Synthetic Studies of Dibenzylbutyrolactone and Aryltetralin Lignans: Bioactive Natural Products and their Derivatives

Abstract

Lignans are a class of natural products that are defined by the linkage of two phenylpropane moieties through their C-8 carbons. Dibenzylbutyrolactone lignans are a structurally diverse subclass which have shown extensive biological activities. This thesis focuses primarily on the synthesis of synthetically challenging dibenzylbutyrolactone lignans and application of the developed methodology to aryltetralin lignans. Arctigenin 15ce is a well-known bioactive dibenzylbutyrolactone lignan which has received very limited investigation around modifications on the C-9' position of the core lactone ring. This provided the rationale to develop arctigenin derivatives (8R*, 8'R*,9'R*)-31ce, (8R*,8'R*,9'S*)-31ce, 76–81, 83–86, 89, 90 from analogues (8R*,8'R*,9'R*)-31cd and (8R*,8'R*,9'S*)-31cd with C-9' methylenehydroxyl substitution. The established synthetic pathway, utilising a key acyl-Claisen rearrangement, completed the synthesis of sixteen derivatives by modifying the C-9' methylenehydroxy group with novel esters or nitrogen-containing functionalities. In addition, deprotected-phenol analogues and a few examples of these compounds with epimeric trans,cis (8R*,8'R*,9'R*) stereochemistry were also completed. An asymmetric approach to C-7 ketone functionalised dibenzylbutyrolactone lignans was also established to complete the first total synthesis of natural products (+)-conicaol B 150, (+)-7-oxoarcitin 149 and (+)-7-oxohinokinin 151, along with five analogues 152bc, 152be, 152bg, 152cb, 152cg with common lignan aryl substitution patterns, as potential undiscovered natural products. The route towards dibenzylbutyrolactone lignans with 7'-hydroxy,7-ketone substitution was modelled off this pathway, with early modifications aimed towards the lignan (‒)-sanguinolignan A. The asymmetric total synthesis of epi-7'-OH-sanguinolignan A 207 was successfully completed as a result. In a separate pathway, use of a Diels-Alder rearrangement was explored in attempts to access a unique aryl tetralin framework in the natural product stelleralignan 127. Whilst this approach to an aryltetralin framework was unsuccessful, the synthetic route towards 7-oxodibenzylbutyrolactone lignans was adapted to access aryltetralin lignans, through a one-step modification, to afford natural product (‒)-isopolygamain 163 and its diol derivative 164. Subsequent anti-proliferative testing of all synthesised lignans against cell lines HCT-116 and MDA-MB-231 revealed cell growth inhibition, with the most potent activity demonstrated by (‒)-isopolygamain 163.