Synthesis of Novel 4-Acyloxy-2′-Bromo-6′-Chloropodophyllotoxin Derivatives Displaying Significant Insecticidal Activity Against Mythimna Separata

In order to explore novel natural product-based insecticidal agent, two important intermediates ( 2 and 3 ) and 4-acyloxy-2′-bromo-6′-chloropodophyllotoxin derivatives ( 4 a – f and 5 a – f ) were designed and prepared, and their structures were confirmed by 1 H-NMR, 13 C NMR, HRMS, ESI-MS, optical rotation and melting point (mp). The stereochemical configuration of compound 4 b was unambiguously confirmed by single-crystal X-ray diffraction. Moreover, we evaluated the insecticidal activity of target compounds 4 a – f and 5 a – f against a serious agricultural pest of Mythimna separata by using the leaf-dipping method. Among all tested compounds, compounds 4 d , 5 d and 5 f exhibited stronger insecticidal activity with a final mortality rate exceeding 60 %. Especially compound 5 d exhibited the best insecticidal activity, with a final mortality rate of 74.1 %. It has been proven that introducing bromine or chlorine atoms at the C-2′, C-2′ and C-6′ positions of the E ring of podophyllotoxin can produce more potent compounds. In addition, the configuration of the C-4 position is important for insecticidal activity, and 4β-configuration is optimal. This will pave the way for further design, structural modification, and development of derivatives of podophyllotoxin as insecticidal agents. Graphical