C15H9ClF3NO5: C, 47.95; H, 2.41; N, 3.73. Found: C, 48.05;
H, 2.40; N, 3.63.
6-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2,3-dihydro-2-
methyl-1,4-benzodioxine-2-carboxylic Acid (21). A mixture of 5.0 g
of KMnO4, 1.75 g of KOH, and 2.5 g of CuSO4‚5 H2O was ground
together with a mortar and pestle to give a dark, pasty material. The
paste was suspended in 75 mL of CH2Cl2, 1.50 g (4 mmol) of alcohol
29 was added, and the resulting mixture was stirred rapidly at ambient
temperature for 3 days. The mixture was cooled in an ice bath, and
saturated aqueous NaHSO3 was slowly added. This mixture was stirred
for 10 min, made acidic with 3 M HCl, and then extracted with two
portions of ether. The combined organic layers were washed with water
and saturated aqueous NH4Cl, dried over MgSO4, and evaporated to
dryness. The residual solid was recrystallized from methylcyclohexane/
acetone to give 1.05 g (67%) of 21 as colorless crystals: mp 205-207
1-[(4-(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)-2-((2-methyl-
2-propenyl)oxy)phenyl]ethanone (27). A mixture of 5.80 g (17.5
mmol) of phenol 23, 2.62 g (19 mmol) of powdered anhydrous K2-
CO3, 1.90 g (21 mmol) of 3-chloro-2-methylpropene, and 50 mL of
DMSO was stirred under N2 at 75 °C for 1 h. The mixture was cooled,
poured into water, made acidic with 3 M HCl, and extracted with two
portions of ether. The combined organic layers were washed with water
and with two portions of 2% NaOH, dried over MgSO4, and evaporated
to dryness. The residual solid was filtered through a short column of
silica gel, eluting with CH2Cl2, and, after removal of solvent, the
resulting solid was recrystallized from hexane to give 4.56 g (68%) of
1
°C; H NMR δ 8.22 (br, 1H) 7.92 (d, J ) 2 Hz, 1H), 6.96 (d, J ) 10
Hz, 1H), 6.65 (m, 2H), 4.51 (d, J ) 11 Hz, 1H), 3.91 (d, J ) 11 Hz,
1H), 1.58 (s, 3H). Anal. Calcd for C16H11ClF3NO5: C, 49.31; H, 2.85;
N, 3.59. Found: C, 49.02; H, 2.81; N, 3.46.
Molecular Modeling. All molecular modeling was performed on
Silicon Graphics R10000 workstations. AM1 (11) and MNDO (12)
calculations were performed with MOPAC93 (13) using keywords
PRECISE, EF, and NODIIS. Conformational analysis of the two ether
bonds was performed using the GRID keyword with an in-house
modification of the MOPAC93 program. This modification allowed
the optimization at each grid point to be started from four different,
fixed values of a third dihedral angle, in this case the aliphatic carbon-
carboxylate carbon torsional angle. The lowest energy of the four was
retained for the contour plot in Figure 3. In this way the optimization
was able to avoid being trapped in a local minimum at each point. The
two ether torsional angles under investigation were sampled at 15°
increments. Ab initio calculations were performed using Gaussian94
(14) with the standard HF/6-31G* and HF/6-31+G* basis sets and the
keyword SCF)DIRECT. Geometries were fully or partially optimized
from the corresponding optimized AM1 geometry, with input files
generated using the program AMPGAUSS (15). Partial optimizations
held fixed the two ether torsional angles. Overlap models were generated
using SYBYL 6.5 (16) via the MATCH function, overlapping the 11
phenyl atoms and the ether oxygen of each molecule.
1
27 as light yellow crystals: mp 93-95 °C; H NMR δ 8.30 (br, 1H),
8.00 (d, J ) 2 Hz, 1H), 7.87 (d, J ) 8 Hz, 1H), 6.79 (m, 2H), 5.12 (br
s, 1H), 5.05 (br s, 1H), 4.50 (s, 2H), 2.65 (s, 3H), 1.88 (s, 3H). Anal.
Calcd for C18H15ClF3NO3: C, 56.04; H, 3.92; N, 3.63. Found: C, 55.67;
H, 3.81; N, 3.57.
4-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2-[(2-methyl-
2-oxiranyl)methoxy]phenyl Acetate (28). A mixture of 3.86 g (10
mmol) of acetophenone 27, 4.75 g (22 mmol) of 80% 3-chloroper-
oxybenzoic acid, and 100 mL of CHCl3 was stirred at ambient
temperature for 12 h and then at reflux for an additional 14 h. The
mixture was cooled to room temperature and filtered, and the solid
was washed with CH2Cl2. The combined filtrates were washed with
saturated NaHSO3 and two portions of saturated NaHCO3, dried over
Na2SO4, and evaporated to dryness. The residue was filtered through
a short column of silica gel, eluting with CH2Cl2 and, after removal of
solvent, the solid was recrystallized from hexane to give 3.17 g (76%)
1
ACCase Inhibition Assays. ACCase inhibition studies were per-
formed as previously reported (2).
of 28 as colorless crystals: mp 82-84 °C; H NMR δ 8.25 (br, 1H),
7.98 (d, J ) 2 Hz, 1H), 7.08 (d, J ) 8 Hz, 1H), 6.78 (m, 2H), 4.02 (d,
J ) 12 Hz, 1H), 3.91 (d, J ) 12 Hz, 1H), 2.80 (d, J ) 5 Hz, 1H), 2.70
(d, J ) 5 Hz, 1H), 2.32 (s, 3H), 1.42 (s, 3H). Anal. Calcd for C18H15-
ClF3NO5: C, 51.75; H, 3.62; N, 3.35. Found: C, 51.47; H, 3.52; N,
3.26.
Biological Analysis. Test species were grown from seed in Grace-
Sierra Metromix 306 in square plastic pots with a surface area of 91
cm2 at a depth of 1.3 cm and maintained in a greenhouse until the
plants had reached the desired stage of growth (typically 1.5-2.5 true
leaves). Natural light was supplemented with greenhouse metal halide
lamps during times in which the natural day length was shorter than
14 h. All species were fertilized each day by subirrigation with a 1/2×
solution of Excel fertilizer.
Samples of test chemicals were weighed into 25 mL vials and then
dissolved in 4 mL of 97:3 acetone/DMSO. A 2 mL aliquot of this
solution was transferred to a second 25 mL vial, acetone/DMSO solution
was added as before, and this serial dilution was repeated for each
additional rate required. Then 13 mL of a stock solution was added to
give a final mixture composed of acetone, deionized water, DMSO,
Atplus 411F (crop oil concentrate), and Triton X-155 in a 48.5:39:10:
1.5:1.0:0.02 ratio by volume. Solutions were sprayed onto the foliage
of test plants using a DeVilbiss atomizer driven by compressed air at
a pressure of 2-4 psi. Plants were sprayed to runoff. After treatment,
plants were returned to the greenhouse under the standard growing
conditions described above. Grass weed test species included AVena
fatua, Digitaria sanguinalis, Echinochloa crus-galli, Setaria faberi, and
Sorghum halepense. Broadleaf weeds tested included Abutilon theo-
phrasti, Amaranthus ss., Datura stramonium, Ipomoea hederacea, and
Xanthium strumarium.
(6-[(3-Chloro-5-(trifluoromethyl)-2-pyridinyl)oxy]-2-methyl-2,3-
dihydro-1,4-benzodioxin-2-yl)methanol (29) and 7-[(3-Chloro-5-
(trifluoromethyl)-2-pyridinyl)oxy]-3-methyl-3,4-dihydro-1,4-ben-
zodioxiepin-2-ol (30). A solution prepared from 12.53 g (30 mmol) of
acetate 28 and 100 mL of THF was cooled under N2 in an ice bath
while a solution of 0.79 g (33 mmol) of LiOH in 20 mL of water was
added. The mixture was allowed to warm to room temperature and
stirred for 3 days. The mixture was made acidic with glacial HOAc
and concentrated on the rotovap, and the residue was partitioned
between water and ether. The aqueous layer was separated and again
extracted with ether, and the organic layers were combined, washed
with two portions of 5% NaOH, dried over MgSO4, and evaporated to
dryness. The residual oil was separated into two fractions by preparative
scale HPLC, eluting with 87:13 hexane/acetone. The more polar fraction
was thoroughly dried to give 7.70 g (70%) of 29 as a colorless, viscous
gum: 1H NMR δ 8.28 (br, 1H), 7.95 (d, J ) 2 Hz, 1H), 6.90 (d, J )
9 Hz, 1H), 6.74 (d, J ) 2.5 Hz, 1H), 6.67 (dd, J ) 2.5, 9 Hz, 1H),
4.19 (d, J ) 11.5 Hz, 1H), 3.93 (d, J ) 11.5 Hz, 1H), 3.74 (d, J ) 12
Hz, 1H), 3.65 (d, J ) 12 Hz, 1H), 1.35 s, 3H). Anal. Calcd for C16H13-
ClF3NO4: C, 51.14; H, 3.49; N, 3.73. Found: C, 51.85; H, 3.56; N,
3.57.
Assessments of weed control were made 14 days after application
of the test chemicals. Plant injury was visually assessed on a scale of
0-100% as compared to the control plants, where 0 equals no injury
and 100 represents complete kill.
The less polar fraction was further purified by preparative scale
HPLC, eluting with 17:3 hexane/acetone. Removal of solvent gave 1.66
g (15%) of 30 as a colorless, viscous gum: 1H NMR δ 8.28 (br, 1H),
7.96 (d, J ) 2 Hz, 1H), 7.05 (d, J ) 9 Hz, 1H), 6.84 (d, J ) 3 Hz,
1H), 6.77 (dd, J ) 3, 9 Hz, 1H), 4.10 (d, J ) 12 Hz, 2H), 3.86 (dd, J
) 4, 12 Hz, 2H), 1.22 (s, 3H). Anal. Calcd for C16H13ClF3NO4: C,
51.14; H, 3.49; N, 3.73. Found: C, 51.08; H, 3.45; N, 3.49.
RESULTS AND DISCUSSION
Conformational Analysis of Haloxyfop Models. Important
clues to the “active,” or binding, conformation of the aryl-

Enantiomeric Selectivity of Aryloxyphenoxypropionic Acids
J. Agric. Food Chem., Vol. 50, No. 16, 2002 4559
Figure 3. Conformational maps of the four models computed with AM1. Contours are in 1 kcal/mol intervals, starting with green at 1 kcal/mol above the
global minimum; red, 2 kcal/mol; and blue, 3 kcal/mol. The AM1 global minimum is marked with a diamond, the MNDO minimum with a square, the
6-31G* minimum with a triangle, and the proposed active conformation with a circle.
clear. An unfavorable steric interaction between the methyl
group of the S-enantiomer and some portion of the enzyme
would provide a simple explanation for this observation. Some
additional analogues of the oxypropionic acid can be used to
test such a hypothesis (Table 1). First, the oxyacetic acid
analogue (4), which is missing the key methyl group, is still a
potent ACCase inhibitor. Thus, the methyl group of the
oxypropionate serves only to enhance the recognition of the
substance by the enzyme. Second, despite maintaining any
intermolecular repulsion associated with the S-methyl of the
inactive S-enantiomer, good inhibition of ACCase is achieved
when yet a second methyl is added to the R carbon of the
oxypropionate as in 5. This demonstrates that the lack of
enzymatic activity by the S-enantiomer is not due to unfavorable
intermolecular steric interaction between the methyl group of
the inhibitor and a particular group on the enzyme. It is instead
an intramolecular property of the R-enantiomer that allows it
to be recognized by the enzyme. We suggest that the active
enantiomer can exist in a conformation that presents a phar-
macophore readily recognized by the enzyme, whereas the
opposite enantiomer cannot easily achieve a conformation that
presents a comparable pharmacophore.
Table 1. ACCase Inhibition by Pyridyloxyphenoxyacetates
compd
model
R
R
I50a (µm)
1
2
2a (R)
2b (S)
4
A
B
C
D
CH
H
H
H
CH
H
CH
0.55
>100
8.8
3
3
5
CH
3
3.7
3
a Maize leaf ACCase.
oxyphenoxypropionic acids are obtained through examination
of the enantiomeric preference of the enzyme and the activity
of some simple derivatives of the oxypropionate fragment of
haloxyfop (2). Thus, as can be seen from Table 1, only the
R-enantiomer (2a) is well recognized by the enzyme, with at
least a 2-3 order of magnitude difference in activity between
the R-enantiomer and S-enantiomer (2b) (2). Such specificity
is not unusual, but the reason for such a profound effect based
on the orientation of a simple methyl group is not immediately

4560 J. Agric. Food Chem., Vol. 50, No. 16, 2002
Turner and Pernich
ranging from roughly 75° to 150°, leaving the most likely active
conformation candidate with a phenyl-oxygen angle near 165°
and an oxygen-propionate value near 75°. This position is
marked with a black circle in the four conformational maps.
Inspection of the conformational map of phenoxyacetic acid (C)
in the lower right of Figure 3 shows that this active analogue
can access this conformation as expected.
Figure 4. Three-dimensional and Newman projections of the proposed
active conformation of the phenoxypropionic acid fragment.
The candidate active conformation is shown in Figure 4. It
is a relatively low-energy conformation of A with the R-methyl
distal to the phenoxy fragment, stabilized by the generalized
anomeric effect around the propionate ether bond (oxygen-
propionate torsion in Figure 3). This conformation represents
the ideal pharmacophore, defined by the relative orientation of
the phenyl group and the carboxylate. Chiral inversion to give
B switches the position of the methyl and hydrogen, raising
the conformational energy through the steric interaction between
the methyl and phenyl groups, thus effectively reducing the
binding energy. The intermolecular interaction with the binding
site should be only a secondary factor in the binding energy.
Isobutyrate D, with two methyl groups, retains the unfavorable
intramolecular steric interaction in all conformers, so with no
viable alternative it can still access the active conformation with
little energy penalty and can readily present the pharmacophore
to the binding site. Finally, it is easy to see that C, without any
methyl-phenyl interaction, can readily access this conformation
as well.
Thus, we searched for highly populated conformations of the
R-enantiomer, which are at most sparsely populated in S.
Conformational Preference of 2 and Its Analogues. Using
the 2-phenoxypropionic acids as a model system for 2, we
searched for easily accessible conformations of the R-enantiomer
(A), which were at least a few kilocalories per mole higher in
energy in the S-enantiomer (B) with identical torsional values
around the two ether bonds and were still accessible to the
phenoxyacetic acid (C) and 2-phenoxyisobutyric acid (D)
models. (The rest of the model molecules including the aliphatic
carbon-carboxylate torsion were fully optimized.) We were
unable to find any candidate conformations, however, using the
Tripos molecular mechanics force field (16). Upon inspection,
we felt that this force field was not adequately treating the
aliphatic carbon-oxygen bond, which should exhibit a general-
ized anomeric effect favoring gauche conformations (17-22).
This effect was reproduced as expected using the AM1 method
(11). Therefore, the latter was used to fully explore torsional
preferences around the two ether bonds while ensuring all
other degrees of freedom of the molecule were fully optimized.
The results are shown in two-dimensional contour maps of
the conformational preferences of the four model systems in
Figure 3.
The conformational map for R-2-phenoxypropionic acid (A)
in the upper left of Figure 3 shows the generalized anomeric
effect that favors oxygen-propionate dihedral angles near 75°
and 285° over values near 180°. The 75° angle is favored relative
to 285° because, in the latter, the R-methyl nearly eclipses the
phenyl group and the steric interaction raises the energy of these
conformations. The real energy of these conformations may be
higher because AM1 is known to underestimate steric barriers
(23). This interaction also restricts rotation around the phenyl-
oxygen bond to dihedral angles near 90°, due to the potentially
unfavorable interaction between the R-methyl and the ortho
hydrogens of the phenyl group, strongest near 165° and 345°
(depending upon the precise orientation of the oxygen-
propionate dihedral.) On the other hand, with oxygen-propi-
onate dihedral angles near 75°, the R-methyl is oriented
generally anti to the phenyl group, relieving much of the steric
congestion and allowing the phenyl-oxygen bond somewhat
free rotation. (Refer to the Newman projection of the oxygen-
propionate bond in Figure 4.) Much of the conformational
manifold of A can thus be understood in terms of these few
simple principles.
The energy of this active conformation relative to the global
energy minimum, as calculated by several methods, is listed in
Table 2 for each of the four model analogues A-D. With the
AM1 method, the S-enantiomer, B, has the most difficulty
accessing this conformation, whereas the R-enantiomer, A, can
access it most easily, as we argued above. However, the energy
difference between B and D does not adequately explain the
large activity difference between analogues containing these
fragments. We felt the AM1 method could be underestimating
the energetic penalty due to the steric interaction between the
methyl and phenyl groups (23). These calculations were repeated
using the MNDO method (12). MNDO is known to overestimate
steric repulsion (11) but may not accurately treat the generalized
anomeric effect. For these calculations, a true global confor-
mational search was completed to find the new MNDO global
minimum energy structure in each case, and for the candidate
active conformation a search of the lowest energy aliphatic
carbon-carboxylate torsion was undertaken similar to the
procedure with the AM1 method. The results with the MNDO
method show that the S-enantiomer, B, clearly has the most
difficulty accessing the active conformation, needing >3 kcal/
mol more energy than the corresponding isobutyric acid D
requires, adequately explaining the differences in activity
between the two analogues. Finally, the calculations were
repeated with an ab initio method using two basis sets. The
6-31G* basis set (24) was chosen because it has been shown to
treat generalized anomeric effects quite accurately (20-22), and
the 6-31+G* basis set was used to model the carboxylate anions,
because although it is quite complex to try to model the effect
of ionization in a condensed phase, especially in the presence
of copious counterions as would be expected in a biological
system, it is valuable to estimate the generalized anomeric effect
in the presence of the more electron donating carboxylate ion.
A true global energy search was not feasible with these methods,
but the global low-energy conformations were estimated for each
model using a full optimization starting from the lowest energy
AM1 geometry, and the active conformation energies were
calculated using a partial optimization starting from the corre-
Identification of Active Conformation of 2. The symmetry-
related conformational map for S-2-phenoxypropionic acid (B),
in the upper right of Figure 3, shows that any conformation
with an oxygen-propionate dihedral angle near 285° is easily
accessed. Thus, the “active” conformation must come from the
family with this angle near 75°. The conformational map for
2-phenoxyisobutyric acid (D), in the lower left of Figure 3,
shows that with this angle near 75°, the phenyl-oxygen dihedral
angle must range from roughly 75° to 180° to be accessed by
this active analogue. (The area from 255° to 360° corresponds
to the symmetry-related phenyl ring rotation of 180°.) However,
the inactive B can access phenyl-oxygen dihedral angles

Enantiomeric Selectivity of Aryloxyphenoxypropionic Acids
J. Agric. Food Chem., Vol. 50, No. 16, 2002 4561
Table 2. Energy of the Proposed Active Geometry above the Global Minimum for the Four Models, Calculated Using Different Methods
Table 3. Carboxylate Carbon Mismatch in A˙ ngstroms between Cyclic
Analogues and Proposed Active Conformation
Figure 5. Proposed conformationally restricted analogues of aryloxyphe-
noxypropanoic acids.
sponding AM1 geometries holding only the two ether dihedral
angles constant. The results displayed in the last two columns
of Table 2 clearly show that all three active analogues, A, C,
and D, can easily access the proposed conformation with the
expenditure of ∼1 kcal/mol or less, whereas the inactive
S-enantiomer (B) can achieve this conformation only with
difficulty, requiring well over 3 kcal/mol. Thus, we feel
confident that we have identified the conformation responsible
for activity in the aryloxyphenoxypropionic acids.
in the new targets where synthetically feasible, and the aryl
portion of the molecule was held constant as the 3-chloro-5-
(trifluoromethyl)pyridine for data comparison purposes.
Conformationally Restricted Analogues of 2. One way to
test the hypothesis described above is to “lock” the molecule
into the proposed conformation and compare the enzymatic
activity of the resulting material with that of its flexible
analogue. Locked conformations of the oxypropionate can be
generated by formation of a new ring between the R-carbon of
the oxyacetate moiety and one of the ortho carbons of the
benzene as illustrated in Figure 5. Because substitution on the
benzene ring is typically detrimental to bioactivity, we sought
to minimize the potential impact of the new ring at this position
by attaching it through both carbon (6, 8) and oxygen (7, 9)
linkages. In addition, we chose to target systems in which the
newly formed ring was embodied within both five- and six-
membered systems because there are significant differences in
the conformational preference of such systems (see below).
Finally, the methyl group of the oxypropionate was included
One can predict which new cyclic analogue should be most
active simply by overlapping truncated models of each with
the proposed active conformation model and looking for the
best fit. Thus, the phenyl carbons of each were overlapped with
the corresponding atoms in the active conformation model, and
the distance between the carboxylate carbons of the cyclic and
acyclic models was measured. The results are presented in Table
3. In general the five-membered ring systems, E, F, and G,
were calculated by the AM1 method to be nearly planar, and
all were able to position the carboxylate moiety within about a
half angstrom of the corresponding position in our proposed
active conformation (Figure 6, left). In contrast, the six-
membered benzo-fused ring systems, H, I, and J, assumed a
pseudo-chair with the carboxylate pseudoaxial in all cases. This

4562 J. Agric. Food Chem., Vol. 50, No. 16, 2002
Scheme 1. Synthesis of Benzodioxolanecarboxylate 7a
Turner and Pernich
a Reagents and conditions: (a) K CO , DMSO, rt (77%); (b1) PCl5, CH Cl2, reflux; (b2) aq KOH, MeOH (73%); (c) CHCl2CO H, K CO , IPA, 72 h; (d1) SOCl2;
2
3
2
2
2
3
(d2) MeOH.
Synthesis. Two general precedented approaches to the
targeted molecules were revealed through retrosynthetic analyses
(Figure 7). The materials that contain two oxygen atoms
attached directly to the R-carbon of the acetate moiety (7, 8)
should be available through condensation of the appropriate diol
with a dihaloacetic acid (25, 26). The remaining two materials,
6 and 9, could conceptually be prepared through intramolecular
nucleophilic ring opening of an epoxide by a phenolic hydroxyl
followed by adjustment of the oxidation state of the resulting
alcohol (27-29). The requisite diaryl ether moieties could in
turn be generated by condensation of a 2-halopyridine, such as
10, with the appropriately substituted phenol.
Synthesis of Benzodioxolane 7. The catechol functionality
of 11 was installed, in protected form, by condensation of
sesamol with fluoropyridine 10, and the two hydroxyls were
then liberated (12) by chlorination and hydrolysis of the
methylenedioxy group (Scheme 1) (30). The overall result of
this transformation was regiospecific arylation of a 1,2,4-
trihydroxybenzene. Cyclization to acid 7 was then effected under
previously described conditions (25) and the acidic product
converted to the corresponding methyl ester, 7a, for ease of
purification.
Figure 6. Overlap of proposed active conformation model (blue) with
benzofuran F (left) and 1,4-benzodioxin J (right.)
conformation was calculated to be >3 kcal/mol more stable than
the pseudoequatorial in the 1,3-benzodioxin (H) case and nearly
0.5 kcal/mol more stable in both of the 1,4-benzodioxin models
(I, J). This is not surprising given the lack of adverse 1,3 steric
interactions across the pseudo-chair and the anomeric stabiliza-
tion of the axial carboxylate conformation. There are two
reinforcing anomeric effects stabilizing the pseudoaxial con-
formation of H, possibly leading to the greater calculated
stability. Finally, we were able to obtain 1H NMR evidence that
the 1,4-benzodioxin (9) exists in the pseudoaxial conformation
in acetone-d6 solution. The 2C-H bond makes a dihedral angle
with both of the 3C-H bonds of ∼60° in the pseudoaxial
conformation, and this leads to two small coupling constants
(J ) 3.5 and 4.0 Hz) with those protons. In contrast, the
pseudoequatorial conformation, in which it makes a 60° and
180° dihedral with the 3C-proton bonds, should give rise to
one large and one small coupling constant. When overlayed with
the proposed active conformation, all three of the six-membered
benzo-fused ring systems, H, I and J, positioned the carboxylate
more than an angstrom from the corresponding position in the
active conformation (Figure 6, right.) We therefore predicted
the five-membered ring systems to be the more active analogues.
Synthesis of 1,3-Benzodioxin Carboxylic Acid 8. The corre-
sponding 1,3-benzodioxin, 8, was obtained by cyclization of
salicyl alcohol 13 with dichloroacetic acid (Scheme 2). The
requisite diol was obtained by mono-hydroxymethylation of
readily available phenol 14 using methodology described by
Nagata (31). Thus, the phenol was first treated with paraform-
aldehyde in the presence of phenylboronic acid and the diol
then released from the intermediate boronate ester (15) with
Figure 7. Retroanalysis for conformationally restricted aryloxyphenoxyacetic acids.

Enantiomeric Selectivity of Aryloxyphenoxypropionic Acids
J. Agric. Food Chem., Vol. 50, No. 16, 2002 4563
Scheme 2. Synthesis of 1,3-Benzodioxincarboxylate 8a
a Reagents and conditions: (a) 50% aq NaOH, DMSO (70%); (b) PhB(OH)2, paraformaldehyde, cat. CH CH CO H, PhH, reflux (57%); (c) 30% aq H O , THF
3
2
2
2 2
(82%); (d) NaH, CHCl2CO H, cat. 18-crown-6, dioxane, reflux; (e1) SOCl2; (e2) CH OH (30% from 13).
2
3
Scheme 3. Synthesis of Dihydrobenzofurancarboxylates 6 and 16a
a Reagents and conditions for 6 (X ) −H): (a) CH dCHCH Br, K CO , DMSO, 70 °C (86%); (b) 210 °C, neat (84%); (c) MCPBA, rt; (d) cat. p-TsOH, PhCH ,
2
2
2
3
3
reflux (82% from 17); (e1) Jones reagent, acetone; (e2) HCl, MeOH, reflux. Reagents and conditions for 16 (X ) −CH ): (a) CH dC(CH )CH Cl, K CO , DMSO,
3
2
3
2
2
3
85 °C (94%); (b) PhNEt2, 210 °C (73%); (c) MCPBA, 0 °C; (d) cat. p-TsOH, CH Cl2, rt (69% from 17a); (e1) Jones reagent, acetone; (e2) SOCl2; (e3) MeOH,
2
NEt3.
hydrogen peroxide. Following cyclization (using somewhat
different conditions from those described above) and subsequent
esterification, the methyl ester of 8 was obtained in reasonable
yield.
phenol 23 as the sole isolable product. The requisite “regiose-
lective” alkylation was then achieved by reaction of this phenol
with epichlorohydrin to give disubstituted acetophenone 24. The
new phenol was finally revealed, as its acetate, by Baeyer-
Villiger oxidation of 24; base-catalyzed hydrolysis of the
resulting epoxy acetate (25) resulted in simultaneous deesteri-
fication and cyclization to form the dioxin ring (26). Attempted
oxidation of the primary alcohol of 26 under a variety of
standard conditions (Jones reagent, PCC, Swern) failed to
provide the desired acid product, 9, or the corresponding
aldehyde. The requisite oxidation was ultimately achieved
through use of the excellent copper sulfate/potassium perman-
ganate procedure of Jefford (32) to provide the targeted acid,
9, in very good yield and purity.
The corresponding 2-methyldihydrobenzo-1,4-dioxin 21 was
prepared in similar fashion from phenol 23 (Scheme 5). In this
case the phenol was first alkylated with the appropriate allyl
chloride, and the resulting allyl ether, 27, was then treated with
3-chloroperoxybenzoic acid to effect both the expected Baeyer-
Villiger oxidation of the acetophenone and the requisite epoxi-
dation of the olefin to give epoxy acetate 28. Once again, the
new ring was formed through base-catalyzed hydrolysis of the
ester and simultaneous intramolecular ring opening of the
epoxide. In this instance, the cyclization reaction resulted in a
mixture of the expected 1,4-dioxin (29) along with a small
Synthesis of Dihydrobenzofuran Carboxylates 6 and 16.
Benzofuran 6 and its R-methyl analogue 16 were also prepared
from phenol 14 as illustrated in Scheme 3. In the case of 6,
ortho alkylation of the phenol via Claisen rearrangement of
intermediate allyl ether 17 served to install all of the remaining
carbon atoms in their proper location. The resulting olefin (18)
was then epoxidized (19) and the dihydrofuran ring (20) formed
by treatment of the epoxyphenol with acid. Oxidation of alcohol
20 to the corresponding acid proved troublesome but was
ultimately achieved, albeit in poor yield, with excess Jones
reagent. The crude reaction mixture was directly esterified (to
give 6a) for ease of purification. The corresponding 2-meth-
yldihydrobenzofuran (16a) was prepared in analogous fashion.
Synthesis of 1,4-Benzodioxincarboxylic Acids 9 and 21.
Regioselective alkylation of one of the two hydroxyls of catechol
12 was required in order to make effective use of the epoxide
ring opening strategy for preparation of the remaining targeted
acids, dihydrobenzo-1,4-dioxins 9 and 21. In practice, this was
achieved through utilization of acetophenone 22 as a masked
form of 1,2,4-trihydroxybenzene (Scheme 4) (26). The ac-
etophenone was first condensed with pyridine 10 to provide

4564 J. Agric. Food Chem., Vol. 50, No. 16, 2002
Scheme 4. Synthesis of 1,4-Benzodioxincarboxylic Acid 9a
Turner and Pernich
a Reagents and conditions: (a) K CO , CH CN, reflux (65%); (b) epichlorohydrin, aq KOH, EtOH, reflux (58%); (c) MCPBA, CHCl3, reflux (68%); (d) 10% aq
2
3
3
NaOH, THF, rt (86%); (e) KMnO , CuSO , KOH, CH Cl2 (63%).
4
4
2
Scheme 5. Synthesis of 1,4-Benzodioxincarboxylic Acid 21a
a Reagents and conditions: (a) CH dC(CH )CH Cl, K CO , DMSO, 75 °C (68%); (b) MCPBA, CHCl3, reflux (76%); (c) LiOH, H O, THF, rt; (d) KMnO , CuSO ,
2
3
2
2
3
2
4
4
KOH, CH Cl2 (67%).
2
amount of the corresponding 1,4-dioxepane 30. The latter must
have arisen from attack of the intermediate phenoxide on the
less hindered, terminal carbon of the epoxide (33). Oxidation
of primary alcohol 29 according to the Jefford procedure (32)
delivered the targeted acid 21 in good yield.
Results. The activity of the targeted conformationally re-
stricted oxyacetates was compared with the open chain analogue,
haloxyfop (2), against maize leaf ACCase (Table 4). Those
materials in which the oxyacetate was constrained through a
six-membered ring (8, 9, 21) uniformly failed to inhibit ACCase
even at very high rates. In stark contrast, each of the corre-
sponding five-membered ring analogues provided a significant
degree of inhibition of ACCase. The activity of the best
inhibitor, dihydrobenzofuran 16, was within an order of
magnitude of that of the open chain oxypropionate 2.
The herbicidal activity of the series of conformationally
restricted oxyacetates against four grass species roughly parallels
the corresponding enzymatic activity. Thus, only the five-
membered ring analogues (6, 7, 16) exhibited activity against
the grass species. Dihydrobenzofuran 16, the most active
ACCase inhibitor of the conformationally restricted analogues,
also provided the highest degree of herbicidal activity. As
expected for ACCase inhibitors, none of these materials
exhibited activity against any of nine broadleaf weed species
at the 4000 ppm rate (Table 4).
mimic for orientation of the aryloxyphenoxypropionic acids at
the active site of ACCase. The placement of the carboxylate
group in an overlay model between these two types of systems
differs by only ∼0.8 Å, however, indicating that the enzyme is
highly sensitive to the location of this group. The five-membered
fused ring systems are closer mimics of the proposed active
conformation of the phenoxypropionic acid than are the six-
membered systems, lending support to our assumption that this
is indeed the binding conformation. The addition of a methyl
substituent aids both binding and herbicidal activity in all cases,
but its spatial location does not seem to be as critical. The methyl
on the 1,4-benzodioxin system J occupies a space only 0.5 Å
from the corresponding methyl in the active conformation
model, whereas in the more active benzofuran system F the
methyl is >1.8 Å away. Thus, the binding pocket occupied by
this group appears to be somewhat accommodating.
The R-methyl group of the highly active phenoxypropionic
acids serves two functions. The first is the more obvious one,
binding favorably to a small lipophilic pocket at the active site,
adding binding energy to any analogue that possesses this group.
The second is a more subtle effect. Its steric presence limits
the conformational flexibility of the necessary phenoxyacetic
acid framework to geometries near the active conformation,
reducing the entropy loss of the system upon binding. The use
of a methyl group in this way could be a clever strategy to
limit the population of conformations far from the binding
conformation because, unlike forming rigid ring systems, the
fragment retains enough flexibility to attain the most favorable
The data presented above suggest that the conformation
adopted by those ring systems which contain a fused five-
membered, but not a six-membered ring, provides a reasonable

Enantiomeric Selectivity of Aryloxyphenoxypropionic Acids
J. Agric. Food Chem., Vol. 50, No. 16, 2002 4565
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Received for review December 11, 2001. Revised manuscript received
May 8, 2002. Accepted May 14, 2002.
JF0116395