SOXCITS · New and Environmentally Friendly Methods for Making Compounds with Medicinal Importance: Novel Singlet Oxygen Chemistry Combined with Cascade Reactions for the Synthesis of Bioactive Natural Product

Final Activity Report Summary - SOXCITS (New and Environmentally Friendly Methods (...)

The main theme of this project research was to develop and use new singlet oxygen-based methodologies to synthesise bioactive natural products in a highly efficient and environmentally friendly manner. Singlet oxygen is a very reactive oxygen species that is particularly well-suited to participating in cascade reaction sequences. Cascade reaction sequences are sought after transformations because they can create multiple bonds and stereocentres in a single operation, thereby maximising synthetic efficiency and assuring the easy transfer of stereochemical information. Singlet oxygen is also commonly employed in nature to synthesise secondary metabolites; therefore, the strategies we employed could frequently count as being biomimetically inspired. The natural products that were originally targeted included the prunolides (cytotoxic natural products isolated from an Australian colonial ascidian), premnalane A (an antibacterial natural product isolated from an Ethiopian shrub) and members of the stolonoxide family (cytotoxic natural products isolated from colonial ascidians harvested from various sites). The intact core of the prunolide molecules was successfully made in just four steps starting from furan using a remarkable singlet oxygen-mediated reaction cascade sequence. Attempts to synthesise the fully-functionalised molecule were ongoing at the time of the project completion. The core prunolide structure was submitted for biological testing. Model studies were used to investigate the strategy we had proposed for the synthesis of the stolonoxide family of natural products. These studies proved that, unfortunately, although in some analogues the proposed strategy worked well, certain features of the stolonoxide precursor prevented the smooth progression of the desired cascade reaction sequence. We successfully synthesised (+)-premnalane A using an elegant and unique singlet oxygen-mediated cascade reaction sequence, firstly employing a [4+2]-cycloaddition between singlet oxygen and a furan, followed by a singlet oxygen ene reaction. In doing so we uncovered many details about how singlet oxygen operated in this particular environment and about how the cascade sequence outcome could be altered by simple changes to the reaction conditions that were employed. Specifically, higher temperatures and non-polar solvents favoured the formation of the 6.5-peroxy-spiro-lactone over the corresponding 5.5-peroxy-spiro-lactone. Furthermore, we also noted the first example of an ene reaction of this type furnishing a Z-double bond. An additional success story emanating from this project was our biomimetic syntheses of litseaverticillols A-G, I and J and the structural reassignment of litseaverticillol E. The syntheses used several different modes of singlet oxygen reaction with the highlight being a one-pot cascade reaction sequence that involved five separate operations to form the fully functionalised litseaverticillol core from a simple furan precursor. Biological testing of these anti-HIV natural products was undertaken in the laboratories of our international collaborator, Prof. H. Fong (University of Chicago, USA). Our successes led to a further expansion of the project. We developed new singlet oxygen based strategies to synthesise core skeletal motifs from a broad range of bis-spiroketal natural products (such as salinomycin, pinnatoxin, pteriatoxin). We already obtained proof of principle for this concept by synthesising various bis-spiroketal units from simple furan precursors using a complex singlet oxygen cascade. Work was then in progress to apply these strategies to fully-functionalised precursors so that the natural products themselves could be readily targeted.

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