Stereoselective Total Synthesis of (−)‐Thallusin for Bioactivity Profiling

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. Fully stereocontrolled synthesis of the algae differentiation factor (−)‐thallusin was achieved by employing a 6‐endo‐cyclization and effective late‐stage sp2–sp2‐coupling using non‐toxic reagents. Quantitative phenotype profiling in the alga Ulva mutabilis gave an EC50 of 4.8 pM. SAR investigations of derivatives uncovered two functionally distinct chemical mediator functions.