Spirodiclofen and spiromesifen - Novel acaricidal and insecticidal tetronic acid derivatives with a new mode of action

Article abstract of DOI:10.2533/000942903777678588

The broad spectrum acaricides spirodiclofen (BAJ2740, trade name: Envidor) and spiromesifen (BSN2060, trade name: Oberon) with an additional excellent activity against whiteflies, both belong to the new chemical class of tetronic acid derivatives discovered at Bayer CropScience during the 1990s. The discovery process starting from herbicidal PPO (protoporphyrinogen oxidase) chemistry, the synthetic routes leading to the products, and some insight into process development of central intermediates is given. Spirodiclofen and spiromesifen have a new mode of action (interference with lipid biosynthesis), show no cross-resistance to any resistant mite or whitefly field population and are therefore valuable tools for resistance management.

Full text of DOI:10.2533/000942903777678588

CROP PROTECTION RESEARCH
697
CHIMIA 2003, 57, No.11
Chimia 57 (2003) 697–701
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Spirodiclofen and Spiromesifen –
Novel Acaricidal and Insecticidal
Tetronic Acid Derivatives with
a New Mode of Action
Thomas Bretschneidera*, Jordi Benet-Buchholzb, Reiner Fischera, and Ralf Nauena
Abstract: The broad spectrum acaricides spirodiclofen (BAJ2740, trade name: Envidor®) and spiromesifen
(BSN2060, trade name: Oberon®) with an additional excellent activity against whiteflies, both belong to the
new chemical class of tetronic acid derivatives discovered at Bayer CropScience during the 1990s. The
discovery process starting from herbicidal PPO (protoporphyrinogen oxidase) chemistry, the synthetic routes
leading to the products, and some insight into process development of central intermediates is given.
Spirodiclofen and spiromesifen have a new mode of action (interference with lipid biosynthesis), show no
cross-resistance to any resistant mite or whitefly field population and are therefore valuable tools for
resistance management.
Keywords: Acaricide · Insecticide · Spirodiclofen · Spiromesifen · Tetronic acid
Fig 1. Spidermite
Tetranychus urticae
Introduction
Spider mites (e.g. Tetranychus spec.) and
whiteflies (e.g. Bemisa and Trialeurodes)
belong to the most serious sucking pests
and cause severe damage in many different
agricultural and horticultural cropping sys-
tems world-wide (Fig. 1).
The broad spectrum acaricides spirodi-
clofen (BAJ2740, trade name: Envidor®)
and spiromesifen (BSN2060, trade name:
Oberon®) with high activity against white-
flies and mites, both belong to the new
group of tetronic acid derivatives discov-
ered at Bayer CropScience during the
1990s [1][2].
In the first part the discovery process of
spirodiclofen and spiromesifen is present-
ed. The synthetic routes leading to both
products together with some remarks re-
Whitefly
Bemisia tabaci
*Correspondence: Dr. T. Bretschneidera
Tel.: +49 21 73 38 38 38
Fax: +49 21 73 38 41 07
E-Mail: thomas.bretschneider@bayercropscience.com
aBayer CropScience AG
Research
Alfred Nobel Str.50
D-40789 Monheim
bBayer Business Services
D-51368 Leverkusen

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
garding process chemistry follows. The last responding C-aryl compounds (Fig. 2).
part deals with the new mode of action of
tution patterns were screened. The 2,4,6-
Interestingly the herbicidal activity of trimethyl-phenyl (‘mesityl’) compounds 3
these compounds and their great value to the 2,4-dichloro derivative 2 switched from and their acylated derivatives 3A showed
farmers resulting from the high activity the original broad activity of compound 1 to an improved acaricidal activity against
against resistant mites and whiteflies activity against grassy weeds. Biochemical Tetranychus urticae, but were not satisfac-
worldwide.
work showed that we had a new class of tory regarding another important mite
herbicides acting on the acetyl CoA car- species, Panonychus ulmi.
boxylase (ACCase) in our hands, a target To improve this Panonychus activity a
well known from the commercial cyclo- broad screening of the substitution on the
Discovery
hexanedions (DIM) and aryloxyphe- ‘left side’ of the lead structures was per-
In the course of a synthesis program in noxypropionate (FOP) herbicides [3].
the area of bicyclic N-aryl PPO herbicides
formed. The monocyclic dimethyl-deriva-
Even more surprisingly the acylated de- tives of type 4 and 4A showed good activi-
of type 1 with activity against broad-leaved rivative 2A showed an acaricidal activity ty against both relevant mite species, but
weeds the central nitrogen atom was re- against Tetranychus urticae. To improve caused phytotoxic effects in some crops.
placed by a carbon atom leading to the cor- this activity many different aromatic substi-
To overcome this drawback the core
structures of the molecules were modified.
The synthesis of the tetronic acid analogues
5 and especially the acylated analogues like
e.g. the pivaloyl derivative 5A showed a
high acaricidal potential together with an
improved plant compatibility [4].
Cl
OR
F
O
O
Cl
N
CN
N
N
O
X
In some sensitive crops however, like
stone fruits or grapes, we still observed
phytotoxic effects under special conditions.
Therefore, in a ‘back to the roots’approach,
we changed the mesityl substitution pattern
back to the dichloro-type examined earlier
in the program. This led to the enol 6 as a
template that combined good acaricidal ac-
tivity against both mite species and a good
plant compatibility in all relevant crops.
The ‘fine tuning’ of these properties was
achieved by scanning a large set of differ-
ent acylating reagents – the optimum was
the 2,2-dimethyl-butyric acid derivative 7,
which was selected for development
under the common name spirodiclofen
(BAJ2740, trade name: Envidor®) [1].
During the acaricidal optimisation
process it was noticed that several com-
pounds, especially acylated 3-mesityl
tetronic acids with a spiro cyclopentyl ring
in position 5, showed additional excellent
activity against white flies (Bemisia
tabaci). The fine-tuning process regarding
activity, spectrum and plant compatibility
finally led to the 3,3-dimethyl-butyric acid
derivative spiromesifen (8) (BSN2060,
trade name: Oberon®) [2].
1
2
R=H
2A R=CO-CMe2-iPr
Me
Me
Me
Me
OR
OR
Me
Me
Me
Me
N
HN
O
R=H
O
3
4
R=H
3A R=CO-tBu
4A R=CO2-CH(Me)Et
Me
Me
Cl
OR
OH
Me
Cl
O
O
O
O
5
R=H
6
5A R=CO-tBu
Some physicochemical properties of the
new products are given in Fig. 2. Both have
a relatively high partition coefficient logP
(octanol/water) in the range of 4.5 to 5.8
and a low solubility in water of approxi-
mately 0.1 mg/l . Therefore after applica-
tion on plants they mainly stay on the leaf
and in the wax cuticle and are not systemic.
The X-ray structure analysis shows that
both compounds crystallise in a monoclin-
ic cell, Spirodiclofen (7) with the space
group P21/n and spiromesifen (8) P21/c
(Fig. 3). The torsion angles between the
tetronic acid ring and the 3-phenylring are
in the range of 50–60°, mainly due to steric
O
O
Cl
Me
O
O
O
O
Cl
Me
O
O
Me
7 (Spirodiclofen)
8 (Spiromesifen)
logPow
melt.point 95°C
water sol. 0.05 mg/l
5,83
logPow
melt.point 98°C
water sol. 0.13 mg/l
4.55
Fig. 2. Discovery of spirodiclofen (7) and spiromesifen (8)

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
a)
b)
Fig. 3. X-ray structures of spirodiclofen (7) and spiromesifen (8). a) Structure of spirodiclofen (monoclinic cell, space group P21/n, phenyl
ring–tetronic acid ring angle 49.7°). b) Structure of spiromesifen (monoclinic cell, space group P21/c, phenyl ring–tetronic acid ring angle 62.3°).
corresponding aldehyde in form of its di-
methyl acetal and than further oxidised
1) NaCN
1) NaCN
2) HCl
3) EtOH, p-TsOH
2) H2SO4/H2O
with hydrogen peroxide under acidic condi-
tions to mesityl acetic acid [5]. A straight-
forward route is the AlCl3 mediated
Friedel-Crafts alkylation of mesitylene
with the C2-building block butyl methoxy-
sulfonyl-oxyacetate yielding 16, which is
than saponified to the free acid [6].
Cl
Cl
3) SOCl2
CO Et
2
Cl
Cl
+
Cl
O
Cl
OH
O
10
9
Cl
CO Et
2
The further route to spiromesifen (8) is
similar to the above shown spirodiclofen
synthesis (Scheme 3). Acylation of the cy-
clopentyl hydroxyester 17 (synthesised
from cyclopentanone via the classical cyan-
hydrine route in three steps) with mesityl-
acetyl chloride (18) leads to the intermedi-
ate 19, which is cyclised to the tetronic acid
20 using e.g. potassium tert-butylate in
DMF.
Cl
O
O
11
KOtBu
O
O
O
Cl
OH
Cl
O
Cl
Cl
O
Cl
O
Several synthesis routes for the 3,3-di-
methylbutyric acid (23), used as the acyl
side chain in spiromesifen (8), were inves-
tigated. One interesting route starts from
trimethylpyruvic acid (21), which is trans-
O
6
7
Scheme 1. Synthesis of spirodiclofen (7)
repulsions of the ortho substituents with the
The combination of these two building ferred to the corresponding hydrazone 22
substituents in position 2 and 4 of the blocks leads in a convergent way to the using hydrazine hydrate (optionally in a
tetronic acid ring system.
‘diester’11, which is treated with a base, e.g. solvent, e.g. triethylene glycol) followed by
KOtBu, to form the tetronic acid 6. The final a reductive cleavage with a base, e.g. potas-
acylation with 2,2-dimethyl-butyryl chlo- sium hydroxide, at elevated temperatures.
Synthesis
ride leads to spirodiclofen (7) (Scheme 1).
Several possibilities for a large-scale niently done in a single step/one pot proce-
The first central intermediate of the synthesis of mesitylacetic acid 12, a central dure [7].
This whole process may also be conve-
spirodiclofen (7) synthesis is ethyl 1-hy- building block in the synthesis of spiro-
The final acylation of the enol 20 with
droxy-cyclohexanecarboxylate (9), which mesifen (8), were examined (Scheme 2). 3,3-dimethylbutyryl chloride leads to
is synthesised from cyclohexanone by Using the classical standard route, mesi- spiromesifen (8).
HCN addition to the cyanhydrine, followed tylene (13) is transferred into mesityl ace-
by saponification and esterification. The tonitrile (14) via chloromethylation and
second central intermediate is 2,4-dichloro- cyanide exchange, which is then saponified Biology and Mode of Action
phenylacetyl acid chloride (10), which is to the aryl acetic acid. Another route exam-
synthesised from 2,4-dichlorobenzyl chlo- ined was the Friedel-Crafts alkylation of
ride by cyanide exchange, saponification mesitylene (13) with 1,3-dichloro-propene spider mites (e.g. Tetranychus urticae) be-
and acid chloride preparation. to the adduct 15, which is ozonolysed to the long to the most serious sucking pests in
Whiteflies (e.g. Bemisia tabaci) and

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
cluding the eggs.Additionally it reduces the
fecundity of the female adults with the re-
sult that the number of eggs laid is strongly
decreased. The eggs of females exposed to
sublethal doses are not fertile. It was ob-
served that the lipid content in treated fe-
male adults of Tetranychus urticae was sig-
nificantly decreased, suggesting an inter-
ference with lipid biosynthesis (Fig. 4).
This is in line with the slightly delayed on-
set of activity of the compounds. On the
other hand they show an excellent long-
lasting effect and good plant compatibility
under field conditions. The biological pro-
file of spirodiclofen (7) has recently been
reviewed by Wachendorff et al. [11].
Spirodiclofen (7) and spiromesifen (8)
were extensively tested on several strains of
Tetranychus urticae collected worldwide
and showing a high level of resistance to es-
tablished commercial acaricides. Both were
shown to perform outstandingly [2][8][12].
Similarly to spirodiclofen (7), the sec-
ond compound in this class, Spiromesifen
(8), is also particularly active against juve-
nile stages. However, it also strongly af-
fects fecundity of mite and whitefly adults
in a dose-dependent manner by transovari-
ole effects. It shows ovicidal effects in
mites, whereas egg hatch in whiteflies was
markedly reduced through transovariole ef-
fects upon pre-exposure of female adults.
Spiromesifen (8) was extremely effective
against whiteflies resistant to pyrethroids,
organophosphates, carbamates, cyclodi-
enes, and neonicotinoids (Table) [2]. Fur-
thermore, field simulator studies revealed
that spiromesifen (8) is also a valuable
tool to control pyriproxyfen resistant white-
flies (Fig. 5). In particular, the combination
with neonicotinoid (chloronicotinyl) insec-
ticides such as imidacloprid renders spiro-
mesifen (8) a new valuable tool in resist-
ance management strategies for whitefly
control [2].
Me
Me
Me
13
BuO C
OSO Me
2
2
1) HCHO,HCl
2) NaCN
AlCl3
Cl
Cl
AlCl3
Me
Me
Me
Me
Cl
Me
Me
Me
MeO
NC
15
Me
O
Me
16
14
1) O3 ,MeOH
2) AcOH/H2O2
1) NaOH
2) HCl
NaOH
Me
Me
HO
Me
O
12
Scheme 2. Synthesis of mesityl acetic acid (12)
1) NaCN
2) HCl
Me
Me
Me
3) EtOH, p-TsOH
CO Et
2
Me
Me
+
Cl
O
OH
(see Scheme 2)
O
Me
17
18
Me
CO Et
2
Me
O
O
Me
19
KOtBu
O
O
O
Me
Me
OH
Me
O
O
Cl
Me
O
Me
O
Me
SOCl2
8
20
Conclusion
KOH
N2H4
O
O
O
N
O
The discovery process of spirodiclofen
(7) and spiromesifen (8) started with an ‘in-
dication shift’, meaning a shift from (in our
case) herbicidal to acaricidal activity in an
closely related chemical structure often as-
sociated with a change in the mode of ac-
OH
OH NH
2
OH
23
21
22
Scheme 3. Synthesis of spiromesifen (8)
many cropping systems. They have devel-
The symptomology of poisoning ob- tion (in our case from protoporphyrinogen
oped a high degree of resistance to many served with the new tetronic acid deriva- oxidase inhibition to lipid biosynthesis).
chemical classes of insecticides and acari- tives indicated a new biochemical mode of The careful follow-up of the only weak
cides commercially available ([8–10] and action not yet observed with any commer- acaricidal activities of the first hits and a
references cited therein). Therefore new ac- cially available acaricide or insecticide. tailor-made acaricidal test in the biological
tive ingredients with novel modes of action They show no signs of neurotoxic activity, research delivering fast results played a vi-
are needed to participate in resistance man- but act on mite and whitefly development. tal role in the first part of the optimisation
agement programmes to control these pests Spirodiclofen (7) exhibited activity against process.
efficiently.
all developmental stages of the mites, in-

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
Process chemistry was an important
piece in the later part of the optimisation
process with the goal to find the most eco-
nomic routes for a commercial large-scale
production of the products. Many different
synthesis routes for the central intermedi-
ates had to be examined as shown in the
case of mesitylacetic acid.
Physiological, biological, and biochem-
ical work revealed a new mode of action for
spirodiclofen (7) and spiromesifen (8) (in-
ference with lipid biosynthesis) and as a
consequence both compounds showed high
activity against mite and whitefly popula-
tions resistant to conventional chemistry.
Especially this attribute of the new tetronic
acid derivatives, combined with their ex-
cellent long-lasting efficacy and the
favourable environmental profile will make
them a valuable tool for farmers worldwide.
18
16
14
12
10
8
Untreated
Treated
6
4
2
0
2h
2d
5d
Fig. 4. Lipid decrease in spiromesifen-treated spider mites
Received: September 16, 2003
[1] U. Wachendorff, E. Brück, A. Elbert, R.
Fischer, R. Nauen, N. Stumpf, R. Tie-
mann, Proceed. Brighton Crop Protect.
Conf. 2000, 1 (2A-6), 53.
[2] R. Nauen, T. Bretschneider, E. Brück, A.
Elbert, U. Reckmann, U. Wachendorff, R.
Tiemann, Proceed. Brighton Crop Protect.
Conf. 2002, 1 (2A-3), 39.
5000
Pyriproxyfen
BSN 2060
4000
3000
2000
1000
0
[3] P. Babczinski, R. Fischer, Pestic. Sci.
1991, 33(4), 455.
[4] J. Bachmann, T. Bretschneider, C. Erde-
len, R. Fischer, B. Krüger, K. Lürssen, H.
Santel, R.R. Schmidt, U. Wachendorff
(Bayer AG), Patent EP 528156, 1993.
[5] R. Lantzsch, R. Fuchs (Bayer AG), Patent
EP 676388, 1995.
[6] U. Stelzer (Bayer AG), Patent EP 665212,
1995.
[7] U. Stelzer (Bayer AG), Patent EP 884299,
1998.
0
10
20
30
40
50
Days after infestation
[8] R. Nauen, N. Stumpf, A. Elbert, Proceed.
Brighton Crop Protect. Conf. 2000, 1 (4D-
9), 453.
Foliar treatment
[9] R. Nauen, N. Stumpf, A. Elbert, C.P.W.
Zebitz, W. Kraus, Pest Management
Science 2001, 57, 253.
[10] I. Denholm, G. Devine, S. Foster, K. Gor-
man, R. Nauen, Proceed. Brighton Crop
Protect. Conf. 2002, 1, 161.
Fig. 5. Comparative effects of pyriproxyfen and BSN 2060 (spiromesifen (8)) on large whitefly
populations (pyriproxyfen-resistant Q-type) of mixed life stages in ‘field simulators’ on cotton
plants
[11] U. Wachendorff, R. Nauen, H.J. Schnor-
bach, N. Rauch,A. Elbert, Pflanzenschutz-
Nachrichten Bayer 2002, 55, 149.
[12] N. Rauch, R. Nauen, Pesticide Biochem-
istry and Physiology 2003, 74, 91.
Table. Resistance factors of several Tetranychus strains against com-
mercial acaricides and spiromesifen (8)
NL-00
AKITA
UK-99
Au
Abamectin
Pyridaben
Fenpyroximate
Hexythiazox
Clofentenzine
54
22
–
–
–
3
–
2
13
5
1100
>770
2000
1400
4
860
74
–
4
–
Spiromesifen
4
1
1
3