Phrymarolin II, a furofuran lignan isolated from Phryma leptostachya L., features a 3,7-dioxabicyclo[3.3.0]octane skeleton. Herein, we report an alternative total synthesis of (±)-phrymarolin II (2), which was performed in 9 steps from commercially available sesamol. The key steps of the synthesis included a zinc-mediated Barbier-type allylation and a coppercatalyzed anomeric O-arylation. Our total synthesis allowed the synthesis of analogues of (±)-phrymarolin II. Most derivatives displayed good to excellent in vivo activity against tobacco mosaic virus (TMV). (±)-Phrymarolin II (2) and compounds (±)-31d and (±)-31g exhibited similar or higher activity than commercial ningnanmycin, which indicated that phrymarolin lignans are a promising new class of plant virus inhibitors.

The synthesis of the originally proposed structure of (±)-nicotlactone A, a potent antiviral lignan with three continuous chiral centers, is reported here in 5 steps from methyl acrylate. The key steps of the synthesis included an In-catalyzed regioselective allylation and a Mn-catalyzed Mukaiyama hydration reaction. Our synthetic strategy also enables us to get the other three epimers and investigate the structure-activity relationship. The NMR data of the synthesized compounds do not match that of the isolated sample, indicating that the structure of nicotlactone A remains to be reassigned. All the synthetic target compounds were evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. Bioassay results indicated that (±)-8-demethylnicotlactone A displayed similar anti-TMV activity to the commercial agent ningnanmycin, thus being a promising candidate or lead compound for developing novel antiviral agents in crop protection.

Natural products have been a valuable source of efficient and low-risk pesticides. In this work, a series of novel sesamolin derivatives A0–A31 and B0–B4 were designed and synthesized via structural simplification of furofuran lignan phrymarolin II, and their antiviral and antibacterial activities were systematically evaluated. The bioassay results showed that compound A24 displayed remarkable inactivation activity against tobacco mosaic virus (TMV) with an EC50 value of 130.4 μg/mL, which was superior to that of commercial ningnanmycin (EC50 = 202.0 μg/mL). The antiviral mode of action assays suggested that compound A24 may obstruct self-assembly by binding to TMV coat protein (CP), thus resisting the TMV infection. In addition, compound A25 possessed prominent antibacterial activities, especially against Ralstonia solanacearum with an EC50 value of 43.8 μg/mL, which is better than those of commercial bismerthiazol and thiodiazole copper. This research lays a solid foundation for the utilization of furofuran lignans in crop protection.