Insecticidal Pyrroles - American Chemical Society

Chapter 25

Insecticidal Pyrroles Discovery and Overview

Downloaded by CORNELL UNIV on June 22, 2012 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch025

R. W. Addor, T. J. Babcock, B. C. Black, D. G. Brown, R. E. Diehl, J. A. Furch, V. Kameswaran, V. M. Kamhi, K. A. Kremer, D. G. Kuhn, J. B. Lovell, G. T. Lowen, T. P. Miller, R. M. Peevey, J. K. Siddens, M. F. Treacy, S. H. Trotto, and D. P. Wright, Jr. Agricultural Research Division, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400 Dioxapyrrolomycin, isolated from a Streptomyces strain, was found to have moderate activity against a number of insects and mites and to be a potent uncoupler of oxidative phosphorylation. These findings, along with the novel structure, led to a search for acidic halogenated nitropyrroles, and pyrroles with other substituent combinations, with useful insecticidal or other pesticidal activity. A progession of new pyrroles described here has led to AC 303,630 which has been chosen for commercial development as a broad-spectrum insecticide/miticide. CI

Dioxapyrrolomycin

A C 303,630

Chemists and biologists who have been involved with the search for new ways to control insects have also been challenged with making that effort as specific as possible for the pest to be controlled. Thus much attention has been paid to modes of action which are specific for invertebrates and would, presumably, spare mammals. On the other hand, finding any new strategy whether chemical or biological which succeeds in holding off the onslaught of the major insect pests remains a daunting challenge. Put another way, strictly from the chemists point of view, finding new chemistry that works and offers some advantage over existing control agents is a difficult proposition. Described in part here is a particular effort to find an effective and acceptable new insecticide whose mode of action is at the cellular level, that is, one whose principle action is as an uncoupler of oxidative phosphorylation. 0097-6156/92/0504-0283$06.00/0 © 1992 American Chemical Society

In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S III

Pyrrolomycins


Of course, we did not choose the mode of action and proceed from there to design a new insecticide. The impetus came from our ongoing insecticide screening program. The lead in this case was an unusual one, having been discovered through the efforts of Cyanamid's fermentation program conducted at the Lederle Laboratories in Pearl River, New York. By screening broths against insects and by the usual methods of coupling biological activity with isolation techniques, the Lederle scientists isolated from a Steptomyces strain and identified the compound shown in Figure 1 (7). At about the same time, this pyrrole was also reported by Meiji Seika Kaisha and the SS Pharmaceutical Company in Japan (2, 3) as an antibiotic. Neither made mention of insecticidal activity. It has been named dioxapyrrolomycin. As shown in Figure 1, dioxapyrrolomycin exhibited α

Pesticidal Activity Species Southern Armyworm (Spodoptera eridania): Tobacco Budworm (Heliothis virescens): 2-Spotted Mite (Tetranychus urticae): Western Potato Leafhopper (Empoasca abrupta) :

* LC50 ppm 40 32 10 > 100

*Leaf-dip assay Figure 1 : Dioxapyrrolomycin

moderate broad spectrum insecticidal and miticidal activity. However, an oral L D of 14 mg/kg to mice showed it to be highly toxic. This combination did not make dioxapyrrolomycin a candidate for development, but the structure was simple enough to warrant consideration as a take-off for synthetic modification. Dioxapyrrolomycin is a recent addition to a series of antibiotic pyrroles largely isolated and identified by Meiji Seika Kaisha scientists and generically called pyrrolomycins. Several are shown in Figure 2 (4, 5). Except for pyrrolomycin D, which has three pyrrole ring halogen atoms, they share a nitro substituent along with halogen atoms. Again, varying degrees of antibacterial and antifungal activities are attributed to these compounds and several others of similar structure, but there has been no indication of insecticidal or miticidal activity. 5 0

Oxidative Phosphorylation Uncouplers We suspected that the pyrrolomycins would be good uncouplers of oxidative phosphorylation. When put to the test, using rat liver mitochondria as the substrate and measuring oxygen uptake, dioxapyrrolomycin was, in fact, shown


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Insecticidal Pyrroles: Discovery and Overview

ADDOR ET AL.

285

to be a potent uncoupler with an I of .025 pmolar. Several pesticides known to function as uncouplers are shown in Figure 3. Of these compounds, dinocap is representative of a number of dinitrophenols and their derivatives which have found utility as acaracides and herbicides. The salicylanilide, niclosamide, is effective in controlling snails (6). The benzimidazole, fenazaflor, appears to have 50

CI

N0

2

OH Pyrrolomycin Β


Pyrrolomycin A

Pyrrolomycin Ε Figure 2:

Pyrrolomycins

been given serious consideration for development by Shell scientists some years ago as an acaricide (7). More recent is work reported by Morton of ICI (8) on the diarylamine acaricide fentrifanil shown later by Nizamani and Hollingworth to be a potent uncoupler (9). Work with a similar series of compounds has been described more recently by Eli Lilly scientists as well as by other groups (70,77). CK

(CH ) CH 2

5

3

CH~

Ο,Ν

NO, Dinocap

CI CF, 0,N

CI -OPh Fenazaflor

Fentrifanil Figure 3: Respiratory Inhibitors


286



Effective uncouplers share two important properties. The first is that they are weak acids. Peter HeyUer suggests a pka in the general region of 4.5 to 6.5 (72). At the same time they are highly lipophilic. These properties appear to allow such compounds to short-circuit the proton gradient across membranes within mitochondria. The net result is that oxidative processes normally designed to convert ADP to ATP, the energy source within cells, becomes disengaged and the cell dies. Of the compounds in Figure 3 dinocap and fenazaflor must be considered as pro-pesticides, hydrolysis being required to produce the acidic phenol or benzimidazole which acts as the uncoupler. In both cases, derivatization serves to reduce the phytotoxicity of the parent compound. An uncoupler may be as damaging to the functioning of a plant's chloroplasts as it is to an animals mitochondria (13). Synthesis and Pesticidal Evaluation As a base line, and to tell us if a nitro group was of special significance, the three trichloropyrroles shown in Table I were synthesized. The simple nitro and cyanopyrroles showed activity, with the cyanopyrrole the better of the two. The ester showed no activity. 3-Nitrotrichloropyrrole had been reported by Meiji Seika (4). Surprisingly, neither trichloro nor tribromo 3-cyanopyrroles had been reported in the literature. Table I: Trichloropyrroles

Army^ worm

Budworm

a

k Mite

Leafhopper

0

(a) Complete kill at: 1000 p p m (+), 100 p p m (++), 10 p p m (+++), 1 p p m (++++) by leaf-dip assay. (b) Complete kill at: 100 p p m (+), 10 p p m (++), 1 p p m (+++) by leaf-dip assay. (c) Complete kill at: 300 p p m (+), 100 p p m (++), 10 p p m (+++) by leaf-dip assay.

In work directed more toward the dioxapyrrolomycin structure itself, 2benzyl-3-cyanopyrrole was prepared as shown in Figure 4 (14). In the course of chlorination, the benzyl methylene group was oxidized and the benzoyl derivative shown, isolated in low yield, demonstrated some insecticidal activity. Based on this result and consideration of the structure of pyrrolomycin D, 2- and 3-parachlorobenzoylpyrroles were prepared by literature methods (75, 16). Halogenation gave the additional structures shown in Figure 4. As indicated, neither compound proved especially active. As a further structural simplification,


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ADDOR ET AL.



TBW LH

SAW TBW

+ + ±

SAW TBW

287

+ +

+ 0

Figure 4: Benzoylpyrroles

2- phenyl-3-cyanopyrrole was prepared utilizing phenylglycine in place of benzylglycine in the scheme in Figure 4 (14). Chlorination provided 2-phenyl3-cyano-4,5-dichloropyrrole (1, Table II). As shown in Table II, 1 was found active against lepidopterous larvae providing impetus for additional work. However, to facilitate preparation of a large number of both cyano- and nitro-containing analogs of 1, a new synthesis strategy was needed. This requirement was met by development of the route shown in Figure 5, one which succeeded in providing good yields for both series of compounds. This scheme has a close analogy in work reported to afford 2-benzoyl- and 2-alkylthio-3-nitropyrroles (77).

CF C0 H 3

2

By this new process, a range of 2-aryl-3-cyano and 3-nitro dichloro and dibromo pyrroles as represented in Table II was prepared for testing. The 4,5-dichloro compounds are shown; there was little difference in activity noted between these and their 4,5-dibromo counterparts. Compounds incorporating halogen atoms on the phenyl ring were found to have good activity against the army worm and the tobacco budworm. With compounds such as 3, 4 and 5 we had achieved activity against lepidopterous larvae superior to that of dioxa pyrrolomycin and, at the sametime,improved on the mouse toxicity. But


288


leafhoppers and mites were unaffected at test levels except for the nitropyrrole 6. Notably, the p-tolyl compound 7 was inactive possibly due to metabolic loss. At least part of the answer may also lie in the reduced acidity of the pyrrole. The numbers at the bottom of Table II show that the pyrrole pka is significandy affected by the phenyl ring substituent with over a pka unit difference between the p-chloro phenyl and the p-tolyl analogs.


Table II: 2-Aryl-3-Cyano/Nitro Pyrroles

a

Leaf hopper

Ε

Armyworm

1. H

CN

++

+

0

0

2. H

N0

++

++

0

0

++

0

0

X

3. 4-CI

2

+ ++

*CN

(5.4) 4 . 4-CI

N0

3

2

a

**CN N0

2

4-CH

***CN

3

CN

8. 4-CF3

0

+ ++

++

0

0

+ ++

++

0

++

0

0

0

0

+ ++

+ ++

+ ++

(1.0) 9. 4-CF3

N0

10. 4-OCF3

CN

2

2

12. 4 - N 0

3

2

CN CN

Dioxapyrrolomycin

(15)

(63)

(9.4)

(7.0)

+ ++

+ ++

++ (41)

+ ++

++

+ ++ ++ (40)

*pka=6.3; c l o g P=4.8

(21)

(10.7)

(4.5) 11. 4 - C 0 C H

(24)

+

(8.2)

7.

Mite

++

(4.7)

6. 3,4-di-CI

a

+ ++ (8.0)

5. 3,4-di-CI

Budworm

+

(19)

++

(23)

++

(9.1)

+ ++ ++ (32)

**pka=6.1 ; clog P=5.7

+

0

0

0

0

+ ++ (10)

+ ±

***pka=7.4; clog P=4.7

(a) Numbers in parentheses are L C 5 0 values in p p m .

Of the compounds in Table II, the 2-(3,4-dichlorophenyl)-3-cyanopyrrole 5 was selected for limited field evaluation. On cotton, 5 showed interesting but uneconomic control of the Heliothis species. However, for lepidopterous larvae on cabbage it was effective at 0.25 kg/ha. Also, in field applications, 5 proved outstanding for the control of resistant Colorado potato beetle at 125 g/ha. These results indicated that certain pyrroles, even though based on a heterocycle not especially noted for its oxidative or photolytic stability, could be made to work effectively as insecticides in the field.



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289

The introduction of a trifluoromethyl or a trifluoromethoxy group on the aromatic ring in this series to give compounds 8, 9, and 10 had the rather dramatic effect of regaining the miticidal activity shown by dioxapyrrolomycin but missing for most of the members of the 2-aryl-3-cyano series. However, there was a drawback since, unlike 5, these compounds were highly phytotoxic. Consequently we were drawn to the need to examine N-derivatization of these pyrroles. As with the earlier described phenol and benzimidazole examples, pesticidally effective derivatives would be metabolized to the parent pyrrole within the insect. Uncoupling activity, which we expected for the active compounds in Table II, was verified by oxygen electrode experiments. For instance, with rat liver mitochondria, pyrrole 5 was shown to have a PI50 of 2 nanomolar. Consistent with this mode of action, experiments with a spruce budworm cell line showed 5 and close analogs to be cytotoxins at the sub-micromolar level. Some results of N-derivatization on insecticidal activities are shown in Table ΠΙ. Clearly, with the dichlorophenylpyrrole series, the worm activity noted for the parent compound 5 is retained by a variety of derivatization products. A surprise resulted when an alpha-methyl group was introduced into the alkoxymethyl substituent, e.g., to give compound 20. In this case worm activity was retained but, unlike 5 itself and the other derivatives, good activity was also found for both the mite and leaf hopper. Introducing the ethoxymethyl group into CI Table III: N-Derivatization

Jj CI^NJ

I

X=3,4-dl-CI

R

Armyworm

R

+ ++

5. H

3

Budworm

a

a

++

Mite

Leafhopper

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

++

++

a

(15) 13. C H 14.

3

CH Ph 2

15. C N 16.

CH CN

17.

CH C0 Et

18.

CONMe

19.

CH OC H

20.

CHOCH3

2

2

2

2

2

2

5

+ + + + + + + +

+ + + + + + +

(3.6)

I

CH

+ + + + + + + +

+ ++ + + +±

(3.5)

(14)

3

X=4-CF

3

+ ++

7. H

(1.0) 21.

+ + + + + + + +

CH OC H 2

2

5

+ ++ (2.7)

+ ++ (9.4)

+ ++

+ ++

+

(7.0) 0

(10)

++ (2.0)

(a) Numbers in parentheses are L C ^ values in p p m .


290

SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S ΠΙ

the />-(trifluoromethyl)-phenylpyrrole 7 to give compound 21 also produced an interesting result, Le., the high activity noted for 7 against the mite was lost while leaf hopper activity was markedly improved. In the effort to eliminate phytotoxicity through such N-derivatization, the grasses, including rice, gained tolerance with 21 but the broadleaves retained their susceptibility. We were also pleased to note that compound 21, among the most potent and broadly active pyrroles prepared up to that time, was also one of the safest, with a mouse oral L D of 144 mg/kg. This was evidence that mammalian toxicity for these new pyrroles need not go hand-in-hand with their insecticidal potency. In addition to examining effects of phenyl ring substituents on insecticidal potency and range, we needed to look at die isomer picture on the pyrrole ring. Confining the search to an aromatic ring, a cyano or nitro group, and two halogens around the pyrrole ring affords six regioisomers for consideration. If a fourth substituent replaces a halogen atom, then one is forced to deal with twelve regioisomers. To provide 2-aryl-4-cyanopyrroles, an adaptation of the recently described procedure of Tsuge and coworkers shown in Figure 6 was used (18). It is lengthy and limited in range by the availability of aryl Grignard reagents. Nevertheless, this procedure, followed by halogenation, provided the initial examples which afforded good worm activity. We searched for an improved synthesis and succeeded with the second scheme shown in Figure 6. Interestingly,foto-benzoylpropionitrileitself with hydrogen chloride in benzene, is reported to form only the imidoyl chloride (19). Also, using concentrated hydrochloric acid in acetic acid, Abdelhamid and coworkers have recently reported that phenacylmalononitrile gives only 2-amino-3-cyano-5-phenylfuran (20). This is a minor by-product under the conditions we used.


5 0

Figure 6: 2-Aryl-4-Cyanopyrroles

Activities for some representative 2-aryl-4-cyano compounds are shown in Table IV. Again, electron withdrawing groups on the aromatic ring promote insecticidal activity. In most instances, the underivatized pyrroles in this group had activity largely limited to lepidopterous larvae. Whereas the para-(trifluoromethyl)phenyl analog in the 2-aryl-3-cyano series had shown excellent two-spotted mite activity, the 2-aryl-4-cyano counterpart 24 was


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ET A L .


291

inactive on this pest. As before, the experience of N-derivatization offered interesting and useful results. Thus compound 26, the N-ethoxymethyl derivative of 23, is highly active against all the species shown. Although slightly more phytotoxic than some of our other candidates, it has undergone considerable evaluation and remains one of our more effective insecticidal pyrroles. Of additional interest was the finding that comparable 2-aryl-4-nitro analogs, as represented here by compound 27, are significantly less active than their cyano counterparts, in this case compound 22. Table IV: 2-Aryl-4-Cyanopyrroles a

Budworm

a

a

Mite

Leafhopper


Armyworm

(a) Numbers in paretheses are L C ^ values in p p m .


a

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SYNTHESIS A N D CHEMISTRY O F A G R O C H E M I C A L S III

The additional four regioisomeric aryl/cyano pyrroles were prepared by the schemes shown in Figure 7. Chlorination of the appropriate pyrroles obtained by these procedures and those described earlier afforded the examples represented in Table V.


2-Aryl-5-Cyano

Figure 7: Isomeric Aryl/Cyano Pyrroles

H

Like the 2-aryl-3-cyano and 2-aryl-4-cyanopyrroles, the 2-aryl-5-cyano compounds also showed good worm activity. However, when the aryl group was moved to the 3-position of the pyrrole ring, activity dropped off generally ten-fold or more. As pointed out earlier, the 2-aryl-4-nitro isomer was less active than the 2-aryl-3-nitro compound. With these aryl-nitro pyrroles, moving the aryl group to the 3-position was also detrimental to activity.


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293

Table V: Isomeric Aryl/Cyano Pyrroles

CI

^CN

CI

CI

1ΓΊΙ cr CI


CI

SAW TBW

+ + + + +

SAW TBW

+ + + + +

SAW TBW

+ + +

SAW TBW

+ +

SAW TBW

SAW TBW

+ + + + +

+ + +

Table VI shows, for the 2-aryl-3-cyanopyrrole type, the effect of some additional variation around the ring. Removal of either of the halogen atoms to give compounds 28 and 29 resulted in a ten-fold loss of activity against lepidopterous larvae. Of the three dinitriles shown, 30, 31 and 32, compound 31, with a hydrogen in the 4-position was the most active against the army worms matching the lead compound 5. In this case, the addition of the bromine atom to give 32 was not beneficial to worm activity but did generate some action against mites. Introduction of a nitro or acetyl group as shown with 33,34 and 35 was of little help. A methyl group in the five position destroyed activity. Compared to a halogen atom, such a change has the effect of increasing the pka of the pyrrole by about 4 units and is likely the major reason for loss of activity. With many biologically active compounds the replacement of a halogen by a trifluoromethyl group often results in an enhanced biological response (27). A number of such replacements were achieved in the current work including putting the trifluoromethyl group in the five-position of a 2-aryl-3-cyanopyrrole to afford 37. The results are as shown in Table VII. Compared to the earlier 4,5-dihalopyrroles, the new compound proved not only more toxic to the tobacco budworm, but, in addition, was highly active against the two-spotted spider mite and the potato leafhopper. The pka of 37 is 5.6; the calculated logP is 5.6. These numbers are not much different from those for the dichloro analog 5, which has a pka of 6.1 and a calculated logP of 5.7.


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SYNTHESIS AND CHEMISTRY O F A G R O C H E M I C A L S m

Ζ


Table VI: Substituent Effects

X

η = 1,2 Leaf hopper

Y

Ζ

Armyworm

Bud worm

5

CI

CI

+ + +

+ +

0

0

28

CI

Η Br

0

0

30

CN

CI

0

0

31

H

CN

0

0

32

Br

CN

+ +

+

33

Br

N0

0

0

34

N0

+ + + + + + + + +

0

H

0

0

35

Br

COCH

+ + + + + + + +

+

29

0

0

0

36

Br

CH

0

0

0

2

2

Br

3

3

+ + + + + + + + +

0

Mite

Table VII: 2-Aryl-3-Cyano-5-CF Pyrroles 3

Armyworm

a

+ + +

+ + +

(3.5)

(3.6)

+ + +

19

Budworm

a

a

Leafhopper

Mite +

+

+

(2.9)

+ + (4.9)

+ +

(4.7)

(15)

+ + +

+ + +

+ + + +

(2.6)

(7.5)

(1.6)

+ + +

+ +

(2.5)

(17)

+ + ± (0.92)

I

(a) Numbers in parentheses are L C

5 0

a

values in ppm.


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295

We once again found ourselves with a severe phytotoxicity problem. However, when the ethoxymethyl derivative 38 (Table VII) was prepared, the compound proved safe not only to grasses, but to broadleaves as well. In addition, there was no loss of activity against the pest species tested. The chemistry which provided 38, which we have designated AC 303,630, as well as some additional work done around it is discussed in the accompanying paper by D. G. Kuhn and coworkers is discussed in the companion chapter of this volume by D. G. Kuhn and coworkers. The oral L D of AC 303,630 to rats (combined sexes) is 662 mg/kg. Dermal toxicity to rabbits exceeds 2000 mg/kg. The L C for Japanese carp is 0.5 ppm. The compound is non-mutagenic in the modified Ames test and the Chinese hampster ovary test Table VIII shows a comparison of the activity of AC 303,630, cypermethrin, and other standards applied as a leaf dip to cotton and fed to third instar tobacco budworms (22). In this test AC 303,630 and cypermethrin are of equal activity and 4 to 16 fold more active than the other standards. Against first instar worms, AC 303,630 is about 1.4 times less active than cypermethrin, as active as methomyl and profenofos, and superior to the other three. By contact of residues on glass it is about 10 fold less active than cypermethrin, 2 to 3 below that of endosulfan and profenophos, and about equal to methomyl and sulprofos (22). 5 0


5 0

Table VIII: Toxicity of Selected Insecticides to Third Instar Tobacco Budworms in a Leaf-dip Assay LC in p p m (95% CI) 5 0

Treatment

n

AC 303,630 Cypermethrin Methomyl Profenofos Sulprofos Acephate Endosulfan

89 148 148 143 318 147 113

1

7.50 7.54 31.77 32.46 42.79 45.31 125.37

(6.69- 8.46) (4.48-11.73) (26.09-39.50) (27.37-37.28) (19.39-99.85) (39.09-51.52) (96.28-208.81)

Number of larvae tested, excluding controls. Source: Reprinted with permission from ref. 22. Copyright 1991.

A summary of some field results versus standards in cotton field trials in Brazil and the USA is shown in Table IX (23). Standards against Tetranachychus urticae and Polyphaqotarsonemus latus were Abamectin at 0.011 kg/ha and propargite at 1.08 kg/ha. Cypermethrin at 0.056-0.067 kg/ha, deltamethrin at 0.005 to 0.01 kg/ha, cyfluthrin at 0.028 kg/ha, and esfenvalerate at 0.034 kg/ha served as standards for the other species shown. A rate of 0.125 kg/ha of AC 303,630 was sufficient to control all but the Heliothis/Helicoverpa spp. a rate of 0.250 kg/ha being required for this species. t

Table IX: Summary of A C 303,630 vs. Standard Treatments - Comparative Results of 1988-89 Cotton Field Trials Conducted in Brazil and the USA Pest (No. of trials) Tetranychus urticae (5) Polyphagotarsonemus latus (2) Alabama argillacea (1) Heliothis/Helicoverpa spp. (9)

A C 303,630 Rate (kg Al/ha) Providing Control >= Standard (P=.05) 0.125 0.125 0.125 0.250

Source: Reprinted with permission from ref. 23. Copyright 1990.


296



In the laboratory, AC 303,630 has been shown to retain its activity against two different strains of pyrethroid-resistant tobacco budworms at both the first and third instar stages (22). Limited fieldwork with a resistant strain confirms this result. The range of activity of AC 303,630 is further shown in Table X for work conducted on vegetables and sugar beets in Brazil, Canada, Italy, the U.K. and the USA (23). Standards included permethrin at 0.1 to 0.112 kg/ha, deltamethrin at 0.008 kg/ha, fenvalerate at 0.168 kg/ha, methomyl at 1.12 kg/ha, phorate at 2.2 kg/ha, pirimicarb at 0.14 kg/ha and propargite at 0.57 kg/ha/. As seen, AC 303,630 was as good or better than the standards on all but one species at 0.125 kg/ha. Table X: Summary of A C 303,630 vs. Standard Treatments - Comparative Results of 1988-89 Tomato, Eggplant, Potato, Celery a n d Sugar beet Field Trials Conducted in Brazil, Canada, Italy, the UK, and the USA

Pest (No. of trials) Aphis fabae (1) Helicoverpa zea (1) Leptinotarsa decemlineata (1) Liriomyza spp. (3) Neoleucinodes elegantalis (1 ) Phthorimaea operculella (1) Spodoptera exigua (1) Tetranychus urticae (1) Keiferia lycopersicella (1 )

A C 303,630 Rate (kg Al/ha) Providing Control >= Standard (P=.05) 0.125 0.125 0.125 0.125 0.125 0.125 0.125 0.125 0.250

Source: Reprinted with permission from ref. 23. Copyright 1990.

AC 303,630 is currently undergoing full scale development for use on a variety of crops and ornamentals. Acknowledgments The authors wish to thank J. G. Hollingshaus for establishing the uncoupling activity of dioxapyrrolomycin. The help of D. M . Gange in sorting out activity relationships based on pyrrole acidities and distribution coefficients is also gratefully acknowledged. And our thanks also go to G. Berkelhammer for his strong interest and support of this project. Literature Cited 1. 2. 3. 4.

Carter, G . T.; Nietsche, J. N . ; Goodman, J. J.; Torrey, M . J.; Dunne, T . S.; Borders, D . B.; Testa, R. T. J. Antibiotics 1987, 40, 233. Nakamura, H . ; Shiomi, K.; Iinuma, H.; Naganawa, H.; Obata, T.; Takeuchi, T.; Umezawa, H . Ibid. 1987, 40, 899. Yano, K.; Oono, J.; Mogi, K.; Asaoka, T.; Nakashima, T. Ibid. 1987, 40, 961. Koyama, M . ; Kodama, Y . ; Tsurouoka, T.; Ezaki, N.; Niwa, T.; Inouye, S. Ibid. 1981, 34, 1569.


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5. 6. 7. 8. 9.


10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.


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Insecticidal Pyrroles - American Chemical Society

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