Toward the Synthesis of the Fungal Metabolite (-)-TAN-2483B

In the search of chemical species with potential therapeutic biological activity, synthetic chemists have looked to nature for inspiration. Molecules built by biological machinery often have structures predisposed for biological interaction.  (-)-TAN-2483B and the related compounds (-)-TAN-2483A, and waol A are fungal metabolites that display biological activity in kinase inhibition and parathyroid-induced bone resorption. Though total syntheses of (-)-TAN-2483A and waol A have been achieved, the established methodology does not afford access to (-)-TAN-2483B owing to the unique relative configuration about the ring system.  Derivatives of D-galactal have been synthesised, and functionalised at the C-1 and C-2 positions, laying the groundwork for a route to (-)-TAN-2483B and analogues. Using D-galactal derivatives is advantageous as it circumvents some difficult transformations in the existing method for analogue synthesis.  The functionalities installed were halide and formyl groups at the C-2 position, and acetylenes at the C-1 position. The synthesis of 2-haloglycals from tri-O-acetyl-D-galactal using N-halosuccinimides was achieved in 32% and <37% for the bromo- and iodo- variants respectively. Vilsmeier-Haack formylation was explored using per-benzylated and per-acetylated galactals as substrates. Formylation of the per-benzylated species was achieved in 78% yield in accordance with literature values. Vilsmeier-Haack formylation on the per-acetylated galactal has not been reported and the glycal was found to be a poor substrate for the formylation. Theories regarding the incompatibility of the per-acetylated species with Vilsmeier-Haack conditions were developed.  Ferrier-type alkynylation of the 2-halo/formylglycals was explored, with yields up to 17% and 13% for the bromo- and iodo- species (unoptimised), and 7% for 2-formylglycal (after optimisation studies). The resulting 1-ethynyl-2-formyl/halo-2,3-unsaturated pyrans could be potential intermediates en route to the furanone ring of the target compound.