Oxepine-Pyrimidinone Natural Products: The Total Synthesis of (+/-) Janoxepin

Abstract

The first total synthesis of (±)-janoxepin I, an antiplasmodial oxepine-pyrimidinone natural product isolated from the fungus Aspergillus janus is described herein. Chapter 1 provides an introduction to janoxepin I and related natural products that have been reported in the literature. In Chapter 2, the available methods for the synthesis of oxepines and pyrimidinones are reviewed, before the preparation of dihydro-oxepine VI from readily available starting materials II-V is described.

The enamine side-chain seen in janoxepin I was introduced by way of aldol-addition to the ketopiperazine ring. The development of methodology to achieve this efficiently, and its application to the synthesis of dihydro-janoxepin VII is described in Chapter 3. The synthesis of janoxepin I was completed by way of a novel dihydro-oxepine elaboration to construct the oxepine ring. This transformation was the subject of much investigation as discussed in Chapter 4.

The proposed biosynthesis of janoxepin I from pyrazino[2,1-b]quinazoline-3,6-dione VIII was identified as an alternative strategy for oxepine synthesis. Chapter 5 first briefly reviews pyrazino[2,1-b]quinazoline-3,6-dione-containing natural products and the available methods for their synthesis. It then describes the preparation of the putative biosynthetic precursor of janoxepin VIII with a view to further investigation of biomimetic methods for oxepine synthesis.