Biomimetic synthesis of natural products via reactions of ortho-quinone methides

In recent times, natural product synthesis has become central to many scientific fields; from chemistry, through to biology and pharmacology. As synthetic chemists, natural products are attractive targets due to their interesting and complex structures, combined with some intriguing biological properties. One field that is of particular interest is the use of a biomimetic approach towards the synthesis of complex natural products. This thesis will describe the use ortho-quinone methides and cascade reactions towards the biomimetic synthesis of the penilactones A and B, the peniphenones A-D, virgatolide B and epicolactone. The total synthesis of ent-penilactone A and penilactone B has been achieved via biomimetic Michael reactions between tetronic acids and o-quinone methides. A fivecomponent cascade reaction between a tetronic acid, formaldehyde, and a resorcinol derivative that generates four carbon-carbon bonds, one carbon-oxygen bond and two stereocenters in a one-pot synthesis of penilactone A is also reported. The total synthesis of peniphenones A-D has been achieved via Michael reactions between appropriate nucleophiles and a common ortho-quinone methide intermediate. This strategy, which was based on a biosynthetic hypothesis, minimised the use of protecting groups and thus facilitated concise syntheses of the natural products. The most complex target, the benzannulated spiroketal peniphenone A, was synthesised enantioselectively in nine linear steps from commercially available starting materials. A synthesis for the ortho-quinone methide precursor of virgatolide B has been developed. A simplified enol ether was employed for the biomimetic [4+2] cycloaddition reaction to afford a simplified virgatolide B analogue. An isomerised compound containing a cis fused ring junction, thought to arise via a [4+2] cycloaddition of an ortho-quinone methide and an endocyclic enol ether formed by acid catalysed tautomerisation in situ will also be reported. Finally, preliminary studies towards the synthesis of epicolactone have been conducted. A synthesis of the proposed key proposed biosynthetic intermediate epicoccone B has been achieved in four steps. Efforts towards the synthesis of epicoccine via our proposed cycloetherification route proved to be challenging. Furthermore, the synthesis of epicolactone through our proposed biosynthesis was not viable, which was also observed by Trauner and co-workers in their 2014 synthesis of dibefurin.Thesis (Ph.D.) -- University of Adelaide, School of Physical Sciences, 2016