New Methods for the Synthesis of Biologically Active Natural Products and Related Compounds

Abstract

The body of this thesis is comprised of six scientific articles and is preceded by an overview that contextualises all of this published/ submitted work.

The first major part of this thesis is comprised of Publication 1 which is an invited digest article on total syntheses of the cochliomycins and certain related resorcylic acid lactones (RALs). The author’s work on the syntheses of paecilomycin F and cochliomycin C is highlighted in this article.

Publication 2 comprises the second major part of this thesis. This describes total syntheses of the RAL type natural products paecilomycin F (A) and cochliomycin C (B). The key step, a macrocyclisation, was realized by subjecting substrate C to Loh-type α-allylation conditions using indium metal and so affording the required 14-membered macrolide framework. In contrast, when the same substrate was treated under Nozaki−Hiyama−Kishi conditions the 12-membered lactone D was formed through a γ-allylation process. A single-crystal X-ray analysis served to confirm the structure of cochliomycin C and, therefore, the effectiveness of Loh- type α-allylation conditions in producing large macrolides.

Publication 3 details a total synthesis of the racemic modification of the tazettine-type alkaloid 3-O-demethylmacronine (E). A key intermediate was compound F embodying the haemanthidine alkaloid core which was assembled via a reaction sequence including an intramolecular Alder-ene reaction. The lactam-to-lactone rearrangement F → G was achieved under acidic conditions and thereby affording the polycyclic framework associated with target E.

Publication 4 describes total syntheses of the Amaryllidaceae alkaloids zephycandidine III (H) and lycosinine A (I). Their inhibitory effects on acetylcholinesterase were also investigated. A palladium- catalyzed Ullmann cross-coupling reaction was used to link two aryl halides in forming the biaryl scaffold of target H while a Suzuki–Miyaura cross coupling reaction was used to construct the alkaloid I. Although compound H has been reported to act as a significant inhibitor of acetylcholinesterase, biological testing of the synthetically- derived sample suggests otherwise.

The total synthesis of marine alkaloid discoipyrrole C (J) is reported in Publication 5. In the key step of the reaction sequence, the 2,3,5- trisubstituted pyrrole K was treated with MoOPH in the presence of methanol to afford the methoxylated 1,2-dihydro-3H-pyrrol-3-one L. Exposure of the latter compound to potassium carbonate then aqueous trifluoroacetic acid resulted in hydrolysis of the acetate and aminol ether moieties and formation of natural product J.

The last paper, Publication 6, details the total synthesis of the aminocyclitol derivative and antifungal agent nabscessin B (M) from the homochiral g-hydroxycyclohexenone N which was, in turn, prepared from L-(+)-tartaric acid over six steps. The rigidifying effect of the 1,2-diacetal protecting group associated with compound N and its derivatives affords high levels of regiochemical control in the construction of the aminocyclitol framework. The structure of nabscessin B (M), including its absolute stereochemistry, was confirmed by the author’s successful enantiospecific total synthesis of this natural product.

The Appendix to the thesis contains reports on the single-crystal X- ray analyses of key compounds synthesized by the author. Those analyses were carried out by Dr Anthony Willis, Dr Paul Carr, or Dr Jas Ward.