Studies towards the total synthesis of Leiodolide A
MetadataShow full item record
In 2006, Leiodolide A (12) was isolated from the marine sponge Leiodermatium sp., which was collected near Uchelbeluu Reef in Palau. Leiodolide A represents a novel class of macrocyclic secondary metabolites, containing a conjugated oxazole moiety within a 19-membered macrolide ring. The purified natural product was tested against the National Cancer Institute’s 60-cell line assay and displayed low micromolar potency against three unrelated cell lines. During characterisation, by employing coupling constant and NOE analysis in conjunction with chemical derivatisation, the absolute stereochemistry of the C15, C16, C17 and C24 positions was confidently determined. Similar analysis of the C4 and C5 stereogenic centres yielded ‘tenuous’ assignments and the remote nature of the C13 stereogenic centre prevented its assignment. This work describes the use of the DP4 structure probability methodology to predict the most likely correct diastereomer from a possible eight. The 4S5S13R diastereomer 128, disparate from the original ‘tenuous’ assignment, was assigned the highest probability and is the principal target of all synthetic work. Initial attempts towards the installation of the C4 and C5 stereogenic centres were unsuccessful but this was resolved with an efficacious application of the Evans anti-aldol methodology. Following the completion of the northern (C10 – C20) and southern (C1 – C9) fragments, the deprotection of the southern fragment could not be realised without degradation. Attempts to remedy this, by exploration of other fragment coupling methodologies, were unsuccessful. However, following the selection of appropriate protection and deprotection protocols, coupling of the key fragments was achieved and elaboration to the corresponding secoacid, required for the study of the crucial Mitsunobu macrolactonisation, represents the most advanced intermediate in a total synthesis of Leiodolide A reported to date.
Thesis, PhD Doctor of Philosophy
Embargo Date: 2025-02-10
Embargo Reason: Thesis restricted in accordance with University regulations. Print copy restricted until 10th February 2024. Electronic copy restricted until 10th February 2025
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.