Stereoselective synthesis of furofurans

Abstract

The 2,6-diaryl-3,7-dioxabicyclo[3,3,0]octanes (or furofurans) belong to the lignan family of natural products. Lignans represent very attractive synthetic targets owing to their large range of biological properties including anticancer, antiviral and immunosuppressant activities. There is considerable structural variation in this series in both the nature and the stereochemistry of the aryl substituents. Since activity is dependent on stereochemistry, synthetic routes, which can provide controlled but tuneable access to one particular class, are very attractive. In this respect, we have been interested in developing efficient ways to synthesise the furofuran skeleton. Based on previous work in our group, the first synthesis of a natural endo-endo furofuran, Epiasarinin, has been achieved via a five step strategy. It included a Darzens condensation followed by a thermal rearrangement of vinyl epoxide to cis dihydrofuran, a Lewis acid promoted cyclisation of a dihydrofuryl alcohol and a reduction of a glycosidic bond. Variations of this methodology afforded the selective the thermal rearrangement has been explored and improvement of this step via different activation methods considered. Another aim of this thesis was to extend this existing method to generate aza analogues. Two strategies have been explored. Generation of furopyrroles can be achieved via the thermal rearrangement of vinyl aziridines or via the acid catalysed cyclisation of dihydrofuryl amines. In conclusion, this short and selective synthetic route leads to a large range of natural or unnatural furofurans and the extension to their aza analogues was also explored.