Synthetic Studies Towards Saccharnan A and B

Abstract

Lignans are a family of natural products that have been isolated from a wide range of plants. This particular group of compounds has attracted a significant amount of attention in the field of drug development, since many members of this family have been found to possess desirable bioactivities, particularly against cancers, viruses and inflammation. Two currently commercialised medicines which are used for chemotherapy treatment, Etopophos and Vumon, have been derived from the classic lignan podophyllotoxin. The common structural feature to lignans is a phenylpropanoid dimer. At present, only the reported natural products saccharnan A and B, megacerotonic acid and shimobashiric acid A, which fall into the neoliganan classification, contain the structural backbone consisting of α-benzylidene-γ-butyrolactone with a C-3-aryl group. The bioactivities of these particular lignans have not been thoroughly investigated. While lignans megacerotonic acid and shimobashiric acid A have been previously synthesised, numerous limitations in their synthetic approach meant bioactivity testing could not be undertaken on these compounds nor on their analogues. A model synthetic route to prepare this unique group of neolignans, and analogues thereof, for bioactivity testing was devised and a study towards the model compound 1.20 was attempted. This route included an acyl-Claisen rearrangement to afford a precursor suitable for subsequent lactone formation. However, this approach meant that the desired benzylidene functionality could not be successfully installed in either the final or the penultimate synthetic step. Subsequently, a new synthetic route employing a Johnson–Claisen rearrangement and an aldol reaction was developed. Following the optimisation of these reactions over a wide range of conditions an analogue of natural compounds saccharnan A and B was successfully synthesised in an overall yield of 22% over 5 steps. Following the success of the model compound synthesis, the syntheses of the true targets, natural products saccharnan A and B, were pursued. Unfortunately, the desired compounds were unable to be obtained due to the instability of the phenol protecting group during installation of the benzylidene functionality.