Starting from milbemycin D (1), milbemycin A4 (2) and milbemycin A3 (3), a series of 5-keto-5-oxime derivatives were synthesized by selective oximation at the a,/?-conjugated carbonyl function of the 5-ketomilbemycins (4-6). The activities of the synthesized compoundswere studied in dogs naturally infested with microfilariae of Dirofilaria immitis. The 5-keto-5-oximes of milbemycin D (7), A4 (8) and A3 (9) had quite high efficacy to control the microfilariae and more potency than their parents, while the 5-O-acyl oximes (ll-15) also exhibited high activity. The synthesis of the 5-keto-5-oxime derivatives is shown in Scheme 1. The 5-keto intermediates ofmilbemycin A3 (6) and A4 (5) were also isolated from a culture broth of Streptomyces hygroscopicus, and were named 2615 milbemycin J and K, respectively
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