Synthesis and Anti-Juvenile Hormone Activity of Alkyl 4-(2-Phenoxyalkyloxy) benzoates and Related Compounds

Abstract

Since juvenile hormone (JH) is involved in a wide range of physiological processes in both developing and mature insects (Riddiford, 1994), compounds that possess anti–JH activity are potentially useful not only as biochemical probes to assist in elucidating the role of JH in insect development and reproduction, but also as insect growth regulators (Staal, 1986). Several compounds including precocenes (Bowers et al., 1976), fluoromevalonate (Quistad et al., 1981), ethyl 4–[2–(tert–butylcarbonyloxy)butyloxy]benzoate (ETB) (Staal, 1982), dichloroallyl hexanoate (Quistad et al., 1985), 1,5–disubstituted imidazoles (Pratt et al., 1990) and brevioxime (Moya et al., 1997) have so far been found to have anti–JH activity. However, none of the compounds has been developed for practical use in pest control as yet. Among them, ETB is known to be a unique anti–JH agent. It shows anti–JH activity as well as JH activity for the tobacco hornworm, Manduca sexta (Staal, 1982) and the silkworm, Bombyx mori (Kiguchi et al., 1984), depending on the dose applied; low doses of ETB induced precocious metamorphosis, a clear JH–deficiency symptom, but at higher doses only JH–like activity was observed. Riddiford et al. (1983) have reported that ETB acts as a partial JH antagonist at the target tissue of the larval epidermis. No other anti–JH agents with such action have been found to date. In our previous studies (Ishiguro et al., 2003), we found that ethyl 4–[2–(6–methyl–3–pyridyloxy)butyloxy] benzoate (1), structurally derived from ETB (Fig. 1), showed stronger activity than ETB. Modifications of the ethyl side chain of 1 revealed that the butyl (2) and isobutyl (3) groups were optimal for high activity (Fujita et al., 2005). Further structure activity relationship studies on this series of compounds indicated that the phenyl analog 4 showed activity comparable to that of 2, suggesting that the 6–methyl–3–pyridyl moiety is not significant for activity (Furuta et al., 2006). Conversion of the 4–ethoxycarbonyl group of 2 and 4 to the corresponding carboxylic acids eliminated the activity, indicating that the ester moiety is responsible for the activity. We therefore synthesized additional analogs in which the ethoxycarbonyl group of 4 was modified, and evaluated their activity to induce precocious metamorphosis in B. mori larvae. We also examined the precocious metamorphosis–inducing activity of both optical isomers of ethyl 4–(4–methyl–2–phenoxypentyloxy) benzoate. We report here the structure–activity relationships of new phenyl ether analogs derived from compound 4. Synthesis and Anti–Juvenile Hormone Activity of Alkyl 4–(2–Phenoxyalkyloxy)benzoates and Related Compounds