Experimental and computational investigations into the (bio)synthesis of the Angiopterlactones

Abstract

This thesis details our experimental and computational investigations into the (bio)synthesis of two related and structurally complex natural products: angiopterlactone A and angiopterlactone B. Chapter 1 introduces these natural products and outlines our biosynthetic speculations. It further describes our successful total synthesis of angiopterlactone B in four steps, starting from commercially available 2-acetylfuran. Particularly noteworthy is the final dimerisation, in which three new bonds, two new rings and three new stereogenic centres are formed in a single step. The structure and absolute configuration of our synthetic material was confirmed by X-ray crystallography and led us to revise the structure of the natural material. Chapter 2 outlines our computational nuclear magnetic resonance (NMR) studies of angiopterlactone A. These were utilised to investigate the relative configuration of angiopterlactone A, which we suspected was assigned incorrectly by the isolation chemists. A number of different methods were applied to predict the chemical shift and coupling constant data for some of our in-house synthesised compounds, as well as for angiopterlactone A. Utilising a combination of biosynthetic speculations, our synthetic experience, as well as our computational studies, we propose a revised structure for angiopterlactone A. Chapter 3 details our computational mechanistic investigations into the (bio)synthesis of angiopterlactone B, as well as its diastereoisomer dia-angiopterlactone B. These studies led us to propose that the key dimerisation step proceeds via a domino oxa-Michael/Michael/ring contraction sequence. Various homo- and cross-couplings of lactones were investigated to shed light on the predisposed reactivity and selectivity at play in the biogenesis of these natural products. We discovered that angiopterlactone A is unlikely to be accessible via this (bio)synthetic route. Chapter 4 summarises the work presented and provides further speculations on the biosynthetic origins of angiopterlactones A and B.