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).

The pyrrole imidazole alkaloids (PIA) is an ever-growing family of structurally related natural products isolated from several species of sponges which now features more than one hundred memebrs. Their complex molecular architectures, and in some cases, significant biological activities, have made these alkaloids the synthetic targets of a number of research groups across the world. In our approach, following early biosynthetic proposal by Kinnel and Scheuer and Al-Mourabit and Potier, it was envisioned that several of these alkaloids, namely palau’amine, axinellamine, konbu’acidin, styloguanidine and massadine, could be derived from a common chlorocyclopentane precursor through different modes of intramolecular cyclization. Building on the work done previously in our research group by Dr. Anja Dilley, Dr. Paul Dransfield, and Dr. Shaohui Wang, my investigations led to the synthesis of the angular aza-triquinane core of axinellamine and the peculiar transazabicyclo[ 3.3.0]octane core of palau’amine. In my further studies mono- and bis-pyrrole advanced intermediates were synthesized that contain the complete carbon framework of the target natural products. However, attempts to induce the pivotal, potentially biomimetic cyclizations expected to deliver the cores of the target alkaloids proved to be rather challenging, resulting in inconsistent and irreproducible results and leading to the exploration of an alternative, “abiotic” approach. My efforts in this direction resulted in the synthesis of a pentacyclic enamine precursor to styloguanidine and a pentacyclic carbinolamine suitable for the synthesis of palau’amine. Final attempts to complete the target natural products were however unsuccessful.