AbstractNarciclasine and structurally related pancratistatin are natural products isolated from Amaryllidaceae flowering plants, such as the daffodils. They display potent and selective anticancer activities, however, their isolation/extraction yields are low. Thus, efficient synthetic routes to these compounds and biologically active derivatives are of great interest. The Caggiano research team has been developing novel synthetic routes to obtain simplified narciclasine analogues. Attempts to synthesise unsaturated narciclasine analogues, ready for further functionalisation, using the Diels-Alder reaction together with the Caggiano modified-Curtius rearrangement reaction as key steps, are described in this thesis. In addition, we explore the synthesis of novel unnatural narciclasine N-analogues using commercially available D-lyxose/L-lyxose with aniline to generate the highly functionalised poly-hydroxylated C-ring.
In Chapter 3, a four-step route to the ABC-ring key intermediates has been developed and is described. Following this synthetic methodology, Benzaldehydes were treated with Meldrum’s acid to afford dienophiles via the Knoevenagel condensation reaction. Subsequent Diels-Alder reaction furnished the corresponding unsaturated C-ring cycloadducts. A stepwise decarboxylation of cycloadducts afforded the carboxylic acids required for cyclization. Finally, acids were readily converted to the ABC-ring key intermediates using the Curtius rearrangement and Friedel-Crafts acylation to afford three analogues in overall yields of 27-73%.
In Chapter 4, the synthetic route started with trans-3,4,5-trimethoxycinnamic acid, which relied on chiral auxiliaries to perform the Diels-Alder reaction with control over the stereochemistry. Initially, an achiral auxiliary was used to explore this approach and a racemic ABC-ring key intermediate was successfully obtained, demonstrating the feasibility of this method. Subsequently, chiral auxiliaries were employed and following enantioselective Diels-Alder reactions, hydrolysis revealed the corresponding enantiomerically pure carboxylic acid for cyclization. Using this approach, two various enantiomerically pure carboxylic acids have been synthesized and readily to be cyclized.
Chapter 5 describes our efforts towards the efficient synthesis of an N-analogue of narciclasine via two complementary approaches: functionalisation of the C-ring after cyclization, or cyclization of a functionalised precursor. The first approach was investigated with the ABC-ring core, obtained from anthranilamide and glutaraldehyde in a single step. Various attempts to further functionalised the enamine present in the C-ring were explored, but unfortunately failed. The alternative approach investigated the use of commercially available sugars D- and L-lyxose to afford a functionalised C-ring analogue. Following the initial synthesis of the AB-system in the first step, various strategies to perform the cyclization to afford the functionalised C-ring were explored. Although cyclization of the unprotected system was achieved in high yield using Mitsunobu conditions, the product obtained was actually a previously unreported fully substituted THF-system with four contiguous stereogenic centres, which was fully characterised, and the stereochemistry confirmed by X-ray crystallography.
|Date of Award||29 Mar 2023|
|Supervisor||Lorenzo Caggiano (Supervisor) & Simon Lewis (Supervisor)|