Author: Matthew Norris
Norris, Matthew, 2016 Biomimetic total synthesis of peroxide-derived secondary metabolites from marine sponges, Flinders University, School of Chemical and Physical Sciences
Terms of Use: This electronic version is (or will be) made publicly available by Flinders University in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. You may use this material for uses permitted under the Copyright Act 1968. If you are the owner of any included third party copyright material and/or you believe that any material has been made available without permission of the copyright owner please contact copyright@flinders.edu.au with the details.
This doctoral thesis reports the first enantioselective total synthesis and structural elucidation of six natural products, each isolated from the extracts of marine sponges collected near Japan, Fiji and the Caribbean Islands. These compounds, named gracilioether B, gracilioether C, des-hydroxygracilioether C, plakilactone B, des-hydroxyplakilactone B and plakilactone C are considered potential targets for the treatment of type II diabetes, have promising levels of antimalarial activity and exhibit some selectivity for cytotoxicity against cancer cells. Their structures, including the relative and absolute configuration of each, were assigned in this study by matching the nuclear magnetic resonance spectra, high-resolution mass data and specific rotation of several synthetic isomers to that reported for the natural material. This is the first and only time in the chemical literature that these important natural compounds have been synthesised in a laboratory and matched unequivocally to the spectral data of original samples.
This thesis also demonstrates a critical understanding of the compound class through a comprehensive review of relevant literature, which has produced new insight to the biosynthetic origin of the gracilioether furanylidenes and plakilactone butenolides from related endoperoxides; and driven development of the methodology reported herein. Notably, the present study is the first to suggest that plakortin endoperoxides, gracilioether furanylidenes and plakilactone butenolides isolated from marine sponges are inextricably linked through their biosynthesis, non-enzymatic dehydrative ring contraction and oxidative scission.
Each target compound was reached through a careful series of synthetic transformations that were selected, trialled and optimised to increase overall yield and to minimise difficult, unnecessary and wasteful procedures. These efforts have produced an expeditious and versatile synthetic route to the natural products, which is amenable to the synthesis of many natural and synthetic analogues of the gracilioethers and plakilactones. At the centrepiece of this approach is a facile biomimetic transacetalisation/dehydration cascade reaction of an advanced synthetic precursor, which was engineered to deliver the unsaturated ‘furanylidene’ heterocycle of the gracilioethers in a single operation. This in turn, was accessed through an unprecedented sodio-lithio aldol reaction of a substituted β-ketoester and hindered neo-pentyl aldehyde substrate. Finally, a novel and chemoselective oxidative cleavage reaction of the gracilioether furanylidenes with pyridinium chlorochromate (Corey-Suggs reagent) facilitated direct access to the plakilactone butenolides.
The results presented herein are of significant value for further exploring the use and appropriation of the gracilioether furanylidenes and plakilactone butenolides for target identification and drug development in a pharmaceutical setting.
Keywords: Biomimetic, gracilioether, plakilactone, cascade reaction, polyketide
Subject: Chemistry thesis, Medical Biochemistry thesis
Thesis type: Doctor of Philosophy
Completed: 2016
School: School of Chemical and Physical Sciences
Supervisor: Michael Perkins