Total Synthesis of All (–)‐Agelastatin Alkaloids

Abstract

The pyrrole-imidazole family of marine alkaloids, derived from linear clathrodin-like precursors, constitutes a diverse array of structurally complex natural products. The bioactive agelastatins are members of this family that possess a tetracyclic molecular framework incorporating C4-C8 and C7-N12 bond connectivities. We provide a hypothesis for the formation of the unique agelastatin architecture that maximally exploits the intrinsic chemistry of plausible biosynthetic precursors. We report the concise enantioselective total syntheses of all known agelastatin alkaloids including the first total syntheses of agelastatins C, D, E, and F. Our gram-scale chemical synthesis of agelastatin A was inspired by our hypothesis for the biogenesis of the cyclopentane C-ring and required the development of new transformations including an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones.

Two-Step Synthesis of 3,4-Dihydropyrrolopyrazinones from Ketones and Piperazin-2-ones

“…3,4-Dihydropyrrolopyrazinones are unique structural motifs found in numerous biologically active natural products and medicinally relevant compounds and thus have received much attention in the organic and medicinal communities. − For example, highly complex natural alkaloids such as immunosuppressive palau’amine, antimetastatic agelastatin A–F, cyclooroidin, phakellin, and anti-HIV investigational compound MK-2048 and aldose reductase inhibitor ranirestat all possess a 3,4-dihydro­pyrrolo­pyrazinone heterocyclic core (Figure ).…”