Chapter 10
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Fungicidal Properties of Acivicin and Its Derivatives Hans-Georg Brunner, Phillippe Chemla, Marcus R. Dobler, Anthony C. O'Sullivan*, Paul Pachlatko, Christian Pillonel, and Daniel Stierli Chemistry Research, Syngenta A G , 4002 Basel, Switzerland
Acivicin is a fermentation product with antitumour activity isolated at Upjohn in 1973. The herbicidal activity was claimed by Rohm and Haas in 1985. We found it has interesting oomycete activity, and prepared analogs varying at positions 3, 5, 2', N H and C O O H . Acivicin inhibits glutaminases, so we tested known glutaminase-inhibitors, and glutamine derivatives with cysteine protease pharmacophores, some of which also showed interesting oomycete activity. 2
Acivicin 1 (AT-125, U-42126) was isolated by scientists at Upjohn in the early 1970s on account of its anticancer activity (1). Upjohn workers also described acivicin's activity against Candida (2). Later in 1996 Rohm and Haas chemists claimed the herbicidal activity of acivicin (3). In the Syngenta heritage company Ciba-Geigy the agricultural fungicidal activity was found after a semi-random screen. While searching for the mode of action of the herbicide hydantocidin 2, it was found to inhibit purine biosynthesis.
© 2007 American Chemical Society In Synthesis and Chemistry of Agrochemicals VII; Lyga, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
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122 A number of purine biosynthesis inhibitors were therefore submitted for screening, of which acivicin showed a promising fungicidal activity (Table 1), with a broad spectrum and good control of oomycetes. It was later shown that hydantocidin 2 inhibits adenylosuccinate synthetase (4), which is a different mode of action to that of acivicin, which is a glutamine antimetabolite (Figure 4). Although the glasshouse results were promising, acivicin (as a racemate) was ineffective in two field trials at high dose rates. Against Phytophthora infestans (late blight) in potato with a dose of 500 g/Ha, 6% control was observed and with a dose of 750 g/Ha 32% control. Against Puccinia recondita (leaf rust) on wheat at 250 g/Ha 10% control and at 750 g/Ha, 18% control was observed. Despite the weak field results, the glasshouse results were so promising that a synthesis program was started.
Acivicin 1 (AT-125, U-42126)
Hydantocidin 2
Table 1. Fungicidal Activity of Acivicin (Foliar Application). Fungus Phytophthora infestans Phytophthora infestans Plasmopara viticola Erysiphe graminis Podosphaera leucotricha Uncinula necator Helminthosporium teres Septoria nodorum Puccinia recondita Botrytis cinerea Botrytis cinerea Venturia inaequalis Pyricularia oryzae
Host tomato potato grape barley apple grape barley wheat wheat tomato grape apple rice
Common Name late blight late blight downy mildew powdery mildew powdery mildew powdery mildew net blotch glume blotch leaf rust grey mold grey mold apple scab rice blast
EC80 (ppm) 5 a
100 20 >200 5 50 50 50 >200 >200 20 >200
a. >20 ppm on soil application b. 20 ppm on soil application
In Synthesis and Chemistry of Agrochemicals VII; Lyga, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
b
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Synthesis Many synthetic approaches have been described to acivicin and its derivatives. The first route was reported by Upjohn chemists involving an N C(3) ring closure (J). Other routes involving 0-C(5) ring closures were later reported (6,7,8). Routes involving cycloaddition with halonitrile oxides (9,10,11) and nitrones (12,13) were reported. Furthermore several derivatives were prepared using nitrile oxide cyclisations (14,15,16,17,18,19). To prepare field amounts and intermediates for a derivatisation program a route suitable for amounts of several hundred grams was needed. The BristolMyers procedure (77) was used (Figure 1), as it is direct and scalable. The erythro isomer resulting in naturally occurring acivicin was separated from its threo isomer at the stage of the alcohol 7 through crystallisation.
NH
b.50%
OH CCI
2 steps " 2 a u
CCI -< 3
OH OH
OH
CCI, 6
n
0
- ° "
c.30%
H
,
d.89% —
B f
-
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.
C00
H
'W c c, f.78% ±— »~
