The pyrrole-guanidine natural products ugibohlin, 4-debromougibohlin and 5-debromougibohlin are marine metabolites containing a 1,5,6,7-tetrahydro-9<i>H</i>-pyrrolo[2,3-f]indolizin-9-one tricyclic ABC core common to many biologically active bromopyrrole alkaloids. These compact natural products additionally contain a guanidyl moiety at the 4-position of the central pyridone ring, and differ only in the substitution and number of bromine atoms located within the pyrrole ring. The synthesis of ugibohlin was previously reported by Lindel in 2009, and was achieved from conversion of presynthesized <i>rac</i>-dibromoisophakellin under acidic conditions. However, the recently discovered debromougibohlins have yet to undergo total synthesis. Regioselective bromination of the 1,5,6,7-tetrahydro-9H-pyrrolo[2,3-f]indolizin-9-one tricycle poses a significant challenge: bromination of C-5 of the pyrrole ring is commonly disfavored relative to C-4 of the pyrrole ring and the C-4 position of the pyridone. Previous reports have focused upon synthesis of the tricyclic ABC ugibohlin core, as it is a central feature to other complex bromopyrrole alkaloids. Introduction of a suitable amino group at the C-4 position of the pyridone ring is especially challenging, as C-4 aminated species undergo facile auto-oxidation to afford α-hydroxy ketones. With these challenges in mind, we sought to achieve the total syntheses of these natural products using a regioselective substitution of the ABC core facilitated by careful protection of the pyrrole nitrogen. This strategy was necessary to confer nucleophilicity at the C-4 position of the pyridone ring and enable potential introduction of the guanidyl moiety. A late-stage selective bromination of the pyrrole is also envisioned to afford the desired bromine substitution pattern. Progress in the syntheses of these natural products by this approach and associated challenges are discussed herein.

Efforts towards the novel total syntheses of the ugibohlins

ACS Spring Meeting 2021

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