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 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 including the yet-to-be-synthesized styloguanidine. 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. The protection of the pyrrole nitrogen with a tosyl group is key to facilitate regioselective functionalization of the central pyridone ring. Late-stage introduction of a guanidyl synthon at the C-4 position is believed to be a key step in this synthetic approach: we believe careful choice of the guanidyl synthon is necessary to avoid the previously reported auto-oxidation of the central ring. Progress in the syntheses of these natural products by this approach and associated challenges are discussed herein.

Efforts towards the novel total syntheses of ugibohlin natural products

ACS Fall 2021

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