Synthesis of Novel 4α-(Acyloxy)-2′(2′,6′)-(di)halogenopodophyllotoxin Derivatives as Insecticidal Agents

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have prepared three series of novel 4α-(acyloxy)-2′(2′,6′)-(di)­halogenopodophyllotoxin derivatives modified in the C and E rings of podophyllotoxin, which is a naturally occurring aryltetralin lignan isolated from the roots and rhizomes of Podophyllum hexandrum. Their structures were well characterized by ¹H NMR, HRMS, ESI-MS, optical rotation, and mp. The stereochemical configurations of compounds <b>5s</b>, <b>6b</b>, <b>6d</b>, and <b>7q</b> were unambiguously confirmed by single-crystal X-ray diffraction. Their insecticidal activity was evaluated against the pre-third-instar larvae of oriental armyworm, Mythimna separata Walker, in vivo at a concentration of 1 mg/mL. These derivatives likely displayed the antimolting hormone effect. Among all the derivatives, especially compounds <b>5a</b>, <b>5n</b>, <b>7f</b>, <b>7n</b>, and <b>7w</b> exhibited the most potent insecticidal activity with final mortality rates of 70% or so. This suggested that a chlorine or bromine atom introduced at the C2′ or C2′ and C6′ positions on the E ring of podophyllotoxin was necessary for obtaining the potent compounds. This will pave the way for further design, structural modification, and development of podophyllotoxin derivatives as insecticidal agents