Understanding the singlet oxygen reactivity of salarin C through synthesis of a simplified macrocyclic analogue; multicomponent, enantioselective organocatalytic synthesis of tetrahydropyridazinones.

Abstract

Natural products are a valuable source of inspiration for the discovery of new anticancer therapeutic agents. Sponges, especially, produce a wide variety of cytotoxic chemical defense agents. The macrolide salarin C is one of those cytotoxic sponge natural products, isolated from a Madagascar sponge. Of particular interest is the marked reactivity of its oxazole moiety with singlet oxygen that converts salarin C to its biologically inactive congener, salarin A. While this photocatalyzed rearrangement, i.e., Wasserman rearrangement, is known typically requiring UV irradiation and a photosensitizer to generate singlet oxygen, salarin C undergoes this transformation without the need for a photosensitizer. Through the synthesis of a macrocyclic model of salarin C, we determined that the macrocyclic conformation of the oxazole is the cause of the aerobic rearrangement. A thiazole analogue of the same macrocycle exhibited decreased reactivity with singlet oxygen, and opens the door to possible aerobically stable analogues of salarin C. Secondly, a multicomponent reaction was developed towards the synthesis of tetrahydropyridazinones. Multicomponent reactions are extremely advantageous methodologies as they allow the formation of complex scaffolds from simple starting materials and have shown great utility in the synthesis of diverse libraries of compounds. We have applied our nucleophile-catalyzed acylammonium methodology to the synthesis of tetrahydropyridazinones using α,β-unsaturated acylammonium salts from commercially available acid chlorides, malonates and azodicarboxylates. While attempting the oxidation of the N-N bond of the derived tetrahydropyridazinone, an unusual rearrangement to a ketene acetal lactone was also observed. This methodology could be used to construct novel nitrogen-containing frameworks found in pharmaceuticals. Finally, outreach and education efforts were undertaken during this degree, notably the creation of two resources for nuclear magnetic resonance analysis, and the creation of posters, images, films, and 3D printed models for chemistry outreach during the Baylor Give Light campaign. Guidelines for creating similar illustrations and models are outlined.