A Concise Total Synthesis of the Fungal Isoquinoline Alkaloid TMC-120B

Abstract

Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11–17 steps, 1.5–2.9% yield). Thus, to access this compound more efficiently, we herein present a concise and significantly improved total synthesis of the natural product. Our short synthesis relies on two key cyclization steps to assemble the central scaffold: isoquinoline formation via an ethynyl-imino cyclization and an intramolecular Friedel-Crafts reaction to form the furanone.

Diversely functionalized isoquinolines and their core-embedded heterocyclic frameworks: a privileged scaffold for medicinal chemistry

“…Haidar et al synthesised isoquinoline alkaloid TMC-120B 22 , an established antiepileptic drug (Scheme 3). 44–47 Sonogashira coupling of 2-bromo benzaldehyde 18 with propyne following alcohol protection generates alkyne derivative 19 . Compound 19 on cascade imino-annulation following acid hydrolysis affords 8-hydroxyisoquinoline adduct 20 , which on successive nucleophilic substitution, basic hydrolysis and Lewis acid catalysis, generates the tricyclic adduct 21 .…”

Deep-Sea Natural Products from Extreme Environments: Cold Seeps and Hydrothermal Vents

“…TMC-120B (40) and TMC-120C (41) were observed to significantly lower PTZ-induced seizures in the larval zebrafish PTZ seizure model [35]. Because compound 41 has significant activity, its total synthesis route was also studied [36]. A new acyclic peroxide derivative, asperoxide A (42), and 13 known compounds (43-55) (Figure 5) were reported in 2020 from the deep-sea cold-seep species Aspergillus nidulans SD-531.…”