Oroidin alkaloids, also known as pyrrole-imidazole alkaloids, have become a hot area of chemical and biological research due to their diverse and intriguing structural features and biological activities. Palau'amine (i), one of the hexacyclic oroidin-derived secondary metabolites, contains a fully substituted chloro-cyclopentane ring, a piperazinone moiety and two cyclic guanidines. With the uniqueness and complexity of its structure, palau’amine has been a synthetic challenge and has not yet succumbed to total synthesis. The overall objective of this work was to explore synthetic pathways toward palau’amine and biogenetically related congeners. Most of the work was focused on developing a synthetic pathway for the palau’amine structure proposed in its isolation report dated back to 1993. Starting from a Diels-Alder adduct (iii), oxidation/chlorination followed by phakellin (ii) annulation afforded an advanced pentacyclic intermediate possessing all the carbon framework and all but one ring system of palau’amine. Recently, however, a series of reports questioned the originally proposed palau’amine structure and called for a revision of the stereochemistry of two carbon centers (iv). Now palau’amine has an identical chlorocyclopentane core with axinellamine (vi). With the target changed, we devised a new biomimetic pathway toward both natural products via a common intermediate (v), which was synthesized in 12 steps from the Diels-Alder adduct (iii).

Oroidin alkaloids, also known as pyrrole-imidazole alkaloids, have become a hot area of chemical and biological research due to their diverse and intriguing structural features and biological activities. Palau'amine (i), one of the hexacyclic oroidin-derived secondary metabolites, contains a fully substituted chloro-cyclopentane ring, a piperazinone moiety and two cyclic guanidines. With the uniqueness and complexity of its structure, palau’amine has been a synthetic challenge and has not yet succumbed to total synthesis. The overall objective of this work was to explore synthetic pathways toward palau’amine and biogenetically related congeners. Most of the work was focused on developing a synthetic pathway for the palau’amine structure proposed in its isolation report dated back to 1993. Starting from a Diels-Alder adduct (iii), oxidation/chlorination followed by phakellin (ii) annulation afforded an advanced pentacyclic intermediate possessing all the carbon framework and all but one ring system of palau’amine. Recently, however, a series of reports questioned the originally proposed palau’amine structure and called for a revision of the stereochemistry of two carbon centers (iv). Now palau’amine has an identical chlorocyclopentane core with axinellamine (vi). With the target changed, we devised a new biomimetic pathway toward both natural products via a common intermediate (v), which was synthesized in 12 steps from the Diels-Alder adduct (iii).