For decades, cyclic imine (CI) toxins have stimulated extensive interest from the broad scientific community based on their unique and potent bioactivity coupled with their captivating chemical structures . The therapeutic potentials of larger members in this family, such as pinnatoxins , spirolides (4), and gymnodimines , have been thwarted by their high neurotoxicity in vivo. More compact members of this family were isolated from benthic dinoflagellate Vulcanodinium rugosum in 2013 and 2018, portimine A (PA, 1) and B (PB, 2) respectively (Fig. , absolute configuration confirmed in 2019) . In sharp contrast to classic CI toxins, preliminary reports indicate that 1 is highly cytotoxic (~3 nM) and induces apoptosis in several cancer cell lines, while also displaying lower acute toxicity in mice relative to other shellfish toxins, highlighting its potential as a therapeutic agent . However, the mechanism of action (MoA) behind its potent activity is unknown. The Achilles heel of such a compound is of course scalable access to its complex architecture. As it is derived from a dinoflagellate in low yield , chemical synthesis appears to be the only means of realistically procuring such molecules. Even if a bioengineered synthesis could be achieved, semi-synthetic analogs with deep-seated modifications would be unworkable. Featuring a spiro-fused five-membered cyclic imine embedded in a highly oxidized all-carbon tricyclic macrocyclic core, 1 and 2 are formidable targets for synthesis. The unusual peripheral oxidations such as that adjacent to imine carbon (C-5) and neighboring labile medium-sized cyclic ketal add to this challenge. In this work, the first total synthesis of 1 and 2 is presented, which features a carefully choreographed sequence to rapidly build up a minimally oxidized carbon framework followed by strategic oxidations and ring-chain isomerizations that minimize concession steps. In addition, this practical synthesis enabled elaborated in situ investigations as well as illumination of the cellular targets of 1 via chemical proteomics, revealing that 1 targets the 60S ribosomal export protein NMD3 and blocks polysome formation.