Insight into dihalogenation of E-ring of podophyllotoxins, and their acyloxyation derivatives at the C4 position as insecticidal agents.

Unexpected sequential E-ring dihalogenation of podophyllotoxin analogues is reported. It demonstrated that a chlorine/bromine atom was prior introduced at the C2' position of podophyllotoxin, and the corresponding free rotation of E-ring around the C1-C1' bond of 2'-chloro or 2'-bromopodophyllotoxin was restricted. When 2'-chloro or 2'-bromopodophyllotoxin reacted with N-chlorosuccinimide (NCS), the chlorine atom was regioselectively introduced at their C6' position on the E-ring. Whereas 2'-chloro or 2'-bromopodophyllotoxin reacted with NBS, the bromine atom was regioselectively introduced at their C5 position on the B-ring. When 2'-chloropodophyllotoxin reacted with different carboxylic acids in the presence of BF3·Et2O, the steric effect of its E-ring for stereoselective synthesis of 4β-acyloxy-2'-chloropodophyllotoxin derivatives was observed. The insecticidal activity of 2'(2',6')-(di)halogen-substituted podophyllotoxin derivatives were evaluated with Mythimna separata Walker.