Synthesis of biologically active lignan natural products via an Claisen rearrangement and an unusual 1.4 diaryl rearrangement

Biologically active natural products have been of increasing interest to chemists due to the growing demand for new medicines. Lignans are a family of secondary plant metabolites known to exhibit both interesting biological activities and immense structural variety. This thesis describes the synthesis of a number of lignan and neolignane natural products and analogues thereof, with the overall aim of synthesizing the complex dineolignane manassantin B 29. The interest in 29 originates from its potent inhibition of the transcription factor HIF-1, which is a potential target for a new class of selective anticancer drugs targeting the hypoxic region common in solid tumours. Initially, a series of 2,5-diaryl-3,4-dimethyl tetrahydrofuran lignans were synthesized via the strategy proposed for the synthesis of the more complex 29. During the course f this work, it was found that varying the substrates in the final cyclisation step could significantly influence the products formed. This serendipitous discovery led to extensive investigation into the mechanisms controlling the reaction and the different compounds synthesized. With this knowledge three different subclasses of lignan were successfully synthesized, with the relative and absolute stereochemistry of a number of the natural compounds determined for the first time. With the test synthesis proving successful the synthesis of 29 was undertaken via the envisaged convergent strategy, the three fragments syn-dimethyl compound 58 and two similar diaryl bromides 59 and 60 were synthesized enantioselectivity and in pleasing yields. Unfortunately the fragments could not be joined using the established aryl lithium addition methodology which had proved very successful on the test substrates. Despite several modifications to the syn-dimethyl compound and adjusted strategies, the synthesis of manassantin B 29 remains elusive. The diaryl bromides 59 and 60 were however successfully employed in the synthesis of a series of 8,4'-oxyneolignans using a Suzuki Miyaura strategy. Selected synthetic natural products and analogues were sent to NCI for testing against a panel of the sixty common cancer cell lines. Whilst a further series of natural and analogous 8,4'-oxyneolignans were sent to the Swiss Tropical and Public Health Institute for evaluation against both leishmania and malaria.