Developing Methodology for the Synthesis of Nitrogen Based Analogues of Bioactive Natural Products

Abstract

This thesis describes the development of synthetic methodology for the preparation of novel nitrogen-containing analogues of bioactive natural products, in particular lignan natural products. Tetrasubstituted 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans exhibit numerous useful biological effects. Chapter two focuses on the development of pyrrolidine analogues of these substituted tetrahydrofuran lignans. Introduction of the amine functionality allows for several variations in the aza-lignan structure, including the substitution on the incorporated aromatic rings and amine. This resulted in the synthesis of aza-analogues of fragransin A2 2.15 and galbelgin 2.14. 1,4-Benzodioxane neolignans are another subtype of lignan that show remarkable biological effects. In particular, 1,4-benzodioxane lignans with a 9-hydroxymethyl group such as silybin A 3.6 have shown inhibitory activity against hepatotoxicants. Many naturally occurring 1,4-benzodioxane lignans are known to have poor aqueous solubility which limits their therapeutic application. 3-Aryl-benzomorpholines were prepared to potentially reduce these solubility problems found in 1,4-benzodioxanes. Aryl addition to benzomorpholine aminols via an N-acyl iminium intermediate was promoted under Brønsted acid conditions to generate a variety of 3-aryl-benzomorpholines as single diastereomers. Application of similar aryl addition chemistry to oxonium ions in the synthesis of nitidanin 3.5, a 1,4-benzodioxane neolignan, was found to be unsuccessful, with the correctly substituted aryl donor found to be unsuitable for this method. However, the discovery of the synthesis of benzofuran 4.124 during this work may allow for the synthesis of natural products such as magnolignan H 4.129. Finally, a series of pyrrole analogues of combretastatin (CA-4) were synthesised using a modification of the chemistry developed for aza-lignans and tested for their anti-proliferative activity against two human cell lines, K562 and MDA-MB-231 with 2,3-diaryl-1H-pyrrole 5.90 exhibiting the most potent activity with IC50 value of 0.07 μM against MDA-MB-231 cell line.