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Chirality and Crop Protection.

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Volume 30
Number 10
October 1991
Pages 1193-1386
International Edition in English
Chirality and Crop Protection
By Gerard0 M. Ramos Tombo * and Daniel BelluS"
Dedicated to Professor Kurt Schaffner on the occasion of his 60th birthday
The modern agrochemical industry is searching, more intensively than ever, for new substances
to combat pests (weeds, deleterious insects, plant pathogens, etc.). In the complex and costly
selection and optimization process, state-of-the-art scientific methods are always needed. The
aims of the interdisciplinary optimization are mainly the reduction of the rate of application
of the new substance, an increase in the selectivity against the target organism, and the optimal
ecological profile. If a promising crop protection compound is a racemate or a diastereoisomeric mixture, the chemist has a unique opportunity to contribute to this optimization process
through the synthesis of enantiomerically pure isomers for testing purposes. If the single
isomer proves to be biologically superior to the racemate, the development of an economical
and ecologically sound process for the production of the single isomer presents an even greater
challenge. The average price of a crop protection compound is much lower than that for a
pharmaceutical product, and this fact imposes a severe limitation upon the flexibility of the
chemist who is concerned with the synthesis and production of a stereochemically pure agrochemical. This forces the crop protection chemist to make full use of both his scientific and
creative capabilities. Fortunately, parallel to the development of the above optimization aims
of a modern and ecologically sound crop protection research, there has been a continuous and
worldwide advance in the area of asymmetric synthesis. Due to the interplay of these two
parallel efforts there has been a great accumulation of chemical, biological, and agronomical
knowledge in recent years, which should have implications beyond merely the synthesis of
enantiomerically pure agrochemicals.
1. Introduction
The pioneering work on the resolution of racemic tartaric
acid by Louis Pasteur in the middle of the 19th century allowed chemists to realize that optical activity is a result of
molecular asymmetry. Since then, the significance of stereoisomerism, not only in relation to physicochemical but also
to biological properties, has been gradually recognized by
scientists.['] Chirality is not a requirement for biological activity, but in those cases in which the bioactive molecule
[*] Dr. G. M. Ramos Tombo, Prof. Dr. D. BelluS
Research and Development Plant Protection
Agro Division, Ciba-Geigy AG
CH-4002 Basel (Switzerland)
Angew. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
contains one or more stereogenic centres, the desired biological property is often strongly related to a given absolute
configuration.['* 31
Besides this so-called principal activityL4]of stereoisomers,
there are often differences in their uptake, transportation, metabolic behavior, elimination, and toxicological properties. Accordingly, the advantages of using stereochemically pure compounds have been recognized for many years, first for pharmaceuticals['I and later for agro~hemicals.[~~
However, due
to practical limitations, only a few substances, mainly of natural origin, have been developed as single stereoisomers.
For a long time, there were no general methodologies for
the synthesis of enantiomerically pure compounds, and the
separation of racemates on an industrial scale was, in gener-
0 VCH Verlagsgesellschafi mbH.
W-6940 Weinheim,1991
$3.50+ .2S/O
al, difficult, inefficient, and expensive. Over the past 15
years, however, significant advances have been made in both
these fields.[51SeebachL6]recently stated that almost no aspect of organic synthesis is generating as many publications
as the preparation of enantiomerically pure compounds.
The dramatic improvements in synthesis and analysis have
provided the scientific basis for a systematic investigation of
the implications of stereoisomerism as one of the many determinant factors of biological properties. Not surprisingly,
the industries involved in the synthesis, development, and
marketing of biologically active compounds are becoming
more and more active in this area. Many examples of the
successful development of economically feasible industrial
syntheses of enantiomerically pure compounds are now
known, and catalytic processes are likely to emerge as a
major focus for research in this field in the near future.[’]
In modern agrochemical R & D all four principal methods
of introducing chirality (Fig. 1) are now used for obtaining
small samples of pure stereoisomers for testing purposes, as
well as for commercial-scale syntheses. In many cases the
development and use of enantiomerically pure compounds
can bring great economic and environmental advantage over
the use of a racemate or a diastereoisomeric mixture: for
example, lower application rates, and fewer or no side effects
or phytotoxicity ; the possibility of precise mode of action
studies; reduced capital requirements for production, transportation, storage. In addition, this represents an exciting
and motivating research field!
It is difficult to obtain precise data on the number of chiral
synthetic agrochemicals which are at present used in enantiomerically pure form, but from various sources it can be
estimated that approximately 10 % for the presently marketed agro~hemicals,[~~
’] and 20- 30 O h of the compounds in the
development pipelines of leading agrochemical companies[”]
Fig. 1 . A chiral Swiss tetrahedron containing Nature in the center as the sole
source of chirality for four principal approaches (inside the cross) to enantiomerically pure compounds of importance for crop protection (outside the
cross). For 700 years now (1291 - 1991), the absolute configurationof the Swiss
cross is determined regularly by voting, either by a show ofhands or by ballot;
it is clearly the R one (right:dextrorotatory) [7]. The centerpiece as well as the
overall design is a tribute to the origins of Kurt Schaffner.
contain one or more stereogenic centres. Although the majority of these products will presumably be marketed as a single
isomer, examples in this paper will show convincingly that the
real situation in crop protection is far from black-and-white
(“good enantiomer, bad racemate”). Six principal possibilities
are frequently met in agrochemicalresearch and development:
Gerard0 M . Ramos Tombo was born in 1952 in Rosario, Uruguay. He studied chemistry in Montevideo (B. Sc., 1976) and at the ETH, Zurich (Diploma, 1979), where he completed his dissertation entitled “Intramolecularadditions to isolated C-C double bonds in sterically compressed
olefin-alcohols and amines” in 1983 under the guidance of Professors 0.Jeger and C. Ganter.
This work was honoured with the Silver Medal of the ETH. In 1983 he joined the Central
Research Laboratories of Ciba-Geigy Ltd. in Basel and in 1987 he transferred to the Agrochemical Division where he leads the Basic Synthesis Research section. His research interests lie in the
conception and development of industrially useful synthetic methods and asymmetric syntheses.
Daniel Bellui was born in 1938 in Trnava, Czechoslovakia and studied chemistry at the Slovak
Technical University in Bratislava. He obtained his Dipl. I g . in 1960 and completed his Ph. D.
in 1967 in the area of the photochemistry ofpolymers. In the same year, he went as apostdoctoral
fellow to the ETH Zurich to work with 0.Jeger and K . Schaffner. Since 1969 he has been with
Ciba-Geigy Ltd. in Basel, 1985-1991 as head of Plant Protection R & D and currently as head
of the Corporate Research Units. From 1980 he has lectured at the University of Freiburg
(Switzerland). His research interests lie in the reactions of small rings,photochemistry, cycloadditions and rearrangements (reactions without reagents), heterocyclic and metal-catalyzed reactions, and crop protection chemicals (1985- 1991). Amongst his honours he prizes the ScientiJic
Award of the City of Basel (1982) and an honorary doctorate (Dr. sc. techn. h.c.) from his Alma
Mater (1991) the highest.
Angew. Chem. Int. Ed. Engl. 30 (1991) ii93-1215
1. The stereoisomers have complementary biological acitvity
(a common case within the triazole fungicides, e.g. propiconazole 25 and 34-37).
2. All stereoisomers possess nearly identical qualitative and
quantitative biological activity (i.e., the fragment containing the chiral center does not interact with the receptor,
e.g. 62).
3. The stereoisomers have qualitatively similar but quantitatively different potencies (a common case, e.g., within
pyrethroids containing two or three chiral centers, Section 4.5).
4.Several stereoisomers are equally active (e.g., O.D.P. 125).
5. The stereoisomers have qualitatively different biological
activities (e.g. (R)- and (S)-22).
6. All the biological activity resides in one stereoisomer (e.g.,
63, (R)-78).
However, in the modern agrochemical industry it is no
longer enough to pursue biological activity only. In order to
make the very costly decision whether or not to develop a
single stereoisomer, it is necessary to adopt a multidisciplinary approach by investigating the translocation, mode of
action, nontarget toxicity, crop safety, and environmental
behavior of each specific substance. If, for insurmountable
economic reasons, a racemate or a mixture of diastereoisomers is chosen for further development, they must exhibit a
clean toxicological and environmental record and offer solutions to specific agronomical problems which are clearly superior to the existing
The complexity of the synthetic route to a given stereoisomer and its amenability to scale-up will also play a central
role in this decision-making process. Our purpose is to illustrate, for the chemistry of crop protection, the activities in
this very dynamic field by means of examples critically selected from recent publications and patents. Apart from a few
important examples from the older literature, only structures, syntheses, and activities of chiral herbicides, fungicides, and insecticides which have been published in the last
four to five years will be considered. Rich sources of very
recent results were the Brighton Crop Protection Conference
1990" 'I and the 7th IUPAC International Conference of
Pesticide Chemistry, Hamburg, 1990.['21We have tried to
include only compounds with rigorously proven biological
activities. The enormous number of chiral natural products
with potential usefulness for crop protection are not described,['31 as such a task would exceed the scope of this
2. Disease Control
The implications of stereoisomerism for the biological activity of f~ngicides1'~'
are difficult to characterize, since the
system involved is a complex one. Receptors and metabolic
pathways must be considered in both the pathogen and the
host plant.
2.1. Acylalanines and Related Acylanilides
The origin of the acylanilide fungicides is closely linked
with research in the herbicide field of the chloroacetanilides
Angen,. Chem. ln6. Ed. Engl. 30 (1991) 1193-1215
such as metolachlor 1, the most active stereoisomer of which
has the (a R, 1 S ) absolute configuration (Scheme l).['"
Replacement of the alkoxyalkyl substituent in 1 by an ester
group led to the prototype racemic compound (2) with the
code number CGA 29212, which exhibited curative and systemic activity against Phytophtora infestans.['61 Resolution
(aR, 1S)-1
(R)- 2 X=CI
(R)- 3 X=OCH3
Scheme 1. The most active stereoisomers of the herbicide metolachlor ( ( a R ,
1 S)-1) and the structurally related fungicides CGA 29212 ((R)-2)and metalaxyl ((R)-3).
and biological testing of the single isomers showed that (R)-2
was an excellent fungicide with low herbicidal activity, whilst
its enantiomer (S)-2 exhibited high herbicidal but no fungicidal activity (Fig. 2).[l6]
Fig. 2. Biological activity A ( % relative to untreated control samples) of the
stereoisomers of CGA 29212(2) [16]. Top: mean herbicidal activity on eight
grassy weeds with pre-emergent application. C = herbicide concentration. Bottom: fungicidal activity against grape downy mildew. C = concentration of the
fungicide in the spray solution.
First attempts at a technically feasible large-scale separation of the racemate CGA 29212 (2) or an enantioselective
synthesis of (R)-2 were unsuccessful. Further work in this
direction was discontinued once the biologically more powerful analogue metalaxyl (rac-3) was discovered, as a result
of an intensive optimization program.["]
In this case the enantiomerically pure stereoisomers of 3
were obtained by the resolution of a racemic precursor
through diastereoisomeric salt crystallization.[’’I In vitro biological testing against Phytophthora infestans and Phytium ultimum showed that (R)-3 was approximately 1000 times more
active than (S)-3. However, in vivo trials revealed smaller
differences in activity: (R)-3 was 3-10 times more active than
(S)-3, depending on the pathogens
l 8 I Unlike 2,
metalaxyl (rac-3) shows no phytotoxic effects, and therefore
a separation of the single enantiomers was not necessary.
As indicated by a range of biological studies,[’41it seems
that a dual mode of action is associated with the acylanilide
fungicides. The effects on fungal growth appear to be dependent on the stereochemistry of the agent; however, the effects
on the plasma membrane and germination are independent
of stereochemical homogeneity.[l61Furthermore, a comparative study of the biochemical and physiological effects
of the stereoisomers of 3 indicated that (R)- and (S)-3 have
the same mode of action but show considerable differences
in their effectiveness in reaching, or binding to, the recep-
Two conceptionally different synthetic routes to the target
molecule 7 were
a)using (S)-malic acid (8) from the “chiral pool”, which
provides both the required absolute configuration and the
correct number of C atoms for the lactone ring of 7 via the
hydroxylactone (S)-10 (Scheme 3).
11 95%ee
Clozylacon (4)t2O]is a new experimental acylanilide fungicide especially suited for soil application against Oomycetes,I2’l where protection from these pathogens is required
for relatively long periods.
Because of the stereogenic centre at C 3 and the atropisomerism due to hindered rotation around the aryl carbonnitrogen bond (marked with an arrow in Scheme 2), 4 consists of four stereoisomers. These stereoisomers have been
separated by several methods.[221
Scheme 3. Synthesis of 7 starting from (S)-malic acid (8). 2.6-DMA
dimethylaniline, DMF = dimethylformamide.
b) in an enantioselective modification of the existing pilot
plant synthesis of 4,I2’I introducing the chiral information
in a key Rh- or Ru-catalyzed asymmetric hydrogenation
of the prochiral enamide intermediate 15 (Scheme 4).1’51
7 89%ee
5 X=CI,Y=H
6 X=H, Y=CI
7 X=Y=H
Scheme 2. Stereoisomerism in the experimental fungicide clozylacon (4) and its
precursor 7.
The diastereoisomeric pairs of enantiomers 5, ent-5 and 6 ,
ent-6 were separated either by crystallization or chromatography on silica gel, and the resulting racemates were subsequently separated on an MPLC column packed with triacetyl cellulose. A more efficient, one-step analytical separation was possible on an HPLC column packed with tris(3methylbenzoyl) cellulose.t221
Biological tests showed that the desired fungicidal activity
arises mainly from 5, the isomer with the absolute configuration c( S , 3 R.IZ2lWork towards an economically feasible process for the stereoselective synthesis of 5 focused on developing enantioselective access to precursor 7. It was known that
7 is easily chlorinated to afford a diastereoisomeric mixture
of 5 and 6 , which can be separated by crystallization. Furthermore, a method had been established to epimerize compound 6 to a mixture of 5 and 6 , thus allowing a recycling of
the undesired isomer.[22J
7 >99%ee
Scheme 4. Syntheses of 7 by catalytic homogeneous hydrogenation of 15.
MCPBA = rnetn-chloroperbenzoic acid.
The key intermediate in route a) is the (S)-3-hydroxybutyrolactone 10, which has the opposite absolute configuration
to the target molecule 7. A nucleophilic subsitution at the
activated 3-position, with inversion of the configuration,
provides the correct stereochemistry. The final acylation step
(+7) was accompanied by some racemization. One single
recrystallization from a 1:l mixture of hexane and ethyl
methyl ketone (MEK) provided optically pure 7.
Route b) presents, as a key step, the enantioselective hydrogenation of the enamide 15. This type of N-acyl substituted enamide has never been hydrogenated before. Therefore,
several chiral Rh- and Ru-catalysts were tested and an extensive screening of experimental conditions carried out. The
best results were obtained with the [Ru(OAc),(S)-BINAP]
Angew. Chem. Inr. Ed. Engl. 30 (1991) 1193-1215
catalyst (BINAP = 2,T-bis(dipheny1phosphino)-I ,l’-binaphthyl; 95% yield, 66% ee). As before, optically pure 7 was
obtained by a single recrystallization of the crude hydrogenation product. Since no deactivation, even at a substrate/
catalyst ratio of 4000: 1, was observed for this system, it was
well-suited for industrial production. This fact made
[Ru(OAc),-(S)-BINAP] the catalyst of choice for this synthesis.
In contrast to 18, the fungicidal activity of the resulting
triadimenol(l9) can clearly be attributed to the (1 S , 2 R)-19
isomer. The stereochemical outcome of the reduction,
18 + 19, and therefore also the resulting biological activity,
are highly dependent on the fungal organism involved. The
experimental work regarding the relationship between fungitoxicity and the nature and rate of the stereoselective metabolic transformation of 18 into 19 has been recently re~iewed.1’~.
2.2. Triazole Fungicides
The triazole fungicides are the most important group
amongst the ergosterol biosynthesis inhibitors (EBI).[I4I The
primary mode of action of the 1,2,4-triazole fungicides is the
inhibition of the cytochrome P-450 dependent C 14-demethylation of lanosterol (16, Fig. 3) or 24-methylene-24,25-dihydrolanosterol, which are intermediates in fungal sterol biosynthesis.[241Besides their fungicidal activity, some of these
compounds also show plant growth regulating activity. This
can often be explained by the inhibition of the cytochrome
P-450 dependent oxidation of the methyl group at C4 of
ent-kaurene (17, Fig. 3), an intermediate in the biosynthesis
of gibberellin, and was used for the development of several
triazole-containing plant growth regulators.1241
Scheme 5. The isomers of triadimefon (18) and triadimenol (19).
The 1-vinyltriazoles are a group of compounds which has
also been developed as fungicides or plant growth regulation
agents. The influence of stereoisomerism on both activities
has been thoroughly investigated for the compounds 20 and
21.r261The biological activity is concentrated in the E isomer
(21). For the racemate 21 (diniconazole), the fungicidal activity is restricted to the R isomer, whilst the S isomer is a
plant growth regulator, which acts by inhibiting gibberellin
Fig. 3. Hypothetical inhibition model for the system trizaole+ytochrome P450 [24]: a) normal oxidative process for the C 1Cdemethylation of lanosterol
(16) (EBI) or CCoxidation of ent-kaurene (17) (PGR); b) strong binding of a
1,2,4-triazole moiety, inhibiting oxidation.
Among the 1,2,4-triazolefungicides most extensively investigated with respect to implications of stereoisomerism in their
biological activity are triadimefon (18) and triadimenol(l9).
Triadimefon (18) is a very weak fungicide for which no
significant activity differences have been found between the
enantiomers ( S ) - and (R)-18.r251The carbonyl group in 18 is
reduced to afford 19, in fungi as well as in plants. This reduction is accompanied by a considerable increase in the fungicidal potency-triadimenol 19 is the active principle.
Angen.. Chem. Inr. Ed. Engl. 30 (1991) 1193-1215
Scheme 6. Isomeric 1-vinyltriazoles: the biological activity is concentrated in
the E isomer 21 (diniconazole).
Very recently, the synthesis and biological properties of
the isomers of a related vinyltriazole, triapentenol (22) have
been reported (Scheme 7).[271Small quantities of both enantiomers (S)- and (R)-22 were obtained by the chromatographic separation of the diastereoisomeric ester mixture 23.
The synthesis of ( S ) - and (R)-22 was based on enantioselective reduction of the corresponding enone 24 by metal hydrides in the presence of chiral amino alcohols (Scheme 8). In
the case of 22, the fungicidal activity was again restricted to
the isomer (R)-22, whereas (S)-22 was responsible for the
plant growth regulating effe~t.1~’~
cursor. Two different approaches were investigated, both of
them returning encouraging results:
a) the hydrogenation of 1-hydroxypentan-2-one (26) catalyzed by a Ru-BINAP complex (Scheme 10).
b) the enzymatic reduction of 2-oxopentanoic acid (28) using
@)-lactate dehydrogenase (Scheme 11).
[RuC12((R) -BINAP)](cat.)
1. HPLC separation
2. O W MeOH
Scheme 10. Enantioselective catalytic homogeneous hydrogenation of l-hydroxypentan-2-one (26).
IS1 -22
Scheme 7. Small-scale separation of the enantiomers of triapentenol (22)
The enantioselective hydrogenation of 26 using a RuBINAPt3” complex as a catalyst proceeds with excellent
enantioselectivity and efficiency. The high dilution of the
catalyst relative to the substrate makes this process very
attractive for the large-scale production of (R)-or (S)-27.f3l1
The use of [RuCI,{(S~BINAP}]affords quantitatively (2 S)pentanediol ((S)-27) with 95% ee. (R)-27 can be obtained in
similar optical and chemical yields by using the Ru complex
with the enantiomeric ligand (R)-BINAP.
Scheme 8. Enantioselective reduction of 24 to (S)-22 [27]. With LiAlH,/( -)N-methylephedrine the yield is 85% (ee > 95%) with BH,.THF/(S)-diphenylprolinol 87% (ee = 83%).
Very remarkable differences in the in vitro activity against
UstiZago madis were recently reported for the stereoisomers of
the dioxolano-l,2,4-triazolefungicide propiconazole (25).CzE1
The isomers with the 2 S absolute configuration were shown
to be more efficient inhibitors of ergosterol biosynthesis.
Scheme 11. Enantioselective enzymatic reduction of 2-oxopentanoic acid (28).
L-LHD = lactate dehydrogenase from bovine heart; FDH = formate dehydrogenase from yeast.
Scheme 9. The broad-spectrum fungicide propiconazole (25). See also
Scheme 12.
Since the described synthesis of all stereoisomers of 25 included an inefficient preparation of enantiomerically pure
(R)-and (S)-l,2-pentanediol (27) starting from the corresponding 2-aminovaleric acid, and a subsequent chromatographic separation of the diastereoisomeric products,[28’a
synthesis more amenable to scale-up was needed. A novel
stereoselective synthesis of all four stereoisomers 34 -37 of
propiconazole (25) was therefore developed.t29]A key step in
this process is the catalytic enantioselective preparation of
pentanediol ((R)-27and (S)-27) from a common achiral pre1198
The enantioselective reduction of cc-keto acids by means of
L-lactate dehydrogenase (L-LDH) is a well-known p r o c e s ~ . ~ ~ ~ ]
For the synthesis of (S)-29 from 28, the required NADH
cofactor was recycled using formate dehydrogenase (FDH)
(Scheme 11). The process was performed either batchwise, or
continuously in an enzyme membrane reactor.[33]The enantiomerically pure (S)-hydroxy acid 29 was obtained quantitatively and was subsequently reduced, in high yield, to ( S ) 27 with borane generated in situ. Similarly, by using D-LDH
(obtained from yeast) the enantiomeric (R)-27 was produced
from the same precursor 27, again with high optical and chemical yields.
Angew. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
The synthesis of the diastereoisomeric mixtures 32 and 33
was carried out using standard procedures (Scheme 12).r281
The separation of the mixtures of 32 and 33 into the single
isomers 34, 35 and 36, 37, respectively, was performed by
crystallization of the corresponding nitrates. Field trials of
the thus available large quantities of the individual stereoisomers 34-37 have shown that the different pathogen spe-
IR )-27
p-TsOH, CeH&H,, A
mixture of diastereoisomers
mixture of diastereoisomers
(ZR, L R)-35
Scheme 12. The stereoisomers (34-37) of propiconazole (25). p-TsOH = p toluenesulfonic acid.
cies discriminate between each stereoisomer. However, the
fungicidal activity as well as the small plant growth regulating effect were not constant across the spectrum of target
organisms (Fig. 4). Consequently, the mixture of all four
stereoisomers was the prerequisite for the extraordinary
commercial success of propiconazole (25), which demonstrates strong activity across a broad spectrum of pathogens.
Triazole fungicides with novel structures continue to be
developed and in some cases the fungicidal activity is clearly
connected with a single isomer. For example, the R enantiomer of tetraconazole (41) has been found to be clearly
more fungitoxic than the corresponding S enantiomer. Both
compounds, (R)-41 and (S)-41, were prepared with ee > 95 %
by hydrolysis of the racemate 38, catalyzed by procine pancreas lipase (PPL), or by PPL-catalyzed monoacetylation of
the prochiral precursor 42 (Scheme 13).[341
Angen. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
40 95%ee
If?) -41
Scheme 13. Chemoenzymatic synthesis of both enantiomers of tetraconazole
The new triazole fungicide 47 with the code number SSF109 contains a cycloheptane ring, which is a unique substructure within the biologically active 1,2,4-triazole fungicides.
The cis compound 47 exhibited generally stronger in vitro
and in vivo fungicidal activity than its trans isomer 50. The
latter, on the other hand, showed a much stronger plant
growth regulating effect.[3s]
This cis compound 47 was synthesized by a chelation-controlled addition of the corresponding Grignard compound
to the triazolylcycloheptanone 46 (Scheme 14). The trans
isomer 50 was prepared in poor yield from the bromohydrin
48 via an oxirane
morpholine fungicides inhibit sterol biosynthesis at two different sites of the same pathway, namely the AI4-reductase
and the A8 -+A7-isomerase enzymes.[37]
Because of their high activity against cereal powdery
mildew and rusts, the morpholine fungicides were mainly
developed for use in cereals. Due to their different mode of
action they also evolved as valuable mixing partners for triazole fungicides. Thus, the morpholine fungicides are able to
control strains of cereal powdery mildew which have become
less sensitive to triazole fungicides.[381This mixing of fungicides, each acting by inhibition of different enzymes of the
same biochemical pathway, proved to be a very successful
antiresistance concept. The most important representative of
this class is fenpropimorph (51), which was selected from a
great number of p-alkyl substituted 3-phenyl propylamines
for further development as a fungicide for use in cereals.[39]
It was shown earlier that the racemic compound 51, with
a cis-2,6-dimethylmorpholine moiety, has a clearly superior
fungicidal activity to the corresponding 52, which contains a
trans-2,6-dimethylmorpholine s u b ~ t i t u e n t . ' The
~ ~ ~ cis and
51 Rq = H.
52 RT = CHS, R2 = H
Scheme 15. The stereoisomers of fenpropimorph (51)
(*) 49
(f)50 (trans)
Scheme 14. Synthesis of cis- and trans-triazolylcycloheptanols47 and 50.
This cis-racemate 47 was resolved by separation of the
corresponding diastereoisomeric L-menthoxyacetates using
column chromatography. The absolute configuration of the
individual enantiomers has not yet been reported. Nevertheless, biological tests revealed that the enantiomer (- ) -47 was
2-4 times more active than the (+)-enantiomer, curiously
both as a fungicide and as a plant growth regulator.[351
On considering the diversity of structures discussed above,
a rather high structural flexibility of the sterol binding site at
the cytochrome P-450 oxygenase involved in C 14-demethylation is evident. This flexibility in the chemical structure of
the inhibitor is generally accompanied by a remarkable stereochemical selectivity. At the moment, conclusions or generalizations on structural or stereochemical requirements for activity must remain tentative, since detailed substrate-receptor
studies are lacking.
2.3. Morpholine Derivatives
Whereas triazole fungicides (see Section 2.2) disturb sterol
biosynthesis in fungi by inhibition of the C 14-demethylation
of lanosterol or 24-methylene-24,2S-dihydrolanosterol,
trans isomers 51 and 52 are separable by distillation. Also the
transformation of 52 into the thermodynamically more
stable 51 could be achieved by using Pd-containing catalysts
at high temperatures.[401Hence, the production of the cis
stereoisomer 51 of a purity higher than 98 % is possible on a
large scale.
The cis racemate 51 was resolved by crystallization of the
diastereoisomeric salts formed with (-)-camphorsulfonic
The absolute configuration of the single isomers was
determined by X-ray structural
Extensive biological testing showed that the S enantiomer
of 51 is equivalent to racemic 51 in its effect against barley
mildew and is superior to racemic 51 against mildew and
brown rust of wheat. On the other hand the R enantiomer of
51 is comparable to rac-51 in its effect against barley mildew,
but clearly inferior against mildew and wheat brown
rUst.[39, 421
Recently the design of new putative inhibitors of the
A' -+ A7 sterol isomerase in the fungal ergosterol biosynthesis pathway was rep0rted.1~~~
As neither the fungal nor the
yeast A8 + A7 isomerase have been purified to homogeneity
or crystallized, this approach was based upon the assumed
mechanism of the enzymic transformation and on the structure of the natural substrate.
The proposed detailed mechanism of the A' -+ A7 isomerization is depicted in Scheme 16. The process starts with
protonation of 53 from the c1 face, which generates an unstable carbocation at C 8 (54). This is followed by removal of
the c1 hydrogen at C 7, to produce episterol (55).
Angew. Chem. Inr. Ed. Engl. 30 (1991) 1193-1215
The absolute configuration of this series was assigned by
comparison of the optical rotations of the enantiomeric ketones (R)- and (S)-57 with known values.[451The latter were
obtained by preparative chromatographic (HPLC) on triacetyl cellulose. The introduction of the tert-butyl group into
the para position of the phenyl ring of ( R ) - and (S)-57 was
achieved regioselectively and without racemization. Reductive amination of the enantiomerically pure ketones (R)- and
(S)-58 produced the desired compounds 59 and 60 as a diastereoisomeric mixture, which could be separated by chromatography on silica gel. In each case the relative cis or trans
stereochemistry of the cyclopentane rings was assessed from
the ‘H NMR data (NOE).[43a1
cellulose triacetate
Scheme 16. Conversion of fecosterol (53) into episterol (55) catalyzed by the
enzyme A* -+ A’ sterol isomerase.
On this basis, the working hypothesis originally outlined
by B e n v e n i s ~ e included
~ ~ ~ ’ the following points:
a) mimicry of the C 8 carbocation by a positively charged
nitrogen, despite the resulting different geometries;
b)use of tertiary amines with pKa values which allow them
to be applied as free bases (advantageous for their permeability through biological membranes) and, on the other
hand, to be protonated at the N atom under physiological
p H to develop the positive charge on the nitrogen atom;
c) simulation of structural elements of the steroid, e.g., rings
B and D, including stereochemistry and lipophilicity.
Based on these three principles Huxley-Tencer et al.[43a1
designed the perceived transition state analogues of the general structure I (Scheme 17) and synthesized many compounds. Maximum fungicidal activity was found when the
1R. 3s
R, :lipophilic side chain
X : CH?,N, 0,S
Scheme 17. General structure of an inhibitor of the enzyme A’
A’ sterol
amine moiety was cis-2,6-dimethylmorpholine and the substituent at C 3 was a para-tert-butylphenyl group. The compounds were first synthesized in a nonstereoselective way,
with the aim of obtaining, after separation, all possible stereoisomers (Scheme 18).
Angen. Chem. In!. Ed. Engl. 30 (1991) 1193-1215
c hrornat.
(lR, 351-59 99%ee
3s)-60 *Lee
Scheme 18. Stereoselective synthesis of A* + A 7 sterol isomerase inhibitors
(1 R,3 9 - 5 9 and (1 S, 3 9-60
, corresponding compounds with the opposite
absolute configuration at C 3 were obtained analogously from (R)-57. Chromat. = Chromatography.
In vitro and in vivo tests showed that (1 R, 3 9 - 5 9 was the
most potent compound, as expected from the natural absolute configuration of the steroidal ring D. In greenhouse tests
against Erisyphe graminis on barley, the compound (1 R,
3 9 - 5 9 showed an ED,,-,, value[461which was approximately 20 times lower than that of fenpropimorph (51). The
fungicidal activity in this series (in vitro and in vivo) followed
the sequence: ( I R , 3 S ) > ( I R , 3 R ) > ( I S , 3 S ) > ( I S ,
3 R).[43a1
The R absolute configuration at C 1 of the designed inhibitor, which corresponds to the stereochemistry at C 14 of the
natural substrate, seems more important for the inhibitory
activity of 59 than the absolute configuration at C3. The
latter should simulate the rather flexible side chain in 54.
3. Weed Control
The structural variability of compounds having herbicidal
activity is large. For many of the herbicidal compounds
which have sterogenic centers the relationship between
stereoisomerism and biological activity is generally not well
understood. The stereoselectivity of herbicides interfering
with auxin activity, for example 2-aryloxypropionic acid
derivatives, has been recently re~iewed.'~']
A very interesting
example within this class of compounds was presented by
Amrein et al. and Cornes et al. in 1989.[481The combination
of the compounds 61 and 62, with the code numbers CGA
184927 and CGA 185072, respectively, in a ratio of 4:1, is a
herbicide(6ltsafener(62) mixture for the selective postemergence control of annual grass weeds in wheat, rye, and triticale. The herbicidal activity of 61 is concentrated in its R
enantiomer, whereas the enantiomers of the safener showed
practically no differences in activity.[481It was shown that
the ability of 62 to protect wheat from injury by the herbicide
61, and to confer partial protection to barley, is related to the
ability of the safener to stimulate herbicide metabolism in
these crop species.[491
63 R = O H
64 R = Ala-Ala-OH
Scheme 20. (S)-Phosphinotricin (63), a naturally occurring phosphorus-containing amino acid, was first isolated from the antibiotic tripeptide 64.
glutamine syntheta~e.[~']
This activity is associated with the
isomer (S)-63.[531
Besides the synthetic approaches through chiral imine alk y l a t i ~ n [ and
~ ~ ] enzyme-catalyzed racemate resolution,[551
there are recent reports on the enantioselective syntheses of
63 that use methods with preparative potential. For example,
alkylation of the enantiomerically pure Schollkopf s bislactime ether 65 obtained from (R)-valine afforded, after a standard two-step hydrolysis and recovery of (R)-methylvalinate, (S)-phosphinotricin 63 with 93 % ee (Scheme 21).[563581
Scheme 21. The bislactime ether route to phosphinotricin (63).
Scheme 19. A 4:l mixture of the herbicide 61 and the safener 62 exhibits excellent postemergence control of annual grass weeds in wheat, rye, and triticale.
Reseach work on the stereoselectivity of the few older
chiral compounds belonging to the important group of the
photosynthesis inhibitors (mainly ureas and cyanoacrylate
derivates) has been the subject of a recent
In the following section we shall concentrate on a few new
chiral herbicides with high biological potential and whose
enantioselective synthesis was accomplished after a great
deal of effort.
Another approach takes advantage of the accessibility of
the chiral pool substance (S)-glutamic acid (68). The conversion of 68 into the protected (S)-vinylglycine derivate 69 can
be accomplished in three steps according to a known proced ~ r e . [Regioselective
addition of ethyl methyl phosphonite to 69 gives, after deprotection, (S)-63 in high yields with
98 % ee (Scheme 22).[56]
B6C 6 9
3.1. (S)-Phosphinotricin
(S)-Phosphinotricin (63) is a naturally occurring phosphorus-containing amino acid. It was first obtained by hydrolysis of the antibiotic tripeptide bialaphos (64).15
Racemic phosphinotricin is the active component of the
broad-spectrum nonselective herbicide with the common
name glufosinate ammonium. Its herbicidal action is apparently due to the inhibition of the ammonia-fixing enzyme
63 98%ee
Scheme 22. A chiral-pool approach to phosphinotricin (63). BOC = tert-butoxycarhonyl.
Angew. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
Finally, an alternative enzymatic process with better prospects for large-scale production of 63 (Scheme 23) was described recently.[571 An aminotransferase capable of transaminating the a-keto acid 71 to 63 was isolated from Escherichia
coli K-12. Substrate-specific studies suggest that this enzyme
is identical with the 4-aminobutyrate-2-ketoglutarate
transaminase (EC The transaminase was immobilized by coupling to an epoxide-activated carrier and was
used in a column enzyme reactor for the continuous production of 63. A fourfold molar excess of glutamate over the
n,c no
i -
lactate reductoisomerase, an important enzyme in the
biosynthesis of branched-chain acids.[621
Scheme 25. The experimental herbicide HOE 063704 (74)
The racemic ester 75 was enantioselectively hydrolyzed by
porcine liver esterase (PLE) to (+)-74. The remaining ester
76 racemized spontaneously under the reaction conditions,
thus attaining a conversion rate of 95 % (+ ( +)-65).[6'1The
absolute configurations shown in Scheme 26 are assumed in
analogy to (R)-acetolactate, but are not yet experimentally
in situ rocemizotion
Scheme 23. Enzymatic synthesis of phosphinotricin (63).
a-keto acid 71 was used to shift the reaction equilibrium to
the desired product 63. Yields of more than 90% of 51 with
production rates of 50 g L-' h-' were then achieved. The
unreacted glutamate could be re~ycled.["~]
Furthermore, the gene encoding the transaminase was
cloned and expressed in E. coli. The transaminase expression
in transformants of E. coli could be increased up to 80-fold
compared with that of a wild-type control. The expressed
transaminase consituted up to 20% of the total protein of
the bacteria. The protein crude extract of the transformants
was used, after a heat precipitztion step, as described above
for the production of 63 in an enzyme
(+) -74
Scheme 26. Enzymatic resolution of 75. Absolute configurations and ee's have
not yet been reported.
The isolated (+)-74 is the biologically active isomer, as
demonstrated by in vivo studies. Also in vitro experiments
with isolated acetolactate reductoisomerase from Daucus
carota and Escherichia coli,indicated that (+)-74 is twice as
active as the racemic compound 74.t6l1
3.3. Imidazole-5-carboxylc Esters
Scheme 24. The biosynthetic precursor of phosphinotricin (63).
Interestingly, the amino acid forming step in the biosynthesis of bialaphos (64) is the transamination of 73 (Scheme
24), which in a later step is methylated at phosphorus.f6']
In the course of a standard herbicide screening program,
unexpected activity was found in compound 77, which belongs to a group of imidazole-5-carboxylic esters with hypnotic and antimycotic activity.[63]
As a result of the synthetic work to optimize the herbicidal
activity of 77, a sterol biosynthesis inhibitor, the compound
78 (Scheme 27) was found to be the most active substance in
3.2. 2-Dimethylphosphinoyl-2-hydroxyaceticAcid
A new, interesting phosphorus-containing experimental
nonselective herbicide is racemic 2-dimethylphosphinoy1-2hydroxyacetic acid (74), code number HOE 063 704.16'] The
herbicidal activity of 74 comes from the inhibition of acetoAngew. Chem. Int. Ed. Engl. 30 ( 1 9 9 I ) 1193-1215
Scheme 27. The herbicide 78, the result of intensive synthetic work to optimize
the herbicidal activity of 77 1621.
this series. In the standard test (against Digitaria sanguinalis)
78 was four times more active than 77.
The stereoisomers of 78 were synthesized in enantiomerically pure form starting from the corresponding amines, (R)or (S)-79,in a multistep synthesis using either a ThorpeL6"]
or a Jones[651cyclization procedure to construct the imidazole moiety. The required enantiomerically pure amines were
prepared by resolution of the racemic compound 79 with
A method of recycling of the
undesired isomer in high yields (> 90 %) was also developed,[661based on treatment of the latter with Raney cobalt
catalyst at 190°C without added solvent (Scheme 28). The
perpositioning studies of 77 with sets of analogues of high
activities and low or zero activity.[63]
Consideration of an optimized orientation of the phenyl
ring with respect to the imidazole moiety revealed a lipophilic
pocket which seems to be relevant for activity. The methyl ester
group points away from the lipohilic groups and the region
below the phenyl ring must remain unoccupied (Fig. 6).[631
methyl ester group
points away from
1 0
occupancy of this receptor
region decreases activity
(red anow)
occupancy of this region
(green arrow)
(R)-78 95%ee
Scheme 28. Stereoselective synthesis of (R)-78 via racemate resolution with
(S)-N-benzoylglutamicacid and recycling of the undesired stereoisomer (S)-79.
compound (R)-78 proved to be twice as active as the racemate 78.Its enantiomer (S)-78was completely inactive in the
D. sanguinalis test. Similar results were obtained with the
stereoisomers of 77, although in this case the S-isomer exhibited a measurable activity (Fig. 5).
A herbicidal pharmacophore structure was proposed based
on conformational analysis, force field and MO calculations,
and CAMM (Computer-Assisted-Molecular Modeling) suFig. 6. CAMM studies of 77 and 78. a) Proposed herbicidal pharmacophore
structure, illustrated with the compound (R)-78.b) Superposition of the imidazole rings of (R)-78(green) and (S)-78 (blue). c) Superposition of the imidazole
rings of (R)-77 (green) and (S)-77 (blue).
(R)-78 (0.5)
(S)-78 (no activity)
(S)-TI (8)
Fig. 5. Activities of some imidazole-5-carboxylic acid derivatives expressed as
relative application rates (in parantheses) against Digitaria sanguinalis.
The differences in biological activity observed for the
stereoisomers of 77 and 78 fit this model. Superposition of
the completely inactive (S)-78 with the active (R)-78 shows
that the methyl group trans to the imidazole ring occupies
the region below the phenyl plane in (S)-78. On the other
hand, although (R)-77 is twice as active as (S)-77,the latter
exhibits some activity. In this case, superpositioning studies
show that the less active stereoisomer does not occupy the
receptor's forbidden region, but that the lipophilic pocket is
less occupied. Superposition studies were also used to predict
the inactivity of the racemic compounds 80 and 81. Neither
four- nor seven-membered rings were able to provide the
Angew. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
Scheme 29. Imidazole-5-carboxylicacid derivatives which are inactive as herbicides.
correct orientation of the phenyl ring plane relative to the
imidazole moiety (Scheme 29).r631
3.4. Further Structural Types
An interesting example of the optimization of in vitro
activity using computer modelling was recently reported by
Mitchell and Bartlett.lb7I
The ketomorpholine 82 (Scheme 30) is a newly discovered
inhibitor of phytoene desaturase, and shows pre-emergence
herbicidal activity. A structural model was constructed by
studying the overlap of a number of structurally diverse inhibitors for which structure-activity relationships were available. By comparing 82 with the model, a pseudoaxial orien-
Scheme 31. Chemoenzymatic approach to the stereoisomers of 85.
cally pure form from waste paper in four steps, starting with
a pyrolysis at 350°C (Scheme 32).1701
a0- e0
Waste paper
Scheme 32. Stereoselective synthesis of the 6,8-dioxabicyclo[3.2.l]octane derivative 92. The starting material 89 is obtained from cellulose by pyrolysis.
Bn = benzyl; TFA = trifluoroacetic acid.
Scheme 30. The herbicidal active ketomorpholine82 and structural analogues
83 and 84. Only the stereoisomer83 shows herbicidal activity.
tation of the benzylic substituent at C 2 was postulated. The
model also predicted that a methyl substituent at C 5, trans
to the benzyl group, should be tolerated. The two trans
stereoisomers 83 and 84 were prepared selectively, and in an
in vitro test the activity was found to reside solely in the (2 R,
5 S)-isomer 83 (Scheme 30).[671
The N-phenyltetrahydrophthalimidesare a known class of
pre- and postemergence herbicides now experiencing a renaissance. Within this class, the compound 85, (code number
S 23121) is a potent postemergence herbicide for cereals.[68]
The selectivity of this compound is apparently related to the
1-methyl-2-propynyloxy substituent.
The stereoisomers of 85 have been prepared enantioselectively from the precursors 87 and 88 (Scheme 31).[691The
single isomers (S)- and (R)-85 exhibited no selectivity in the
inhibition of protoporphyrin IX
The bicyclic compounds 92 is a potent herbicide of a new
structural class with an as yet undetermined mode of act i ~ n . *It~can
~ ] be ingeniously synthesized in stereoisomeriAngew. Cheni. I n f . Ed. Engl. 30 (1991) 1193-1215
A number of structural analogues, mainly of the types d and
e, and also some with different configurations as C 2 and C 4,
were prepared stereosele~tively.[~~~
The key step was an aldol
reaction between a chiral aldehyde of type a and an enolate of
type b (Scheme 33). In spite of considerable synthetic work,
compound 92 remained the most potent in this series.
R', R2,I?=H, Cc1,
Scheme 33. Aldol approach to polysubstituted 6,8-dioxabicyclo(3.2.i]octane
The newly described herbicide hydantocidin (93)possesses
an unique structural feature, namely a spiro hydantoin ring
at c 1 of ~-ribofuranose.[~*~
The compound 93 was isolated from a Streptomyces hygroscopicus (SANK 63 584) culture. Interesting properties
were described for 93: very low toxicity, systemic mode of
action, broad spectrum, and low selectivity. Its weed-control
activity is similar to that of glyphosate (94).[72*
Scheme 34. Two herbicides with similar weed control activity: hydantocidin
(93) and glyphosate (94).
Hydantocidin (93) and all its 15 stereoisomers were synthesized starting from derivatives of tartaric acid. The synthesis of the D series, starting from ethyl D-tartrate is described in Scheme 35.[731
The L series was synthesized analogously, starting from
ethyl tartrate.[^^] Not only the preparative effort of S. Sugai
et al., but also the stereoselectivity of the biological activity is
impressive: only the N ' - ~ - D
isomer 93, and to a much lesser
extent the N'-z-Disomer 108, exhibit herbicidal properties.[731
4. Insect Control
Much work has been done over the past years trying to
understand the interrelation of stereochemistry and biological activity of synthetic and natural insect controlling agents.
The topic has been recently reviewed for most of the important classes of insecticide^.^^^
4.1. Organophosphates
The biochemical and toxicological properties of chiral
organophosphate enantiomers differ widely.[741A very recent study from Hirashima et al.[751illustrates the complex
interplay of stereochemical, toxicological, and metabolic
factors for the insecticide salithion (112) and its oxidation
product salioxon (113) (Scheme 36).
Enantiomerically pure ( S ) - and (R)-112 was obtained via
(S)-proline methyl ester derivatives; the diastereomers were
separated by crystallization and subsequent acid catalyzed
The corresponding salioxon enantiomers
(R)- and (S)-113 were obtained from the salithion enantiomers by meta-chloroperbenzoic acid (MCPBA) oxidation
as shown in Scheme 36.[75b1
(S)-112 was a more potent insecticide by topical application than (R)-112 on Musca domestica female adults correlating with the acetylcholine esterase (AChE) inhibition in
vivo. However, against Tribolium castaneum the R enantiomer of 112 had a stronger larvicidal activity than the S
enantiomer three days after treatment.
Scheme 35. Stereoselective synthesis of hydantocidin (93) and all its 15
stereoisomers. CAN = cerium(1v) ammonium nitrate.
Angew. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
On the other hand, (R)-113 was a stronger house fly AChE
inhibitor in vitro than the S enantiomer, whereas the latter
((S)-113) was a more potent T castuneum larval AChE inhibitor than the R enantiomer. In all the discussed cases, the
oxidized form 113 occurs during metabolism in the insect. The
(S)-11 2
column.t771The absolute configuration could not be determined for this series.
The enantiomers of 114 showed a different insecticidal
activity in laboratory trials against Heliothis virescens L-1.
The (+)-isomer was a factor of 1.7 better than the racemate
114 and 2.2 times better than the (-)-enantiomer. However,
the differences in the biological activities of the enantiomers
of 114 were practically nonexistent in field trials and did not
justify the very expensive and tedious chromatographic separation. As a consequence, compound 114 will be developed
as a racemate.
4.3. Pheromones
(S) -11 3
Scheme 36. The stereoisomers of salithion (112) and salioxon (113)
reversed stereospecificity between M . domestica insecticidal
and T castaneum larvicidal activity of salithion enantiomers
((R)-and (S)-112) might be a result of a stereospecific difference in the intrinsic potency of salioxon enantiomers ((S)and (R)-113) as AChE inhibitors of the two species.[75c]
4.2. Benzoylureas
Benzoylureas are insect growth regulators, acting by inhibition of chitin synthesis and so interfering with the formation of the cuticle.[761An interesting example of a compound
of this class possessing stereoisomerism was recently reported by Drabek et al. (Scheme 37).r771
Scheme 37. The benzoylurea insecticide 114. Its precursor 115 was resolved by
chromatography on a tribenzoyl cellulose column.
The compound 114 with the code number CGA 184699 is
a benzoylurea with good environmental behavior and interesting activity. Both enantiomers of compound 114 were
obtained in pure form from the corresponding intermediates
(+)-and (-) -115, which were obtained by chromatographic separation of the racemic 115 on a tribenzoyl cellulose
Angew. G e m . I n t . Ed. Engl. 30 (1991) 1193-1215
Pheromones are semiochemicals (semion (greek) = a mark
or signal) which act between members of the same species.
Since the first isolation of a pheromone from the silkworm
moth by Butenand et al. in 1959,'781over 100 chiral pheromones have been isolated and identified. Outstanding synthetic work has been performed to obtain enantiomerically
pure pheromones, mainly aimed at the determination of the
absolute configuration of the natural products. An excellent
review of this topic was published recently by M ~ r i . " ~ ]
Pheromones are very often blends, the components of which
may act synergically and should be present in a definite ratio.
This synergism frequently relates double-bond isomers and/
or isomerism due to the presence of one or more stereogenic
centers in the molecule. The interrelation between stereoisomerism and biological activity can be manifold. In some
cases only one isomer is active, in others both, either as
synergist, inhibitor, or independently active compounds.[80]
4.3.1. (S)-Zpsenof
Various species of bark beetles are dangerous pests for
coniferous forests throughout the world. Among these are
beetles of the genus Ips and Pityokteinus. (S)-ipsenol(l24) is
an aggregation pheromone of several species belonging to
these genera.[811The absolute configuration was established
by Mori in 1976 by chemical correlation.1s21
The enantioselective synthesis of large amounts (50 g) of
(S)-ipsenol (124) was recently reported by Oertle et
(Schema 38). The material was used for extended field trials
to control the population of Pityokteinus curvia'ens. The key
hydroxyacid intermediate 121 was obtained in enantiomerically pure form (ee > 99 YO)by an enantioselective aldol reaction
using the chiral titanium complex 118.[851The subsequent
transformation of the carboxy group of 121 followed, with
some modifications on the silicon directed diene synthesis
described by Jenkins et
In this way 56 g of enantiomerically pure (ee > 99%) (S)-ipsenol (124) has been prepared
in one batch, starting from 160 g of P-hydroxyacid 121.
4.3.2. The Oviposition-Deterring Pheromone (ODP)
in Rhagoletis cerasi
The cherry fruit fly ( R . cerusi) lays one single egg into halfripe cherries. It was demonstrated in field tests that double or
23 steps. 12% from suberic acid
120 R = t h
1. OH'
121 R = H
(38% from 116)
1. NaOAc
2. Bu.NF
82% yield
on glycosidotion
z w
Scheme 38. Enantioselective synthesis of (S)-ipsenol (124) on a large scale
(2 mol). LDA = Lithium diisopropylamide, OR* = 1,2:5,6-di-O-isopropylidene-a-o-glucofuranos-3-O-y1,
TBDMS = tert-butyldimethylsilyl.
triple oviposition into the same fruit occurred with a much
lower frequency than would be expected if deposition had
taken place randomly.[87]Consequently, the hypothesis was
put forward that the females mark the fruit.[881Since fruits
infested by maggots are not accepted by the consumer, cherries have to be protected against the oviposition of fruit flies.
Isolation and purification of the active component from
the faeces made possible a partial structural analysis of the
ODP (125).[891ODP contains two stereogenic centres at C8
and C 15 besides the sugar moiety. Since the assignment of
the absolute configuration was not possible by spectroscopic
means, an enantioselective synthesis of all four stereoisomers
at C 8/C 15 was carried out.[g01The general retrosynthetic
concept is illustrated in Scheme 39.
As anticipated, the glycosidation to a P-glycoside derivative proved to be an extremely difficult step. Finally, an
excellent and highly stereoselectiveglycosidation was achieved
by using tetra-0-pivaloylglucopyranosyl fluoride according
The absolute stereochemistry of the natural
to Kunz et
ODP was assigned by employing both spectroscopic methods and comparative studies of the biological activity. It was
demonstrated that the natural ODP is a diastereomeric mixture, namely, (8 RS, 15 R)-125.[92]Since the stereochemistry
at C 8 need not be controlled, a much shorter synthesis, suitable for large-scale production of "natural" ODP could be
By spraying (8 RS, 15 R)-127 (10 mg L-') on cherry trees,
the infestation rate of cherry fruit fly eggs was reduced (i.e.,
1.85-2.5 YOinfestation of treated trees against 21.4-23.35 YO
infestation of untreated trees) in summer field trials in
Switzerland in 1989.[921
138% from suberic acid)
IL6% from
p-hydroxybutyric acid)
Scheme 39. Retrosynthetic concept of an enantioselective synthesis of all four
stereoisomers C 8jC 15 of 125. PMP = p-methoxyphenyl.
4.4. Insect Antifeedants
Insect antifeedants are currently attracting much research
interest owing to their effect on a range of major crop p e ~ t s . [ ~ ~ l
An antifeedant is a chemical which inhibits feeding but does
not kill the insect directly.[941The insect often remains near
the antifeedant source and possibly dies through starvation.
The limited information presently known does not allow
generalizations on the mode of action of antifeedants.tg5I
Considerable attention has been focused recently on the
extremely potent natural antifeedant azadirachtin (132,
Scheme 40).[961
Scheme 40. Azadirachtin 132 and two synthetic substructures with similar
antifeedant activity against S. littoralis.
Angew. Chem. Inl. Ed. Engl. 30 (1991) 1193-12f5
The high level of interest in 132, which has been isolated
from the neem tree Azadirachta indica, stems from its exceptional biological activity. Compound 132 is the most potent
antifeedant against Lepidopterus species isolated to date. It is
100 per cent lethal at only 10 ppm concentration through a
variety of processes including antifeedancy, growth disruption, and moulting inhibition. Despite such high toxicity
towards certain insects, azadirachtin is apparently harmless
to higher forms of life and exhibits no p h y t o t o ~ i c i t y . [ ~ ~ ~ ]
Although it is possible to use extracts of neem seeds for
crop protection, 132 itself is quite unstable and its low abundance in the plant makes it difficult to obtain pure 132 for
agricultural use. Efforts are being made to synthesize 132;[971
however, any synthesis of such a structurally complex and
chemically unstable molecule containing 16 chiral centers is
not going to be amenable to commercial development. In an
alternative approach, substructures of 132, for example 133
and 134, were synthesized and screened for antifeedant activity.[97a1Both of these compounds were found to be active
against Spodoptera littoralis and 134 was almost as potent as
the natural product 132 at 10 ppm concentration.
The mixture of compounds shown in Table 1 is responsible
for their remarkable and rapid action on a wide range of
insects. Pyrethrin I (135) is especially effective for kill and
pyrethrin I1 (138) for the rapid knockdown of flying insects.
Early attempts at synthesizing compounds similar to the
natural pyrethrins produced a range of products which, although having an inherent problem of instability to light, did
find significant success as insecticides in the household sector. Whereas 141- 143 (Table 2) are esters of chrysanthemic
acid and have the natural (1 R)-trans configuration (which is
conferred on its precursor by the chiral enzymatic microenvironment in the flower heads, Fig. 7), the majority of com-
4.5. Pyrethroids
Fig. 7. 1,3-Cycloeliminationin nature: suggested enantioselective pathway for
(1 R)-trans-chrysanthemol pyrophosphate formation from isopentenol pyrophosphate in the flower heads of Chrysanthemum cin.. according to Naumann
[98b] and Crombie [loo].
The insecticidal properties of the pyrethrum powder extract
from the flower heads of Chrysanthemum cinerariefolium
have been well documented for over 100 years. A few years
ago about 23000 tons were produced annually.t98a1
The flowers, grown in Kenya, contain on average 1.3% of enantiomerically pure esters of (1 R)-trans-chrysanthemic acid 135- 137
and (1 R)-trans-E-pyrethric acid 138- 140 (Table
Table 1. The mixture of natural enantiomerically pure insecticides present in
Chrysanrhemum cinerariefolium flower heads.
name (% in mixture)
stereochemistry [98]
mercial household chrysanthemates are racemic and take
advantage of the elegant and simple access to the racemic
chrysanthemic esters (Scheme 41).
( 1 RS)-trans-C
pyrethrin I (35)
1R trans, US
cinerin I(10)
1R trans; US
jasmolin I ( 5 )
1R trans; aS
pyrethrin I1 (32)
1R trans, E ; US
Scheme 41. 1,3-Cycloelimination in the chemical industry: Synthesis of
racemic trans-chrysanthemic ester C according to Martell [loll, ingeniously
utilising the simplest starting materials, and the arylsulfonyl group as both an
activating and a leaving group.
However, the pyrethroids started to gain commercial importance as agricultural insecticides only when at the beginning of the 1970’s Elliot11Q2’
combined phenoxybenzyl alcohols with photostable derivatives of chrysanthemic acid,
containing dihalovinyl moieties instead of the dimethylvinyl
substituent on C 3, thus creating the very potent insecticides
permethrin 155 (4 stereoisomers), cypermethrin 156 (8 stereo-
(lR, S)-ds, trans-155 X = H
1R trans: E ; US
(1R. S)&
trans - (aR S)-156 X = CN
Scheme 42. The potent insecticides permethrin (155) and cypermethrin (156).
Angew. Chem. Int.
Ed. Engl. 30 (1991) 1193-12f5
Table 2. Commercially used semisynthetic (141-143) and synthetic (144-154)enantiomerically pure pyrethroids [lo31
stereochemistry [98] common name
141 [a]
1R trans; US
domestic and industrial hygiene
1 R trans
as 141
1R trans: U S
household use
1R trans
as 143
1R cis
kadethrin [lo61
as 143
1R cis; US
against lepidoptera, coleoptera in cotton, vegetables,
fruits etc.
1R cis, 1'RS; U S
as 146
1R cis, Z: US
acrinathrin [I071
against mites in citrus, fruits, grapes etc.
1R cis, Z
as 146
1R trans
1R trans
benfluthrin [lo81
2s; a RS
as 146
2s: a RS
against Aphididae, Lepidoptera in broad range of
2s; uRS
against Aphididae, Cicadellidae in cotton fruits sunflowers, etc.
[a] R
= CH(CF,),.
- -CH(CF&
[b] R
= CI.
[c] R
= OCHF,.
isomers) and especially the enantiomerically pure ester deltamethrin 146 (Table 2). Elliot's discovery triggered an enormous synthetic activity all over the world, aiming in the
1970's mainly at the search for new, improved derivatives
and analogues of the archetypal esters 135 and 155, as well
as on the circumvention of existing patents. The emphasis in
the 1980's shifted to the cost-effective and enantioselective
synthesis of selected leading compounds, as well as to the
mosquitos, flies, moths in the air
fine-tuning of their biological and ecotoxicological properties, for example, to decrease their toxicity to fish.
An excellent overview of the wealth of splendid pyrethroid
chemistry, performed mostly by industrial chemists, was
published in 1990 by N ~ u r n u n n . ~He
~ ~critically
about 2600 references from the scientific patent literature
published until 1987. Therefore we selected only a few recent
examples with an emphasis on enantioselective synthesis.
Angew. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
Complete transformation of racemic constituents into a
single enantiomer or diastereoisomer without loss of any
material, requires refinement of many resolution methods
and their adaptation to industrial scale. The underlying principle of all industrially successful separations of stereoisomers is the removal of the target product (or its diastereomeric salt or chiral precursor) in crystalline state from the
reaction mixture, on the basis of its relative insolubility. This
is accompanied by a continuous epimerization of the undesired stereoisomer in the solution, utilizing the mobility of an
activated hydrogen. A striking example of the application of
this methodology is the preparation of deltamethrin 146: the
most active. enantiomerically pure (1 R)-cis-aS isomer is now
produced at a rate of 200 t per annum from the eight possible
isomers, despite of the involvement of two racemates (racemic
trans-chrysanthemic acid and racemic ~ y a n h y d r i n e ) . ~ ' ~ ~ ]
Eight diastereoisomerically and enantiomerically related
isomers of 156 have different biological properties, the (1 R)To achieve an economic
cis-as being the most
synthesis of its consituent (1 R)-cis-162,a cost-effective resolution of a cyclobutanone derivative into pure enantiomers
had to be accomplished on an industrial scale for the first time
(Scheme 43).[' I '1 The easily available racemic cyclobutanone
crystallization. The mild hydrolysis liberated the properly
configurated (2 S, 4 R)-cyclobutanone 161 for the subsequent
enantioselectiveFavorskii rearrangement to (1 R)-cD-162.The
unwanted enantiomer (2 R, 49-160 could be readily racemized with Bu,NCl to (+)-cis-157 and utilized again in the
separation steps. Thus, the whole procedure represents a chirally economic synthesis of (1 R)-cis-162 (permethric acid).
An approach incorporating an inversion of configuration
by an S,2 substitution of C-a of the undesired alcohol enantiomer was chosen in the industrial synthesis of the new
household insecticide (S)-prallethrin 143.['O41 Principally, it
represents a combination of an enzyme-catalyzed reaction
and a chemical reaction, which ensures no loss of valuable
starting material (Scheme 44). At a substrate concentration
(a R) -164
(96%) A
(a S) -165
-1:l ; 9 P ? e e
(a S)-1 67
(a R) -166
1. so2
2. R'NH2
(a S)-143
(IS,25,4.9-159 (32%)
(I R. 2R. 45)-158
(ZR, 45)-160
R"H2 =
(ZS, 4R)-161
Scheme 43. A "cyclobutanone" route to (1 R)-cis-permethric acid (162).
157 was converted into the bisulfite adducts."
Fortunately, by using the cheap auxiliary (1 S)-phenylethylamine only
two of the four possible diastereomeric salts were formed.
Isomers 158 and 159 could be readily separated by fractional
Angeu,. Chern. In(. Ed. Engl. 30 (1991) 1193-1215
Scheme 44. A complete conversion of a racemic acetate 163 into the enantio
merically pure alcohol 167 by a chemoenzymatic approach.
of 8.8 w/v YO (a R, 9-163, an enzyme concentration of
3 mg L- pH 7.0, and 40 "C,a lipase from Arthrobacter species yielded enantiomerically pure (a R)-164 and the (a S)acetate 165. This mixture of products was then esterified
with methanesulfonyl chloride to afford a mixture of the
corresponding (a R)-sulfonate 166 along with unaffected
(aS)-165 acetate. Both esters were hydrolyzed in the presence
of a small amount of CaCO,. The (aR)-sulfonate 166 was
converted into the desired (a 5')-cyclopentenolone 167 with
inversion of configuration, while (a 8-165 was hydrolyzed
with retention of configuration. Consequently, all the racemic
acetate was converted with maximum efficiency into (aS)-167.
A similar chemoenzymatic approach was recently applied
to the complete transformation of racemic a-cyano-3-phenoxybenzyl alcohol into the (a S ) e n a n t i ~ m e r . [ ' ~ ~ l
(1 R)-trans-caronaldehyde 168 can be prepared by ozonolysis of chrysanthemic acid. Compound 168 and its (1 R)-cisisomer 169, or, more precisely, the lactolic form 170, are
mutually interconvertible.
Both caronaldehyde isomers are extremely valuable chiral
building blocks, because many versatile transformations, especially olefinations of the Wittig type, lead ultimately to a
variety of interesting pyrethroid acids.[98b1For this reason,
new synthesis of caronaldehydes 168 and 169 from natural
121 1
compounds like (+ )-a-pinene, a-limonene, and (+)-A-3carene are frequently reported. None of them seem to be technically attractive as yet, because several more or less laborious degradation steps are necessary in each case to remove
one or more supernumerary atoms of the carbon skeleton.
+ R02C-CH2-S0,R’
(R,R’= t@u)
ZRequiv Na2S20, R 0 2 C ~ c o ‘ ”
Zequiv NaHCO,
(1R)-trans-1 6 8
1 (lR)-cis-169
lexclusivel yl
1”neorly exclusively”)
Scheme 45. Interconversion of (1 R)-rruns-caronaldehyde (168) and its (1 R)cis-lactolic isomer 170.
Recent syntheses by Kriefof (1 R)-cis-175lack this disadvantage,[’l3] as shown in Scheme 46. The optically active
unsaturated esters 171 and 173 are derived from easily available (S)-2,3-O-isopropylideneglyceraldehyde and ( R ,R)2,3-O-isopropylidene tartaric acid.
b ; p
Scheme 47. Enantioselective synthesis of the acid part of acrinathrin (148)
from the caronaldehyde derivative (1 R)-cis-169.
addition of dialkynyl zinc reagents to aldehydes in the presence of chiral amino alcohols.[’16]
Pyrethroid insecticides have achieved a high share (19.4 %
in 1989) of the total insecticide world market, which amounted to 9.6 billion Swiss Francs in 1989.[1’71Alongside the
1 7 2 98%de
96% ee
1. aq.HCIO,, THF
2. NalO,, MeOH, pH 7
(IR,aS)-cis -180
(IRJ-cis-1 75
1. aq.HCIO,, THF
9233 ee 2. NalO,, MeOH, pH 7
(ZZ)-1 73
174 >92%de
Scheme 46. Synthesis of (1 R)-cis-caronaldehyde methyl ester 175.
(&) -182
Scheme 48. The use of 2-phenylethylzinc bromide asalkynyl-delivering reagent
in asymmetric synthesis of experimental pyrethroid 180.
Very recently, the tert-butyl ester of (1 R)-cis-caronaldehyde 169 was used for the synthesis of the new pyrethroid
acrinathrin (148) according to Scheme 47.[‘071
Finally, the successful preparation of the alcohol constituent of the enantiomerically pure experimental pyrethroid
CGA 221 869 (180) which has diminished fish toxicity[’’41is
worth mentioning for at least two
Firstly, 2phenylethynylzinc bromide was applied for the first time in
an asymmetric addition to an aldehyde in the presence of a
chiral amino alcohol, the lithium salt of (- )-N-methylephedrine (Scheme 48). Secondly, the optical induction (88 YOee)
in this easy addition reaction, 181 --t 182, is considerably
higher than the enantioselectivities usually reported for the
natural mixture of esters 135- 140 and the enantiomerically
pure synthetic esters 141-154, there are more than 15 other,
constitutionally uniform although stereochemically heterogeneous, pyrethroids on the market. As the wealth of products
brought to the market by two decades of synthetic efforts is
impressively large, suggestive of exhaustiveness, the impression may arise that there is no longer anything new to discover in this area, either in terms of structure or activity. This is
probably largely true. At the same time, however, investigations are being undertaken to overcome some of the deficiencies of the current products and explore new market niches.
Angen. Chem. In(. Ed. Engl. 30 (1991) 1193-1215
For example, the new pyrethroids which have neither an
ester group nor a cyclopropane residue (their low fish toxicity makes them appropriate for use in rice fields) have nothing in common structurally with the archetypal pyrethrin
135, except the outer surface of the molecules which is important for recognition by the binding site.“ 1 8 ]
184 R ’ = F , R ~ = H
185 R‘=H, R2=0r
Scheme 49. Pyrethroids containing neither ester nor cyclopropane groups.
The only enantiomerically pure derivatives 183- 185 are
missing even the usual geminal methyl group![11g1 (See
Scheme 48; (2 R ) enantiomers are more active than (2 S) ones.)
5. Conclusions and Outlook
As the above results indicate, the syntheses and investigations of enantiomerically pure agrochemicals have developed from isolated curiosities to become serious aims of
modern agrochemical research and development. Clearly,
the phenomenon of chirality will play an increasingly important role in crop protection by influencing both the thinking
and the direction of the research programs of the scientists
From an agrochemist’s point of view, it is still an important and rewarding task to discover and develop new and
inexpensive methods of introducing chirality which are a)
applicable not only to model substances, but b) also take
account of the chiral-economic requirements of both industry and environment (for instance, by the recycling of unwanted stereoisomers or by using catalytic reactions whenever
possible). The examples shown above have been selected to
demonstrate what has been achieved to date in this respect.
From an agrobiologist ’s point of view, performing modeof-action studies with pure stereoisomers improves the understanding of the factors that influence biological activity,
and hence enables the best compounds to be discovered more
rapidly. The complex interaction of chiral substrates with
natural chiral receptors, as well as their uptake, transportation, metabolism, etc., inside the chiral constituents of target
organisms (e.g., peptides, polysaccharides, polynucleotides)
may frequently lead to surprising insights and stimulate synthetic chemistry by the design of bioactive substances.
From an agronomist’s point of view, the use of a single
stereoisomer may offer an additional possibility for the
solution of certain agronomical problems (e.g., reduction in
phytotoxicity, fewer effects on beneficial insects and other
non-target organisms, etc.). First and foremost, however,
one principal question has always to be answered : To which
of the six principal categories (see Section 1) does the investigated crop protection product containing one or more cenAngeM. Chem. Int. Ed. Engl. 30 (1991) 1193-1215
ters of chirality belong? Thus, the increasing flow of racemic
and diastereoisomeric experimental compounds as well as
their enantiomerically pure constituents from chemical laboratories will assist the agronomists in the refinement of their
greenhouse and field testing evaluations.
Thanks to these interdisciplinary interactions, further exciting scientific progress, as well as economical and ecological benefits, can be expected in the fledging area of “Chirality in Crop Protection” in the near future.
The authors would like to thank heartily their colleagues Drs.
Urs Burckhardt, Hans-Peter Buser, Philippe Chemla, John
Dingwall, Hanspeter Fischer, Robert Nyfeler and David
Wadsworth, who critically read this article, and Christa Fletcher
and Dr. Victor Fliick who helped to prepare the manuscript,
drawings, and jigures.
Received: March 22, 1991 [A 8341;
G e m a n version: Angew. Chem. 103 (1991) 1219
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of Plant Protection (W. S . Bowers, W. Ebing, D. Martin, R. Wegler
(Eds.), Springer, Berlin 1990: a) Vol. 4 by K. Naumann: Synthetic
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1991 For the most part we follow in this paper the unambiguous designation
ofchiral pyrethroids proposed by N. F. Janes (Pestic Sci. 18 (1987) 149).
The “1 R, cis” system of designation of stereochemistry of the cyclopropane ring substitueuts, avoids a confusing R vs. S change at C3,
Angew. Chem. Inr. Ed. Engl. 30 (1991) 1193-1215
required by Cahn-Ingold-Prelog convention, when priority orders of the
side-chain substituents are changed.
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[lo31 There are, however, four exceptions in this table: three non-cyclopropane
pyrethroids (152- 154) are marketed apparently as esters containing
racemic 3-phenoxybenzaldehyde cyanohydrin [98a], whereas commercial
tralomethrin 147 is a 60:40 mixture of two diastereoisomers arising from
the brominated side chain at C 3. In contrast to other cases, the two diastereoisomers of 147 are about equally effective because they act first by
losing bromine. thus behaving as ‘propyrethroids’ for 146.
I1041 a) T. Umemura, H. Hirohara, ACSSymp. Ser. 389 (1989) 371; H. Danda,
Y. Fukuwara, T. Umemura, Synlett 1991, 441.
[lo51 144 is sometimes called ‘bioethanoresmethrin’; see e.g., J. P. Leahey
(Ed.): The Pyrethroid Insecticides, Taylor & Francis, London 1985.
11061 Marketed always in mixtures with 142 or 146.
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p. 93.
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