Total Synthesis of the 2-Nitropyrrole Natural Product Heronapyrrole C

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.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2015

Author dc:creator

• Ding, Xiaobo

Advisor dc:contributor.advisor

• Brimble, M

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/26696

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/26696