Bioinspired Synthesis of Sceptrin, Ageliferin and Six Piperine Dimers by Photo(Flow) catalysis: [2+2] vs [4+2] Cycloaddition

We describe a unified, bioinspired total synthesis of eight dimeric natural products, including nigramide R, chabamide, dipiperamide F and G and the emblematic marine alkaloids sceptrin, dibromosceptrin, ageliferin and dibromoageliferin. Central to this approach is a photocatalytic dimerization of either piperine, or fully elaborated hymenidin- and oroidin-type precursors via catalyst-controlled [2+2] or [4+2] cycloadditions. Notably, this work constitutes the first total syntheses of sceptrin, ageliferin, dibromosceptrin, and dibromoageliferin achieved by direct assembly of the native hymenidin and oroidin frameworks. To overcome the limitations of prolonged photochemical exposure and photodegradation, we transitioned from traditional batch processing to low-cost, 3D-printed PhotoFlow reactors, enabling improved efficiency and scalability. Ultimately, this approach offers a general platform for the streamlined synthesis of dimeric marine alkaloids.