A Gram‐Scale Batch and Flow Total Synthesis of Perhydrohistrionicotoxin

The total synthesis of the spiropiperidine alkaloid (?)‐perhydrohistrionicotoxin (perhydro‐HTX) 2 has been accomplished on a gram scale by employing both conventional batch chemistry as well as microreactor techniques. (S)‐(?)‐6‐Pentyltetrahydro‐pyran‐2‐one 8 underwent nucleophilic ring opening to afford the alcohol 10 , which was elaborated to the nitrone 13 . Protection of the nitrone as the 1,3‐adduct of styrene and side‐chain extension to the unsaturated nitrile afforded a precursor 17 , which underwent dipolar cycloreversion and 1,3‐dipolar cycloaddition to give the core spirocyclic precursor 18 that was converted into perhydro‐HTX 2 . The principal steps to the spirocycle 18 have successfully been transferred into flow mode by using different types of microreactors and in a telescoped fashion, allowing for a more rapid access to the histrionicotoxins and their analogues by continuous processing.