Total Synthesis of the 2-Nitropyrrole Natural Product Heronapyrrole C

Abstract

This thesis describes the enantioselective total synthesis of the marine natural product heronapyrrole C (3). Heronapyrrole C was isolated from a Streptomyces sp. (CMB-M0423) from a shallow water sand sample collected off Heron Island (Australia) by Capon and co-workers. It belongs to the exceptionally rare family of nitropyrrole natural products, known examples of which are limited to the 3-nitropyrrole pyrrolomycin class of Streptomyces antibiotics. It is also one of the first documented examples of natural products bearing a 2-nitropyrrole functionality. Heronapyrroles A-C were found to display promising activity against the Gram-positive bacteria without cytotoxicity toward mammalian cell lines. Alkene 136 was initially identified as a key intermediate for the synthesis of heronapyrrole C. Two synthetic strategies were investigated in this work for construction of alkene 136. While strategy I using a transition metal catalysed coupling reaction of 137 and 138 failed to afford the desired alkene 136, the Julia-Kocienski olefination of aldehyde 186 and sulfone 187 afforded stereoisomeric mixtures of 136. The low efficiency encountered in preparation of sulfone 187 also limited further investigation of this strategy. A revised strategy was next developed, utilising key intermediate 255 for access to heronapyrrole C (3). Two key fragments, aldehyde 172 and sulfone 255 were synthesised using readily available starting materials. Aldehyde 172 was obtained from pyrrole 146 in 5 steps and sulfone 255 was prepared from geraniol 146 in 11 steps. Unification of the two fragments was achieved via a Julia- Kocienski olefination. The key alkene intermediate 255 was converted into epoxide 274 by Shi epoxidation. The construction of the bis-THF scaffold was achieved by successive double TES deprotection and epoxide opening cyclisation. N-Protection of the 2-nitropyrrole motif was key to the successful synthesis of heronapyrrole C. The BOM group was initially used, but could not be removed in the final step. A revised protecting group strategy using Boz group enabled the successful synthesis of heronapyrrole C (3). A more flexible unified synthetic strategy, designed for synthesis of all the heronapyrroles, was also investigated. The strategy hinged on convergent synthesis of the key intermediate, alkene 294, by a vinylation of iodide 299 with a suitable vinyl organometallic species (300). The iodide coupling partner 299 was successfully synthesised from 2-nitropyrrole 144. A successful model reaction between iodide 299 and vinyltributyltin indicated the viability of the vinylation strategy, however, the synthesis of coupling partner 300 needs further investigation.