Intramolecular N-aza-amidoalkylation in association with Witkop-Winterfeldt oxidation as the key step to synthesize Luotonin-A analogues

An expedient four-step approach for the synthesis of a short library of original analogues of the Topo-I Luotonin-A inhibitor, substituted at their C8- and N15-positions, was investigated. This consists of Rutaecarpines formation, their Witkop-Winterfeldt oxidation followed ultimately with functional adjustment of the pyrroloquinolone intermediates. In the first step of these investigations, Rutaecarpines including the Topo-I poison Evodiamine were obtained via the new tandem N-acylation/aza-amidoalkylation using a nitrogen atom as an internal nucleophile with or without association with a decarboxylation.

An expedient and straightforward four-step approach for the synthesis of a short library of new and original analogues of the topoisomerase-I Luotonin-A inhibitor, substituted at their C8- and N15-positions, was investigated. This consists of a succession of an intramolecular N-aza-amidoalkylation reaction with a nitrogen atom as internal nucleophile in a tandem process, the Witkop-Winterfeldt oxidation of Rutaecarpines as intermediates, followed ultimately with functional adjustment.