Chemical mediators are key compounds for controlling symbiotic interactions in the environment. Here, we disclose a fully stereoselective total synthesis of the algae differentiation factor (−)-thallusin that utilizes sophisticated 6-endo-cyclization chemistry and effective late-stage sp2–sp2-couplings using non-toxic reagents. An EC50 of 4.8 pM was determined by quantitative phenotype profiling in the green seaweed Ulva mutabilis (Chlorophyte), underscoring this potent mediator‘s enormous, pan-species bioactivity produced by symbiotic bacteria. SAR investigations indicate that (−)-thallusin triggers at least two different pathways in Ulva that may be separated by chemical editing of the mediator compound structure.