Efficient synthesis of fused bicyclic ethers and their application in herbicide chemistry

Article abstract of DOI:10.1016/j.bmcl.2014.08.043

A series of triketones 2 and 3 featuring novel fused bicyclic aryl ethers have been prepared. The syntheses utilized ring-closing olefin metathesis (compounds 2), or oxidative cyclization of allylphenols as the key steps. The herbicidal activity of the ta

Full text of DOI:10.1016/j.bmcl.2014.08.043

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4643–4649
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Efficient synthesis of fused bicyclic ethers and their application
in herbicide chemistry
a
a
a
a
Jürgen Schaetzer a, , Andrew J. F. Edmunds , Katharina Gaus , Stefano Rendine , Alain De Mesmaeker ,
⇑
Willy Rueegg b
a Syngenta Crop Protection Muenchwilen AG, Schaffhauseserstrasse, CH-4322 Stein, Switzerland
b Syngenta Crop Protection AG, Werk Rosental, Schwarzwaldallee 215, CH-4058 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of triketones 2 and 3 featuring novel fused bicyclic aryl ethers have been prepared. The syntheses
utilized ring-closing olefin metathesis (compounds 2), or oxidative cyclization of allylphenols as the key
steps. The herbicidal activity of the targeted triketones 2 and 3 on various grasses and broad-leaved
weeds was determined and compared with compound 1. The strength of the novel compounds 2 and
3 is their good herbicidal activity on broad-leaved weeds in post-emergent applications, whereas activity
on grasses was inferior compared to 1. In addition, computational methods have been applied to provide
a deeper understanding of the SAR found for compounds 2 and 3.
Received 26 June 2014
Revised 14 August 2014
Accepted 20 August 2014
Available online 28 August 2014
Keywords:
Benzoylcyclohexanedione
Triketone herbicide
Ó 2014 Elsevier Ltd. All rights reserved.
4-Hydroxyphenylpyruvate dioxygenase
(HPPD)
Structure–activity relationship (SAR)
4-Hydroxyphenylpyruvate dioxygenase, which is
a
Fe(II)-
In this regard, we were interested to determine the impact of
conformational restriction on the biological activity by replacing
the methoxy group in 1 with ring systems of various sizes.12 Com-
pound 1 was chosen as comparison for the bicyclic compounds as
it has previously been identified as a potent HPPD inhibitor with
very good control of dicot and monocot weeds in maize at selective
rates13 and it was a potential development candidate for Syngenta
for use in corn. In addition, we were also interested in investigating
the influence of the bicyclic dione portion in comparison with the
mono cyclohexane-(1,3)-dione (Fig. 1).
A retrosynthetic analysis for construction of such novel trike-
tones 2 with fused six-, seven- and eight-membered ether rings,
indicated ring closure metathesis (RCM) to be the strategy of
choice, the precursors for the RCM themselves being obtained by
Claisen rearrangement of suitable precursors. The so obtained
bicyclic acids could then be coupled to the appropriate cyclohex-
ane-1,3-diones by well-established methodology. Alternative
strategies were envisaged for smaller rings (compounds 3), not
readily accessible by RCM, and included intramolecular Mitsunobu
reaction, oxidative cyclization of 2-(allyl)-phenols as the key steps.
Such strategies have already been applied successfully in the past
by various groups.14
dependent, non-heme oxygenase (HPPD), is the enzyme that cata-
lyzes the oxidative decarboxylation and rearrangement of hydroxyl
pyruvic acid (HPP) to homogentisate (HGA), the first committed
step in tyrosine degradation.1
However, whereas HPPD-dependent tyrosine degradation is a
process common across aerobic organisms,1b HPPD inhibitors are
uniquely toxic to plants.2 In plants, the HGA product of the HPPD
reaction is not only an intermediate in tyrosine degradation but
also an essential intermediate in the pathways to the biosynthesis
of tocopherols and plastoquinone (PQ).3,4 Depletion of carotenoids
is associated with light-dependent generation of singlet oxygen
which damages lipids and proteins and causes disassembly of the
photosynthetic complex and release of free chlorophyll. Free chlo-
rophyll is photodynamically photodestructive and itself generates
further singlet oxygen eventually leading to the destruction of all
leaf pigments and the characteristic white bleaching.5
Several triketone HPPD corn herbicides have reached the mar-
ket place, including, Mesotrione,6 Tembotrione,7 and further are
in development (Bicyclopyrone).1 Clearly, the HPPD herbicidal
mode of action is still highly interesting to the major Agro chemical
companies,8–11 and the search for novel structural types continues
(Schemes 1 and 2).
Beginning with the preparation of compounds with general
structure 2, the required diene RCM precursors 7a–7e were
obtained as shown in Schemes 3 and 4.
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2014.08.043
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

4644
J. Schaetzer et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4643–4649
HPPD
O
OH
O
O–
O2
O–
O
HO
HO
- CO2
homogentisate (HGA)
4-hydroxyphenylpyruvate (HPPD)
Scheme 1. Reaction catalysed by HPPD.
O
N
O
O
O
O
O
O
NO
2
O
O
O
Cl
O
O
CF
3
SO CH
2
SO CH
3
2
3
Bicyclopyrone
Scheme 2. Some commercial examples of HPPD-inhibitors as herbicides.
Tembotrione
Mesotrione
2
OH
CH CH
3
O
O
3
R
O
OH
O
O
( )n
O
O
OH
O
O
1
R
1
SO CH
2
3
R
SO CH
2
1
3
R
SO CH
1
2
3
R
2
R1 = H, CH2-CH2,
n = 0, 1, 2, 3, 4
1
3
R1 = H, CH2-CH2
oxidative cyclization
of allylphenols
Olefinmetathesis/Hydrogenation
2
R
O
( )n
O
O
O
HO
HO
SO CH
SO CH
2
3
2
3
cyclohexane-1,3-dione
portion
cyclohexane-1,3-dione
portion
+
+
Figure 1. Replacement of benzoyl part in 1 with fused bicyclic benzoyl arylethers and retrosynthetic analysis.
Thus, commercially available 4-nitro-3-hydroxy-methylbenzo-
rearrangement, and subsequent alkylation afforded the desired
RCM precursors 7c–7e (Scheme 4).
ate 4 was initially converted into its corresponding aryl allyl ether
5 on reaction with allyl bromide in DMF/K2CO3. Subsequent Claisen
rearrangement afforded the phenol 6, which was again subjected
to allylation to give 7a. Aromatic nucleophilic displacement of
the nitro group of 4 with NaSCH3 provided 7b.
Further RCM precursors were obtained as shown in Scheme 5.
Thus, treatment of phenol 10 with PdCl2(CH3CN)2 in benzene at
room temperature led to isomerization of the double bond;16 and
subsequent allylation delivered 7f as a mixture of cis and trans iso-
mers. Finally, reaction of 10 with acrylic acid chloride in methylene
dichloride in the presence of Hünigs base resulted in formation of
7g (Scheme 4), which upon RCM would provide a seven-membered
fused lactone system.
In a similar manner, nucleophilic substitution of the nitro group
of 4 with NaSCH3, selective oxidation15 with NaBO3, Claisen
RCM of the diene precursors 7a–7f proceeded smoothly with
[Cl2(PCy3)2Ru@CHPh] (Grubbs I)17a catalyst in methylene chloride
at room temperature. In general, the reactions required 1–20 h to
reach completion at substrate concentration ranging from 0.08 to
0.27 mol/l. We were pleased that both the sulfide and sulfone
group were tolerated by Grubbs I catalyst; also a nitro group (see
11a) did not impair the reaction, and all the desired bicyclic ethers
were obtained in high yields, further underlining broad applicabil-
ity of this methodology.17b
Unfortunately, no RCM product was detected for 7g. Even in the
presence of titanium isopropoxide as a co-catalyst, cyclization of
7g to 11g could not be affected. We assume that complexation of
the Ru-center of Grubbs I with one of the oxygen of the carbonyl
ester groups leading to a stable chelate complex was the cause
for this inefficient RCM18 (Scheme 6). Using the more reactive
Grubbs II catalyst19 also proved unsuccessful. Instead of cyclization
CO CH
CO CH
2 3
2
3
CO CH
2
3
b) 68%
yield
a) 97%
OH
O
OH
NO
NO
2
2
NO
2
5
6
4
CO CH
2
3
CO CH
2 3
a) 85%
c) 74%
O
O
NO
2
SCH
3
7a
7b
Scheme 3. Reactions and conditions: (a) Br–CH2–CH@CH2, K2CO3, KI, DMF; (b)
160 °C, 8 h, ortho-dichlorobenzene; (c) NaSCH3, DMF, 0–20 °C, 3 h.

J. Schaetzer et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4643–4649
4645
CO2CH3
CO2CH3
CO2CH3
a) 97%
b) 74%
c) 93 %
O
OH
O
SO2CH3
NO2
SCH3
9
8
4
CO2CH3
CO2CH3
d) 77%
m = 1 7c
e) 92 - 98%
m = 2 7d
m = 3 7e
O
OH
SO2CH3
m
SO2CH3
10
Scheme 4. Reaction and conditions: (a) NaSCH3, DMF, KI, 0–20 °C; (b) Br–CH2–CH@CH2, K2CO3, DMF; (c) NaBO3, AcOH, 20–40 °C, 2.5 h; (d) 175 °C, ortho-dichlorobenzene,
5 h; (e) Br–(CH2)m–CH@CH2, (NBu4)-I, DMF.
reduction step with NaBH4. Subsequently, the allyl group was oxi-
datively cleaved using OsO4/NaIO4 to yield the hydroxybenzofura-
nyl 14, which was reduced with NaBH4 in methanol to yield 15.
The key intramolecular cyclization of 15 applying Mitsunobu condi-
tions22 afforded the desired tert-butyl ester 16 in excellent yield.
Hydrolysis and conversion to the acid chloride 17 was achieved
by known methods.
A further key intermediate 19 was also synthesised from 10 via
oxidative intramolecular cyclization with m-CPBA as shown in
Scheme 9. Ring opening of the transient epoxide 18 by the phenolic
hydroxyl group furnished selectively the desired 2-hydroxy-
methyl-2,3-dihydrobenzofuran 19. It is of interest to note that for-
mation of an isomeric 3-hydroxychroman did not occur. This is in
complete agreement with earlier findings and was confirmed by
the 1NMR chemical shifts23 that are similar with the values
reported.14e Final methylation and allylation was achieved with
methyl iodide and allylbromide in methylene dichloride in the
presence of Ag2O as catalyst24 to furnish the 2,3-dihydrobenzof-
uranyls 20a–b. Hydrolysis with LiOH in THF/H2O and activation
with (COCl)2 gave the acid chlorides 21a–b.
H CO C
CO CH
2 3
CO CH
3
2
2
3
b) 56%
c) 82%
O
a) 97%
O
O
OH
SO CH
SO CH
SO CH
2
3
2
3
2
3
7f (cis/trans)
7g
10
Scheme 5. Reactions and conditions: (a) CH2@CH–COCl, Hünigs base, 0–20 °C, 1 h;
(b) PdCl2(CH3CN)2, benzene, 20 °C, 3 h; (c) Br–CH2–CH@CH2, K2CO3, KI, DMF, 20–
50 °C, 3 h.
CO2CH3
CO2CH3
11a R = NO2, m=1
a) 83 - 94%
11b R = SCH3, m=1
11c R = SO2CH3, m=1
11d R = SO2CH3, m=2
11e R = SO2CH3 m=3
( )
( )
O
R
m
O
R
m
7a - 7e
CO2CH3
CO2CH3
a) 76%
For the preparation of the 2,3-dihydrobenzofuran 24 we used
the method developed by Yum and co-workers.25 Thus, allyl-phe-
nol 10 (see Scheme 4) dissolved in methylene dichloride was trea-
ted with anhydrous AlCl3 at room temperature to provide the
desired 2,3-dihydrobenzofuran 22 in 70% yield, along with small
amounts of lactone 23. Hydrolysis of 22 with LiOH afforded key
intermediate 24, which was transformed into the acid chloride
25 (Scheme 10).
O
O
SO2CH3
SO2CH3
11f
7f
Scheme 6. Reactions and conditions: (a) (Cl2)(PCy3)Ru@CH–Ph (5–10 mol %),
CH2Cl2, 20 °C, 1–18 h.
With the key intermediates in hand, their conversion to the
final target structures was readily achieved as shown in Scheme
11-12.26
The main feature was O-acylation of the cyclohexane-1,3-
diones 28a (R1 = H) and 28b (R1 = CH2–CH2) with corresponding
acid chlorides (see Schemes 11 and 12) and subsequent cyanide-
catalyzed rearrangement26a,b to yield the required target com-
pounds 2,27 3a–c28 and 3d27 in moderate to good yield.
CO2CH3
CO2CH3
Grubbs I
O
O
O
SO2CH3
O
SO2CH3
no reaction
7g
11g
Scheme 7. Reactions and conditions: (a) (Cl2)(PCy3)Ru@CH–Ph (10 mol %), CH2Cl2,
20 °C, 18 h.
The herbicidal activities of compounds 1, 2 and 3 are summa-
rized in Table 1 and illustrate the structure–activity relationship
(SAR). The activity is expressed in percent as two numbers: the aver-
age of each of five warm climate broadleaf (Abutilon theophrasti,
Amaranthus retroflexus, Euphorbia heterophylla, Ipomoea hederacea,
Xanthium strumarium) and warm climate grass weeds (Brachiaria
plantaginea, Digitaria sanguinalis, Echinochloa crus-galli, Setaria
faberi, Panicum dichotomiflorum). In addition, the tolerance of maize
is defined as visual injury in percent; the description of the test
methods has been previously published in detail.13,28
we assume that pseudo dimerization20 and polymerization deriv-
ing from cross-metathesis occurred according to higher molecular
masses detected in MS (Scheme 7). We were not able to separate
and fully characterize a defined product from the complex reaction
mixture.
As shown in Scheme 8, the previously described sulfone inter-
mediate 10 was again used as starting material to prepare 2,3-
dihydrobenzofuranyl derivative 17. Accordingly, the methyl ester
was first transformed to the tert-butyl ester 1221 since lactonization
preferable occurred with the corresponding methyl ester during the
The minimum structural requirements3,29 for the pharmaco-
phore of HPPD inhibitors for potent in vitro and in vivo expression
have found to be an enolizable b-dicarbonyl system and an

4646
J. Schaetzer et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4643–4649
CO2CH3
CO2H
b) 66%
a) 74%
OH
SO2CH3
OH
SO2CH3
12
10
CO2tBu
CO2tBu
d) 94%
c) 89%
OH
OH
O
SO2CH3
SO2CH3
14
13
CO2tBu
OH
CO2tBu
COCl
f) quant. (crude)
g) quant. (crude)
e) quant.
OH
SO2CH3
O
O
SO2CH3
SO2CH3
16
15
17
Scheme 8. Reactions and conditions: (a) LiOHÁH2O, dioxane/H2O (4:1) 24 h, 20 °C; (b) Me2N–CH(OtBu)2, toluene; (c) OsO4 cat, NaIO4 Et2O/H2O (1:1), 18 h, 20 °C; (d) NaBH4,
MeOH, 3 h, 20 °C; (e) DEAD, Ph3P, THF, 0–20 °C, 2 h; (f) CF3CO2H, CH2Cl2; (g) (COCl)2, DMF cat, CH3CN.
CO2CH3
CO2CH3
CO2CH3
O
a) 85%
OH
OH
SO2CH3
O
OH
SO2CH3
SO2CH3
10
19
18 (not isolated)
COCl
CO2CH3
b) 92%
c) quant.
OR
d) quant. (crude)
OR
O
O
SO2CH3
SO2CH3
21a (R = CH3)
21b (R = CH2-CH=CH2)
20a (R = CH3)
20b (R = CH2-CH=CH2)
Scheme 9. Reactions and conditions: (a) m-CPBA, CHCl3, 20 °C, 18 h; (b) CH3–I, Ag2O, CH2Cl2, 48 h, 20 °C; (c) Br–CH2–CH@CH2, Ag2O, Cl–CH2–CH2–Cl, KI, 65 °C, 18 h; (d)
(COCl)2, DMF cat, CH2Cl2, 1–18 h, 20 °C.
the methylsulfonyl group (r = 0.72) could modulate perfectly the
O
O
CO CH
CO CH
physicochemical profile required (pKa <5, low logP) for HPPD
inhibitors.30 It also became apparent from previous SAR studies
that a wide range of substituents at the benzoyl 3-position is toler-
ated, which led to excellent herbicidal activity9–11 in this subclass.
Finally, earlier studies indicated that increasing substitution at the
2
3
2
3
a) 70%
+
OH
O
OH
SO CH
SO CH
SO CH
3
3
2
3
2
3
10
23
22
a-ketone positions of the cyclohexanedione moiety, increases the
herbicidal activity as in planta metabolism, that is, hydroxylation
at position 4 or 6, is inhibited.5 The bicyclic dione moiety seems
to provide the optimum for decreasing metabolism, whilst not
leading to over persistence. Triketone 1 fulfils all of these criteria
and thus shows very strong herbicidal activity.
b) 93%
CO H
2
COCl
c) 91%
Clearly, the strength of compound 1 was its excellent grass
activity in pre-emergence application, neither compounds 2 or 3
could reach this level of activity. Most notable is also the excellent
maize selectivity seen with 1, causing only 10% injury at
O
O
SO CH
2
3
SO CH
2
3
25
24
125 g ai hÀ1
.
Scheme 10. Reaction and conditions: (a) AlCl3, CH2Cl2, 20 °C, 2 h, N2; (b) LiOHÁH2O,
MeOH/H2O (5:1); (c) (COCl)2, DMF cat, CH2Cl2, 20 °C.
Comparing the prepared compounds 2 and 3 it can be deduced
from Table 1 that the compounds providing the best combination
of activity and selectivity (see injury on maize) were compounds
2a, 2b and 2d. Most notable is their good activity on broadleaf
weeds (dicotyledons) and in all cases the excellent crop selectivity,
which is even superior, to that of 1.
electron-deficient 2,4-disubstituted benzene attached to one of
these carbonyls. In addition, the electronic effects of the benzene
substituents have been studied in detail and it has been shown that

J. Schaetzer et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4643–4649
4647
a) 82 - 98%
b) 86% - quant
c) crude, directly
used
CO CH
COCl
2
3
( )n
O
OH
O
O
d) crude (in situ)
e) 23 - 51%
1
R
( )
( )
O
O
m
m
SO CH
1
2
3
R
SO CH
SO CH
2
3
2
3
26-a
26-b
26-c
2c-i R1 = H, CH2-CH2, n = 1, 2, 3, 4
m =1
m= 2
m =3
11-c
11-d
11-e
see Table1 for structures
d) crude (in situ)
e) 38 - 71%
a) quant.
b) 87%
c) quant. (crude)
O
COCl
CO CH
2
3
1
R
O
1
O
O
R
SO CH
SO CH
2
3
2
3
28a ( R1 = H )
28b ( R1 = CH2-CH2 )
11f
27
Scheme 11. Reagents and conditions: (a) H2, 5% Pd/C or H2, 5% Rh/C, THF, rt; (b) LiOH, dioxane/H2O or THF/H2O (5:1), rt; (c) (COCl)2, CH2Cl2, DMF cat; (d) 28a or 28b, Et3N,
DMAP cat, 3–18 h, 20 °C; (e) acetone cyanohydrine cat, Et3N, CH3CN, 20 °C, overnight.
R2
COCl
a) crude (in situ)
b) 22 - 80%
O
O
O
Furthermore, the impact of the bicyclic dione versus the mono
cyclohexane-1,3-dione on activity in series 2 and 3 is negligible.
A general trend cannot be deduced from Table 1, although it seems
that some of the bicyclic compounds (see i.e., 2a vs 2b or 2f vs 2g)
are slightly more active.
R2
O
R1
O
SO2CH3
R1
SO2CH3
17 (R2 = H)
Compounds 3a and 3b provided good herbicidal activity on
broadleaf weeds but in part at the cost of insufficient crop selectiv-
ity (20% injury on maize for 3a). Compounds 3c and 3d showed a
bias towards broadleaf weed control but were clearly the weakest
listed in Table 1.
Since the structure of HPPD from Arabidopsis thaliana (AtHPPD)
in co-complex with a benzoylpyrazole inhibitor was already solved
by Walsh and co-workers31a we have made use of the available
structure data set (see PDB code 1TFZ) and performed some addi-
tional docking studies. To this end ligands 1, 2b, 2g and 3a were
modelled into the AtHPPD binding site using standard soft-
wares.32–34 As a representative example the binding pose of HPPD
2a-b
21a (R2 = CH2-OCH3)
3a-d
21b (R2 = CH2-OCH2-CH=CH2)
25 (R2 = CH3)
(see Table1)
Scheme 12. Reaction and conditions: (a) 28a or 28b, Et3N, CH2Cl2, DMAP cat,
3–18 h, 20 °C; (b) acetone cyanohydrine cat, Et3N, CH3CN, 20 °C, overnight.
There is a clear tendency that increasing the ring size of the
fused bicyclic ether in compounds of formula 2, the weaker the
herbicidal activity. Nevertheless, even the nine-membered ring
system (see 2h and 2i) still showed fair to good activity on broad-
leaf weeds in post-emergent application.
Table 1
Herbicidal activity and maize tolerance of triketones 1, 2 and 3a
R2
OH
O
O
OH
O
O
OH
O
O
CH3 CH3
O
( )n
O
O
R1
R1
SO CH3
SO CH3
SO CH3
R1
R1
2
2
2
1
2
3
No.
n
R1
R2
Post-emergence
Post-emergence
Maize injury (%) Pre-emergence
Pre-emergence
Maize injury (%)
grass activityb (%) broadleaf activityb (%)
grass activityb (%) broadleaf activityb (%)
1
—
0
0
1
1
2
3
3
4
CH2–CH2
H
CH2–CH2
H
CH2–CH2
H
H
CH2–CH2
H
CH2–CH2
H
CH2–CH2 CH2–OCH3
—
—
—
—
—
—
—
—
90
52
84
40
64
46
28
36
42
42
4
88
88
88
78
76
66
68
76
72
84
70
78
58
60
20
10
10
10
10
20
0
10
20
20
20
0
96
26
28
9
28
52
26
32
16
6
72
78
84
76
84
66
30
38
24
40
70
60
0
10
0
10
40
10
0
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
0
20
20
20
20
20
0
—
—
4
—
—
—
—
CH2–OCH3
0
24
0
34
6
8
H
H
CH2–OAllyl
CH3
0
20
12
38
10
a
Application rate: 125 g ai haÀ1
.
b
The results are expressed as an average of the sum of each of five broadleaf and five grass weeds, see text for description.

4648
J. Schaetzer et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4643–4649
ligand 2g (eight-membered fused bicycle) is shown in Figures 2
and 3.35
in vivo activity on broad-leaved weeds. However, differences in
herbicidal activity between single compounds 2 and 3 cannot be
explained with this docking study. Certainly, this could also be
caused by a number of other factors, such as different metabolic
decomposition, degradation in soil, or differential binding affinities
at the target site.
In conclusion, we have prepared a series of conformational
restricted analogues of the triketone herbicide 1 by enclosing the
methoxy group of 1 into rings of various sizes. The compounds
could all be successively docked into the AtHPPD binding site and
as such showed the expected herbicidal activity. The differences
observed are mainly in pre-emergence application, where com-
pound 1 clearly showed stronger activity than compounds 2 and 3.
Figure 2 depicts the typical binding mode of HPPD inhibitors:
the central metal ion (Co or Fe, see Ref. 31) is coordinated by two
histidine groups (His287 and His205), a well conserved water mol-
ecule (WAT), a glutamic acid residue (Glu373) and the 1,3-diketone
portion of 2g forming an octahedral complex. Furthermore, there
are favorable interactions between the inhibitor 2g and two phen-
ylalanine residues (Phe 403, 360) due to p-stacking. Finally, the dis-
tances from the ligand hetero atoms to the metal ion (M–N, M–O)
have been measured and were found to be in the range of
1.9–2.4 Å; thus all binding features being fully in line with the pre-
vious published data set31a,b as expected.
Figure 3 shows the view from the top of the entrance of the
AtHPPD binding site. The fused bicyclic ether portion is pointing
towards the gate thus illustrating that even fused eight or nine
membered rings (see i.e., 2h and 2i) do not face repulsions with
the amino acid backbone and thus are able to occupy the binding
pocket. Consequently, a clue can be given why molecules with such
ring sizes fit into the binding site, and therefore, still express good
Acknowledgments
The authors thank the following scientists for their dedicated
contributions to the discovery and development of the novel trike-
tone herbicides: R. Beaudegnies, H.G. Brunner, R. Hall, C. Luethy, K.
Seckinger, R. Viner, S. Wendeborn.
References and notes
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Figure 2. Inhibitor 2 g in the HPPD active site. The catalytic metal ion M is liganded
in regular, octahedral geometry by
a bidentate interaction with 2 g, a water
molecule (WAT) and three active site residues (His205, His287 and Glu373).
12. Presented in part: (a) Schaetzer, J.; Edmunds, A. J. F.; Rueegg, W., 10th IUPA
Conf. Pest Chem, Poster Presentation, 2002; Basel, Switzerland; (b) Schaetzer,
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23. 19: 1H NMR (CDCl3, 600 MHz) d: 7.76 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H),
5.24 (dddd, J = 4.0, 4.7, 6.6, 9.7 Hz, 1H), 3.96 (s, 3H), 3.73 (dd, J = 4.0, 10.9 Hz,
1H), 3.67 (dd, J = 4.7, 10.9 Hz, 1H), 3.68 (ddd, J = 0.9, 10.0, 17.6 Hz, 1H), 3.51
(ddd, J = 0.8, 6.6, 17.8 Hz, 1H), 3.43 (s, 3H), 3.23 (s, 3H).
24. Bouzide, A.; Sauvé, G. Tetrahedron Lett. 1997, 38, 5945.
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Wilzer, K. R.; Waters, R. M. Synthesis 1990, 1117.
Figure 3. View from the top of the entrance of the HPPD binding cavity. The fused
bicyclic ether portion of 2 g is pointing towards the entrance whereas the bicyclic
cyclohexane-1,3-dione moiety is deeply buried in the binding site.

J. Schaetzer et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4643–4649
4649
27. NMR of selected compounds 2 and 3. The novel compounds (2a–2i and 3d)
were prepared by coupling acid chlorides (25, 26a–26c and 27) and
cyclohexanediones (28a and 28b) using the O-acylation rearrangement
chemistry described in reference26a,b. 2a: 1H NMR (CDCl3, 300 MHz) d: 16.85
(s, 1H), 7.68 (d, 1H), 6.88 (d, 1H), 4.82 (t, 2H), 3.27 (t, 2H), 3.20 (s, 3H), 2.80 (t,
2H), 2.50 (t, 2H), 2.09 (quin, 2H). 2 b: 1H NMR (CDCl3, 600 MHz) d: 17.03 (s,
1H), 7.70 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.88–4.76 (m, 2H), 3.34–
3.21 (m, 2H), 3.20 (s, 3H), 3.19–3.15 (m, 1H), 2.99–2.95 (m, 1H), 2.29–2.14 (m,
3H), 2.02 (dddd, J = 1.7, 4.0, 9.2, 13.1 Hz, 1H), 1.81–1.73 (m, 2H). 2c: 1H NMR
(CDCl3, 600 MHz) d: 17.23 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz,
1H), 4.43–4.37 (m, 2H), 3.23 (s, 3H), 2.81 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4 Hz,
2H), 2.48–2.41 (m, 2H), 2.12–2.01 (m, 4H). 2d: 1H NMR (CDCl3, 600 MHz) d:
17.23 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 4.39 (dd, J = 5.4,
4.8 Hz, 2H), 3.23 (s, 3H), 3.18–3.14 (m, 1H), 2.97–2.89 (m, 1H), 2.74–2.59 (m,
2H), 2.30–2.11 (m, 3H), 2.10–1.98 (m, 3H), 1.83–1.72 ppm (m, 2H). 2 e: 1H
NMR (CDCl3, 300 MHz) d: 17.30 (s, 1H), 7.80 (d, 1H), 6.89 (d, 1H), 4.10–4.22 (m,
2H), 3.24 (s, 3H), 2.79 (t, 2H), 2.77–2.66 (m, 2H), 2.38–2.50 (m, 2H), 2.14–1.93
(m, 4H), 1.78–1.58 (m, 2H). 2f: 1H NMR (CDCl3, 600 MHz) d: 17.29 (s, 1H), 7.87
(d, J = 8.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 4.43–4.36 (m, 2H), 3.24 (s, 3H), 2.82
(t, J = 6.4 Hz, 2H), 2.76 (m, 2H), 2.43 (t, J = 6.6 Hz, 2H), 2.07 (quin, J = 6.5 Hz,
2H), 1.75–1.70 (m, 2H), 1.66 (quin, J = 6.3 Hz, 2H), 1.60–1.54 (m, 2H). 2g: 1H
NMR (CDCl3, 600 MHz) d: 17.26 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 6.96 (d,
J = 8.1 Hz, 1H), 4.38 (dd, J = 5.7, 4.4 Hz, 2H), 3.23 (s, 3H), 3.15–3.19 (m, 1H),
2.87–2.91 (m, 1H), 2.73 (br s., 2H), 2.19–2.29 (m, 2H), 2.11–2.19 (m, 1H), 1.98–
2.07 (m, 1H), 1.69–1.82 (m, 4H), 1.59–1.69 (m, 2H), 1.52–1.58 ppm (m, 2H). 2h:
1H NMR (CDCl3, 600 MHz) d: 17.25 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 6.94 (d,
J = 8.1 Hz, 1H), 4.40–4.35 (m, 2H), 3.23 (s, 3H), 2.81 (t, J = 6.5 Hz, 2H), 2.85 (br
s., 2H), 2.43 (t, J = 6.6 Hz, 2H), 2.07 (quin, J = 6.5 Hz, 2H), 2.04–1.98 (m, 2H),
1.63 (tt, J = 6.6, 12.7 Hz, 4H), 1.42–1.32 (m, 2H). 2i: 1H NMR (CDCl3, 600 MHz)
d: 17.25 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 4.30–4.44 (m,
2H), 3.23 (s, 3H), 3.20–3.15 (m, 1H), 2.91–2.86 (m, 1H), 2.77–2.85 (m, 2H),
2.28–2.19 (m, 2H), 2.15 (dddd, J = 13.8, 11.2, 7.1, 4.2 Hz, 1H), 2.06–1.96 (m,
3H), 1.80–1.68 (m, 2H), 1.67–1.56 (m, 4H), 1.39–1.31 ppm (m, 2H). 3d: 1H NMR
(CDCl3, 300 MHz) d: 16.88 (s, 1H), 7.69 (d, 1H), 6.85 (d, 1H), 5.23–5.12 (m, 1H),
3.37 (dd, 1H), 3.19 (s, 3H), 2.92–2.71 (m, 3H), 2.49 (t, 2H), 2.10 (quin, 2H), 1.53
(d, 3H).
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