Chemistry and Fungicidal Activity of Soraphen A1Î± Derivatives - ACS

Chapter 19

Chemistry and Fungicidal Activity of Soraphen A Derivatives 1α

1

1

1

Bettina Böhlendorf , Gerhard Höfle , Michael Kiffe , Anthony C. O'Sullivan , Dietmar Schummer , and Marius Sutter 2

1

2

Downloaded by MONASH UNIV on November 10, 2015 | http://pubs.acs.org Publication Date: March 19, 1997 | doi: 10.1021/bk-1997-0658.ch019

1

Gesellschaft für Biotechnologische Forschung, 38124 Braunschweig, Germany Crop Protection Division, Ciba-Geigy AG, 4002 Basel, Switzerland 2

The macrolide soraphen A 1 was isolated from the myxobacterium Sorangium cellulosum (strain So ce 26). It shows potent and broad fungicidal activity. The molecule was derivatised at various positions and many analogs were found with excellent fungicidal activity, some more potent than soraphen A itself. The fungicidal activity of soraphen A derivatized at positions 2, 5, 11, and 12 is described here. 1α

During the study of mycobacterial metabolites by Hôfle and Reichenbach at the Gesellschaft fur Biotechnologische Forschung in Germany , Soraphen Αι 1 was isolatedfromSorangium cellulosum}^ It was tested in the Ciba greenhouses against a battery of pests in greenhouse trials, and was found to possess excellent activity against fungal pathogens on plants. In common with many agrochemical companies, Ciba has a policy of screening natural products as potential agrochemicals. In Table 1 soraphen A i is compared with several commercial and indevelopment fungicides. It is apparent that it has potent and broad activity against many important fungal pests. Only the recently introduced strobilurin type fungicides azoxystrobin and kresoxim have such a broad spectrum, but with a different mode of action. This breadth of fungicidal activity prompted an intensive study of soraphen both at the GBF and Ciba. Finally, however, the compound was not commercialised because of its teratogenic effects in animals. Soraphen A i exerts its action through inhibition of acetylcoenzyme A carboxylase, * which converts acetate to malonate in the fatty acid synthesis pathway. As implied by its macrolide structure, biosynthetic studies have shown it to be a polyketide, assembled from acetate and propionate with two C-2 units arising from glycerol by an unknown pathway. The polyketide synthase gene cluster 1,2

β

5

e

6

e

7

8

9

© 1997 American Chemical Society

In Phytochemicals for Pest Control; Hedin, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.


-

0.6 0.02 0.2 6

-

200 -

20

0.06 0.02 0.2 0.2 -

0.6

6

2

0.6

-

Difenoconazole

Epoxyconazole

Flusilazole

Fenpropimorph

Metal axyl

0.6

0.02 2

2

0.02

200

0.06

2

Kresoxim

-

0.02 2

2

0.02

60

2

2

Azoxystrobin

-

2 20

60

2

2

0.6

2

Soraphen A (1)

0.6

-

-

-

-

20

0.6

20

0.2

Foliar

Foliar

Foliar

Foliar

Soil

Soil

Soil

-

Venturia inequalis on Apple

Plasmopara viticula on Grape

Phytophthora infestans on Tomato

Cercospora arachidicola on Peanut

Pyricularia oryzae on Rice

Erysiphe graminis on Barley

Puccinia recondita on Wheat

Compound

α

Table 1. Comparison of the fungicidal activity of soraphen Αι with some standards


19.

Chemistry of Soraphen A. Derivatives 251

BÔHLENDORF ET AK

10

responsible for this biosynthesis has been identified and partially sequenced. The total synthesis of soraphen A has been reported, as well as a number of reports of the synthesis of substuctures. " When the producing strain was reexamined, more than 20 congeneric metabolites were isolated, forming a soraphen family. At the same time a collaborative derivatization program was initiated starting from the major metabolite soraphen Α 1. Some of the results of this work are presented here. 11

12

17

18

ία

Tautomers 1 contains a hemiacetal group, which readily enters an equilibrium with its hydroxyketone tautomer 2 on dissolution in water (Figure I). » This compound is a β-keto ester which in turn tautomerises readily to its enol form 3. E/Z isomerism of the double bond of the enol 3 and epimerisation at C(2) in 1 and 2 make possible a large number of tautomers. Three of these tautomers 1, 2, and 3 were prepared separately, and their interconvertion to the same equilibrium mixture was followed in aqueous solution. The tautomers 1 and 2 show different reactivity and stereoselectivity in their reactions even at functionalities distant from the hemiacetal / hydroxy-ketone moieties. The selectivity of the reactions of these tautomers has been described.


19

20

19

21

OMe

OMe

9

OH Soraphen A (1)

3

OMe

"OH

2

Figure 1. Tautomerisation of Soraphen A.


252

PHYTOCHEMICALS FOR PEST CONTROL

Synthesis. In the course of the collaborative studies on the derealization of soraphen Αι , virtually the whole molecule was subject to modification. Apart from the work described here, replacement of the C(17)-phenyl ring with other groups has been accomplished. Furthermore extensive derivatisation of the south east ring encompassing positions 2-7 has been described. In addition the 9,10 double bond was functionalised. As with the derivatisation of other macrolides, the observation was continually made that substitution reactions involving SN2 reactions failed, whereas S N I reactions often led to the desired products. α

22

20,23,24

21


25

Position 2. Starting from the hydroxy-ketone 2, the enol 3, the enolate of 3 or protected analogs of these compounds, electrophiles were introduced into position 2 20,24 g compounds delineated in Figure 2 and Table 2 were prepared. It was not possible to determine the stereochemistry of the two epimeric fluoro derivatives. Of the compounds in Table 2 the halo substituted derivatives are fungicidally most active. The most potent of the fluoro compounds has fungicidal activity approaching that of soraphen Αι itself. From this result it is clear that the attainment of the enol 3 or enolate tautomers is not neccessary for soraphen Αι to manifest fungicidal activity. v

m e g e

m e a n s

m

e

α

α

OMe

OH

Figure 2. Structure of the compounds shown in Table 2 Position 5. Derivatives at C(5) were prepared directly from soraphen Αι 1. The hydroxy group was alkylated, forming the ethers shown in Table 4, and acylated with conventional reagents to the esters listed in Tables 5 and 6 (Figure 3). The carbonates and carbamates in Table 6 were prepared analogously. Oxidation yielded the 5-ketone, which was transformed further to the oximes and hydrazones shown below (Table 3). The βΟΗ compound (Table 3) was obtained by reduction of the ketone and its mesylate was formed (Table 3) by further treatment of this alcohol with mesyl chloride. Treatment of soraphen A i with PCI5 yielded the 5a-chloride (Table 3). The 5-O-deoxy compound (Table 3) was prepared by radical reduction of the thionocarbonate (Table 4). Silylation and sulfonation was also successful (Table 4). α

e

26



CN

20 60 b b b

b

m

c c c c c

6

6 6 6 c c c

C

C

Soil

Foliar

20 20 60 b 20 b b 60



1

6 6 b b 60

6

20 2 2 b 6 20 6 6

Foliar

Erysiphe gramanis on Barley

6 6 c c c

0.6

2 6 c 2 c c 2

C

Soil


1

b 60 b b b

b

nt b b b b 20 b 60

Foliar


c 6 c 6 c

6

nt c c c 6 c c c

Soil

1


20 6 20 20 b

20

6 2 6 6 6 20 20 60

Foliar


20 6 b b b

60

2 0.6 2 20 6 60 b 6

Foliar


a. Values are ECgQ mg litre" ; b. = >60 mg litre" ; c. = >6 mg litre" ; nt = not tested

3

Me β^ aEt βΑΙΙγΙ aAllyl

I

3

3

F F βα βΒΓ ctBr βΝ αΝ

R (Fig. 2)

0.6 6 b b b

2

2 0.6 2 0.6 6 6 6 2

Fruit

Botrytis cinerea on Apple

a

6 2 b b 20

20

6 2 20 6 2 b 20 20

Foliar

Botrytis cinerea on Bean

Table 2. The fungicidal activity of soraphen A derivatives modified at position 2.


c c c c c

c

nt nt c

C

C

C

C

C

Soil

Rhizoctonia solani on Rice


C

C

C

C

60

b

b

20

b

aCl

βΟΗ

β080 Με

aNHCOMe

=0

=NOH

C

C

C

20

b

b

2

=NNH

=NNHTs

1

C

b

=NOMe

C

b

C

b b

b

b

c c c c c

b b 20 b 60

b b 6 b 20

b b 6 b b

b b 6 60 60

c c 6 c c

b b b b b

6 c c

c

C

b b nt

b

nt

nt b

C

b b 60

b

C

b

20

b

C

b 20

60

60

C

b

C

b

c 20

2

b

C

b

c 6

0.6

60

20

Soil

Foliar

Fruit

Foliar

Foliar






b

1

Soil

Foliar

b

1



a. Values are ECgQ in mg litre' ; b. = >60 mg litre" ; c. = >6 mg litre' ; nt = not tested

=NNMe

2

b

c

b C

C

b

C

C

C

C

C

b

b

b

C

Soil

Foliar

6



b

2

C

60

Soil

Foliar

H

R



Table 3. The fungicidal activity of soraphen A derivatives modified at position 5*



3

2

b b b b b

b

c c c c c

c

c c

1

b b b 60 b

b

b b

c c c c c

c

c c

1

b b b b b

60

b b

6 c c c c

c

c c

1

b b 20 20 b

60

b b

b 60 6 60 60 20

c c nt c c c

b b nt b b b

Cercospora arachidicola on Peanut Foliar

Pyricularia oryzae on Rice Soil

Pyricularia oryzae on Rice Foliar

b b 60 nt b

20

b b

b 20 20 b b b

Venturia inequalis on Apple Foliar

a. Values are ECgo in mg litre" ; b. = >60 mg litre" ; c. = >6 mg litre" ; nt = not tested

OSO2T0I

OSiMe OSiOHtBu OCSOPh OS02Me

2

0N

^OMe

OBn

oO ο ο

b 60

c c c

60 b b

c c c

b b b

OMEM

2

OCH CH OMe

2

c c c

b 60 6

c c 6

Erysiphe gramanis on Barley Soil

Erysiphe gramanis on Barley Foliar

Puccinia recondita on Wheat Soil

b 20 20

Puccinia recondita on Wheat Foliar

OMe OAllyl O-^^^r

(Fig. 3)

D

a

b b 60 20 b

b

b b

b 20 20 b b 20

Botrytis cinerea on Apple Fruit

b b b b b

60

b b

b 6 20 b b b

Botrytis cinerea on Bean Foliar

Table 4. The fungicidal activity of soraphen A derivatives modified at the 5ot-OH.


c c c c c

c

c c

c c c c c c

Rhizoctonia solani on Rice Soil


c 2

c c

b 6 60 b b b 20

c

2

c

c

c

c

2

b

6

20

60

b

b

tBu

CHC1

6

c

1

6

2 6

6 6

60

1

b

b b b

c

b

c b b

nt 60 c

c

2 6 6

2

c

c 20

6 6

6

c

6 0.6 0.6

6

6

b

b

b

b

c

c b

b b

b

b

60 nt

20

2

6

c

c

c 20

60

20

nt

2

c 6 6

6

nt

6

c 6

6

nt

2

2

6

2

0.6

nt

0.2

Soil

c

Soil







a

c

60

b

b

b

20

b


a. Values are ECgo in mg litre" ; b. = >60 mg litre" ; c. = >6 mg litre" ; nt = not tested

2

CH OMe

-O-CF3

Ph

1

c

60

c

b

iPr

20

6

20

c

b

nPr

c

2

6

c

b

Et

Vinyl

2

20

2

b

Me

2

0.6

2

0.6



b

Puccinia Puccinia recondita recondita on on Wheat Wheat Soil Foliar

H

X=RCOO (Fig. 3)

Table 5. The fungicidal activity of soraphen A derivatives esterified at the 5-OH.



2

c

c c c c

b b b b

6

b

b

c 2 c

0.6

6

b 6 b

2 c

b b

Puccinia Puccinia recondita recondita on on Wheat Wheat Foliar Soil

1

20 b b b

60

6

b 6 b

0.6

60 6


0.6 c 6 c 6

0.6 60 2 b 2

0.6 6 6 mg litre ; nt = not tested

-1

c 20 b

6

6

nt

nt

6

20

c

b

Cl

-1

c 20 60

60

6

c

b

c

60

c

b

Η

C

b

b

b

60

C

b

c

b

c

b

βΟΗ

C

6

0.6

6

nt

2

b

2

6

6

60

OH

Soil

Foliar

Fruit

Foliar

Foliar

Soil

Foliar

Soil

Foliar

Soil

X =R (Fig. 4)

Foliar











a


Table 7. The fungicidal activity of soraphen A derivatives modified at position 1 l .



ν

E

u t r e

1

c

c

2

0.6

6

2

6

6

6

2 20 6


1

b

b

b

60

b

b

b

b

b

b

b

b


c

c

c

2

6

c

c

c

c

c

2 2

1

Pyricularia oryzae on Rice Soil

b

6 20

2

20

6

6

6

20

2 6 20


b

6 6

20

60

6

20

20

20

6 6 20


~ ; b. = >60 mg litre" ; c. = >6 mg litre" ; nt = not tested

c

m

b

60

c

b

m

6

20

20

6

20

20

6

20 6 6


6

c

c

c

c

c

c

c

c

2


6 20

b

b

b

b

b

a. Values are ECgo

^—Ph OMe NHMe NHPh

^—Ph

.NHBoc

2

"X/^SMe NH

ΊΡΓ NHBoc

^NH

2

b

.NHBoc

ΊΡΓ

b

60 60


COOH

2

H CH OMe

X = OCOR (Fig. 4)

a

2 6 20

20

b

6

20

6

20

2 0.6 6


Table 8. The fungicidal activity of soraphen A esterified at position 1 l .


b

6 6

20

b

20

b

60

b

b

6 2


c

c

c

c

c

c

c

c

c

c

c

c

Rhizoctonia solani on Rice Soil


A\

2

2

2

2

2

60 60 60 20 20 b

60 60 20 60 b b 6

m

m

1

0

2 6 2 2 2 60

0.6 2 2 2 20 20 2

Foliar

Barley

0

Erysiphe gramanis n

2 0.6 6 0.6 0.6 2

0.2 2 6 c c c 6

Soil

Barley

0

Erysiphe gramanis

1

n

Rice

b b 2 2 6 mg litre ; nt = not tested

6 6 c 6 6 c

2 c c c c c c

Soil

n

Foliar

0

Wheat

0

Puccinia recondita

Wheat

0

Puccinia recondita

a. Values are ECgo

ΟΛΑ*/*

QAc

2

2

2

2

2

2

OCH OMe OCH OEt OCH OiPr OCH OnBu OCH OnOct OCH OBn OCH OCH CH OMe OCH SMe OCH OAc OTHP OCHMeOMe OCHMeOMe

(Mg. 4;

(Έ'

X =R 0

2 0.6 6 2 2 20

0.2 0.6 2 2 6 6 0.6

Foliar

Apple

n

Venturia inequalis 0

a

2 6 2 2 2 20

0.6 2 0.6 2 20 20 0.6

Fruit

Apple

n

Botrytis cinerea

Table 9. The fungicidal activity of 11-acetal derivatives of soraphen A .


0

n

2 20 0.2 2 0.6 b

0.6 0.2 0.2 2 b 6 2

Foliar

Bean

Botrytis cinerea 0

n

6 c 6 6 c c

2 6 6 c c 2 6

Soil

Rice

Rhizoctonia solani


262

PHYTOCHEMICALS FOR PEST CONTROL

OMe

Figure 5. Structure of the compounds shown in Table 10 and 11. Nearly all of the compounds in this series described here were very weak fungicides. However, the 12p-iodo compound showed a high level of fungicidal activity, approximately equal to that of soraphen A itself. This is particularly surprising as there is no longer an oxygen-containing substituent at this position. A further distinctive feature of this compound is that on soil application no control at all was observed with the highest dose, but on foliar application it showed activity as potent as that of soraphen Αι . We can offer no explanation for this observation. α

Model Compounds. It is difficult to draw conclusions from structure-activity data derived from such a complex target system as a fungus infecting a plant embedded in the earth. On trying to decide which parts of the molecule were important it was thought initially that the bottom-half was more relevant than the top-half. This was because the 11-OMe could be extensivly modified without loss of activity, and the 12-OMe could be replaced with iodide. The 9,10 dihydro compound (soraphen F) is also quite active, so that it appeared to us that the functionality present in the top half of the molecule is non-essential, and that the role of the top-half may be to maintain the bottom-half in the appropriate conformation.



C

C

C

C

C

b

b

b

b

6

βΟΗ

αΟΗ

Η

αϊ

Soil C C C C C

Foliar

b

60 b b 6

C C C C

b b b b

c

C

c

c

b

b

60

b

βΟΗ aMeO

OCONHPh

OS0 Me

OCSOTol

a. Values are E C g o

C C C

c 2 c c c c c c

60 b 20 b 6 mg litre ; nt = not tested

CI

OCO-QJ

OCOPh iCI

/

oco^îj

2

OCOCH OMe

OEt OBn OAllyl OtBu OCOMe OCOtBu

2

OCH OMe

2

C



R (Fig 5)

CH OMe

a

b b

Chemistry and Fungicidal Activity of Soraphen A1Î± Derivatives - ACS

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