The Asymmetric Synthesis of 1,4-Benzodioxane Lignan Natural Products

Abstract

Lignans are a large class of natural products defined as the products of an oxidative dimerisation of two or more phenylpropanoid units. 1,4-Benzodioxane neolignans are a significant subtype of lignan natural products that showcase a range of biological activities. Previous syntheses of 1,4-benzodioxane lignans are predominantly racemic and do not easily allow for the main points of variation between related and analogous products. This thesis focuses on the development of a flexible asymmetric synthesis of 1,4-benzodioxane compounds and its subsequent application to natural product synthesis. Initially, a model study was undertaken to investigate the key steps required in this synthesis. Following the model study, the developed synthesis was then applied to the first asymmetric synthesis of the rodgersinine family, successfully yielding all rodgersinine natural products 21, 83, 84 and 87 and their enantiomers. Through chiroptical analysis, it was found that the original assignment of 83 and 87 was incorrect, and the ECD comparison of 1,4-benzodioxane natural products and model compounds is not reliable. Members of the eusiderin family, eusiderins A (19), B (243), C (194), G (37), L (260) and M (245) and analogues were synthesised in a highly divergent manner from chiral aldehyde 259. An ECD study also confirmed the absolute stereochemistry of 19 and 194 from different natural sources, and provided a reference for stereochemical assignment of future eusiderins. The adaptation of the synthesis to 2-hydroxymethyl-1,4-benzodioxane neolignans was shown with the successful synthesis of (-)-isoamericanin A (24) and (+)-isoamericanol A (20). Further application of this synthesis to complex trilignan magnolianin 278 was unsuccessful following the failure to synthesise ether 351 because of steric restrictions. The formal asymmetric synthesis of silybin B (358) and isosilandrin B (364); 1,4-benzodioxane flavonolignans well-regarded for their potent activities, was achieved, demonstrating the applicability of the developed synthesis to this notable group of compounds. Subsequent testing by Eli Lilly and a leading anti-HCV expert, of selected synthesised 1,4-benzodioxane compounds identified them to exhibit activities with applications in areas of cancer and neurological treatments, as well as hepaprotective properties that are currently undergoing further exploration.