Green Synthesis of a Cantharidine Model Compound Based on the Diels-Alder Reaction of Anti-Aromatic Tetracyclone and Maleimides as a Pharmacological Probe for Topical Application

Using tetracyclone (2,3,4,5-tetraphenyl-2,4-cyclopentadien-1-one), and N -phenylmaleimide in a Diels-Alder (DA) approach, the synthesis of a lipophilic cantharidine-like phamacological probe has been designed to permit its topical use for the treatment of colon cancer or the West-African vector-borne parasitic trypanosomiasis. For the development of the target compound, special emphasis was put on implementation of green chemistry practices. This work underscored the anti-aromatic nature of tetracyclone and its consequences regarding the reactivity of this diene. Tuning of this peculiar DA reaction (n-butanol, 120°C, and 1.5 h) allowed to obtain selectively the endo-adduct with a final yield of 88%.