Synthesis of Bioactive Natural Product Analogues

Abstract

Natural products have been turned to as a treatment source for a diverse range of diseases with plants being used in traditional medicines for thousands of years. More recently the isolation and characterisation of the bioactive compounds found in these organisms has led to their use as synthetic targets for drug design. With their complex privileged structures, they are important compounds in the search for new treatment methods for disease such as Alzheimer’s and cancer where more efficient therapies are required. Methyllycaconitine (MLA) 26 is the principle norditerpenoid alkaloid isolated from Delphinium brownii. It is a highly potent antagonist of post synaptic α7 nicotinic acetylcholine receptors (nAChRs) and shows potential as a neuroprotective agent for the treatment of Alzheimer’s disease. This thesis describes the synthesis of BE ring analogues of MLA. The synthetic strategy centres around a one-pot cyclisation using ethyl-α-(bromomethyl)acrylate 40, various primary amines and cyclic ketones to construct bicyclic analogues of various sizes and substitutions in a single efficient procedure. This synthetic approach led to the first examples of BE ring analogues that contain the natural 2-[2-(S)-methylsuccinimido]benzoate substituent, crucial for MLAs 26 binding activity. Use of (R)-α-methylbenzylamine allows the synthesis of BE ring analogues as single diastereomers and we report the first synthesis of a chiral BE ring analogue with the N-ethyl substitution found in the natural product MLA 26. Naturally occurring indolic enamides are a synthetically interesting class of bioactive natural products. They have been found to have anti-tumour, anti-inflammatory and HIV-inhibitory properties. This thesis describes the synthesis of (Z)-indole enamides igzamide 133 and (Z)-coscinamides A 166 and B 167 and the first reported synthesis of their analogues along with the synthetic studies towards kottamide E 134. Our convergent approach to these natural products and their analogues utilises a Z-selective ruthenium-catalysed addition of primary amides to indole acetylenes to form a variety of indolic enamides. The use of the Z-selective pathway solves the low Z:E enamide ratios observed in previous syntheses of Igzamide 133. The first reported biological testing data for analogues of Igzamide 133 and (Z)-coscinamides A 166 and B 167 and their analogues 230 and 231 is also presented.