Design and synthetic approach to isocoumarin and isoquinoline precursors of cassiarin a as potential anti-malarial scaffolds

The emergence of drug-resistant Plasmodium falciparum underscores the need for new antimalarial agents. Cassiarin A, a chromone alkaloid from Cassia siamea, exhibits potent activity (IC₅₀ = 0.005 µg/mL), a high selectivity index, and low cytotoxicity toward mammalian cells (MCF-7), making it a valuable lead scaffold. This study focused on developing a synthetic approach to the key precursors of cassiarin A—isocoumarin and isoquinoline frameworks. The initial route comprised eleven steps, beginning with an SN2 substitution of 3,5-dimethoxybenzyl bromide using NaCN, followed by NaOH hydrolysis to the acid, esterification with methanol and H₂SO₄, Vilsmeier–Haack formylation with POCl₃ in the presence of DMF, Pinnick oxidation with NaClO₂ in the presence of NaH₂PO₄, and direct thermocondensation. This pathway was discontinued when the thermocondensation failed to yield the isocoumarin scaffold. A revised five-step sequence was then established: oxidative coupling of 3,5- dimethoxybenzoic acid with terminal alkynes reacted with iridium-catalyst (Cp*IrCl2)2, aminolysis with formamide, triflation with triflic anhydride and DIPEA, Sonogashira coupling catalyzed by Pd(PPh₃)₂Cl₂ and CuI, and final cyclization. Metal-catalyst assistance proved essential, enabling successful transformations and affording both isocoumarin and isoquinoline derivatives in an overall yield of 20%. This work achieved its objectives by delivering and characterizing the essential precursors of cassiarin A, thus laying the groundwork for further optimization of catalyst systems in coupling and cyclization toward the complete synthesis of its tricyclic skeleton.