Total Synthesis and Antimalarial Studies of Caelestines A-C

Caelestines A-D are 2-carboxy-4-quinolones (2C4Qs) first isolated from the Australian ascidian Aplidium caelestis. The caelestines are brominated analogues of kynurenic acid and xanthurenic acid, and the only brominated 2C4Qs isolated from nature. A convenient methodology exists for the Conrad synthesis of 2C4Qs from substituted anilines and acetylene dicarboxylates cyclised in Eaton's reagent. This approach yields regioisomers from asymmetric anilines and is hampered by the absence of chromatographic methods for isolation of pure isomers. Here, we report de novo synthesis of caelestines A-C using this methodology, constituting the first reported syntheses of caelestines B and C, as well as the first reported synthesis of five other novel bromo-quinolones and three related intermediates. The first chromatographic separation of caelestine isomers yielded by Conrad synthesis is described, and structure-activity relationships of caelestines A-C (and related bromo-quinolones) against the Plasmodium falciparum 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains are elucidated.