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 sp 2 –sp 2 ‐couplings using non‐toxic reagents. An EC 50 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.