Enaminones as precursors for lamellarin akaloids and related heterocycles

Abstract

The synthesis of alkaloids at the University of the Witwatersrand (Wits) has been led by Professor Joseph Michael for more than thirty years now. Throughout this time he has pioneered the use of enaminones as building blocks to provide alkaloids and other nitrogen-containing heterocycles. The ambident nucleophilicity and electrophilicity of the enaminone scaffolds makes them particularly suited to annulation reactions, allowing these positions to be chemically stitched together with suitable linkers to provide nitrogen-containing rings. In this thesis, we present the successful application of this kind of strategy to the synthesis of pyrrolizines and indolizines, as well as a variety of natural and synthetic lamellarin alkaloids. Chapter 1 provides some background into alkaloids, concentrating on the lamellarins themselves, including a selection of some of the most significant contributions to their synthesis published thus far. Thereafter, the Wits enaminone strategy for the construction of heterocyclic alkaloids is discussed in greater detail, alongside a selection of pertinent examples that have been published by the group. This leads up to Section 1.3.3, in which previous Wits contributions to this lamellarin project are described. Chapter 2 summarizes the preliminary investigations carried out during the first year of this project, beginning with a methodological study into the cyclization of simple N-(ethoxycarbonyl) methylpyrrolidine-derived enaminones to pyrrolizines under acidic conditions. This reaction was discovered almost twenty years ago in our laboratories and ever since then it has been investigated as a potential route to making the pyrrole component of lamellarins. The culmination of this work, past and present, paved the way for the development of our [4 + 1] cycloaddition strategy that is introduced in Section 2.3.2. The strategy entails the reaction of suitable enaminones with ethyl bromoacetate, which respectively contribute NC3 and C1 units to the newly formed pyrrole. This reaction serves as a key step in all three of the relevant publications that constitute Chapters 3, 4 and 5 of this thesis, and is arguably one of the most reliable and convenient methods for the preparation of these kinds of pyrrole systems now available. Chapter 3 details the successful application of our [4 + 1] enaminone cycloaddition strategy to the synthesis of lamellarin G trimethyl ether, during a collaborative green chemistry project with Professor Till Opatz at the Johannes-Gutenberg University in Mainz, Germany. This approach from an enaminone precursor was an exceptionally efficient method for the preparation of lamellarins, providing the target alkaloid in the second-highest yield ever reported at the time. Chapter 4 details how the introduction of the alkaloids’ lactone ring was tackled in a unique way, using a late-stage demethylative lactonization reaction between an aryl methyl ether and a nearby carboxylic acid. This reaction, in combination with the [4 + 1] cycloaddition strategy, allowed the completion of the synthesis of the trimethyl ethers of lamellarins G and D, as well as the naturally occurring lamellarins H and A4, in overall yields of above 80%, making this by far the most efficient route to these targets ever reported. Furthermore, this was the first-ever reported synthesis of a lamellarin at the gram-scale. Chapter 5 then describes how this game-changing methodology was successfully applied to the synthesis of the pharmacologically active, though more complex, hydroxylated lamellarins. The naturally occurring lamellarin ɛ as well as the synthetic dehydrolamellarin J were selected as targets, because they are representatives of the two ring-A structural variations that provide optimal cytotoxic potency. While our [4 + 1] cycloaddition strategy and the demethylative lactonization reaction remained pivotal, significant methodological adaptations were required for the synthesis of the enaminone precursors to allow for the inclusion of isopropyl-ether protecting groups of the obligatory phenols. Three unique reactions were developed, including a one-pot phenol esterification-Fries rearrangement to form the phenolic deoxybenzoin ketone precursor, a mild isothiocyanate cyclization reaction to prepare the thiolactam precursors, as well as a particularly noteworthy novel isopropyl ether deprotection method. All three of these methodologies were facilitated with the use of the topical and “green” organic acid methanesulphonic acid. During these investigations, various methodological alterations were made to avoid the use of column chromatography altogether, whilst maintaining the excellent efficiency of our strategy. The culmination of this work gave rise to the first-ever reported chromatography-free synthesis of more than 25 g of the active lamellarin analogue dehydrolamellarin J, which was prepared in two decagram-scale batches in order to prove the reproducibility of our results