Pallimamine (1) is a structurally unique quaternary carbon-containing pentacyclic tetrahydroberberine. Synthesis of key C13-disubstituted tetrahydroberberine intermediates, as separable diastereomeric iso-mers, was achieved using a formal [4 + 2] cycloaddition of 4-methylhomophthalic anhydrides with 6,7-dimethoxy-3,4-dihydroisoquinolin-8-ol. Intramolecular Mitsunobu reactions provided installation of the dihydropyran generating pallimamine (1) and its non-natural diastereomer epi-pallimamine (33). (c) 2022 Elsevier Ltd. All rights reserved.