Stereoselective synthesis of 2α-Chloropicropodophyllotoxins and insecticidal activity of their esters against oriental armyworm, Mythimna separata walker.

As part of ongoing efforts to discover new natural-product-based insecticidal agents, in the present study, an efficient method for the stereoselective α-chlorination at the C-2 position of 2'(2',6')-(di)halogenopodophyllotoxin derivatives was first developed. Subsequently, a series of novel esters of 2α-chloro-2'(2',6')-(di)halogenopicropodophyllotoxin with modified C, D, and E rings of podophyllotoxin were smoothly obtained. Finally, all of the title compounds were tested against the pre-third-instar larvae of oriental armyworm (Mythimna separata Walker) at 1 mg/mL. It was found that besides their 2'-halogen-substituted E ring, the stereoselective α-chlorination at the C-2 position of 2'(2',6')-(di)halogenopodophyllotoxins was also related to the chlorination reagents. Especially 2α-chloro-4α-(benzoyl)oxy-2'-chloropicropodophyllotoxin (6e) and 2α-chloro-4α-(2-chlorophenylacyl)oxy-2'-bromopicropodophyllotoxin (8f) showed the most potent insecticidal activities, with final mortality rates of >60%. For 4α-(alkylacyl)oxy derivatives of 2α-chloro-2'(2',6')-(di)halogenopicropodophyllotoxin, the effect of the length of their side chain at the C-4 position of podophyllotoxin skeleton on the insecticidal activity was not very obvious. For 4α-(arylacyl)oxy derivatives of 2α-chloro-2'-chloro/bromopicropodophyllotoxin, an electronic effect of the substituents on their phenyl ring at the C-4 position of podophyllotoxin skeleton on the insecticidal activity was observed.