Synthesis And Insecticidal Activities Of 2α/β-Bromo-4α-Alkyloxy-Podophyllotoxin Derivatives

Podophyllotoxin, a naturally occurring aryltetralin lignan, has significant antitumor and anti-HIV activity. Meanwhile,it also exhibited the interesting insecticidal activity. Based on the above results and in continuation of our program aimed at the discovery and development of natural products-based insecticidal agents, in this thesis we designed and synthesized a series of 2α/β-bromo-4α-alkyloxypodophyllotoxin derivatives from podophyllotoxin, and their insecticidal activity was evaluated against the pre-third-instar larvae of Mythimna separata Walker. The main results were summarized as follows:1. 11 novel 2α/β-bromo-4α-alkyloxypodophyllotoxin derivatives were designed and synthesized. Their structures were well characterized by 1^H NMR, (13)^C NMR, IR, MS, HRMS, 1^H-1^H COSY, optical rotation and mp. Especially the absolute configuration of four compounds was further determined by X-ray crystallography.2. When 4-O-tetrahydropyranylpodophyllotoxin was allowed to react with Br2 in the presence of LDA, the ratio of two stereoisomers, 2β-bromo-4-O-tetrahydropyranylpodophyll -otoxin and 2α-bromo-4-O-tetrahydropyranylpicropodophyllotoxin, could be well controlled by the reaction temperature.3. Due to the intramolecular steric effects, 4α-alkyloxy-2α/β-bromopodophyllotoxin derivatives were readily prepared with excellent stereoselectivity by the reaction of 2α-bromopicropodophyllotoxin or 2β-bromopodophyllotoxin with alcohols in the presence of BF₃·Et₂O.4. On the other hand, whether 4α-alkyloxy-2α-bromopicropodophyllotoxin could be obtained completely depended on the reaction time. When the reaction time was prolonged to 310-430 min, they were all converted to the same by-product (15) in 46-68% yields with the more rigid structure via an intramolecular Friedel-Crafts (FC) alkylation reaction, and its configuration was confirmed by X-ray crystallography. However, to 4α-n-butoxy-2β-bromopodophyllotoxin, even if the reaction time was prolonged to 44 h at room temperature or 17.5 h under reflux, the proposed by-product (16) was not detected by thin-layer chromatography.5. Finally, the insecticidal activity of 4α-alkyloxy-2α/β-bromopodophyllotoxins was evaluated against the pre-third-instar larvae of M. separata by the leaf-dipping method at the concentration of 1 mg/mL. Five compounds displayed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide. Meanwhile, some interesting results of structure-activity relationship were concluded. In general, the proper length of straight-chain or branched-chain alkyloxy at the C-4 position of 2α-bromopicropodophyllotoxins was very important for the insecticidal activity. And theβconfiguration of C-2 bromine atom of 2-bromopodophyllotoxins was usually necessary for the insecticidal activity.