Dictyosphaeric Acids, Colletofragarones and Novel Drug Discovery Scaffolds: Doubly Tethered Intramolecular-Michael Approach

Dictyosphaeric acid A, a recently-discovered natural product, has been shown to inhibit methicillin-sensitive Staphylococcus aureus and MRSA. The closely related colletofragarones are also biologically active (germination self-inhibitors). The unique tricyclic core present in both families of natural products appears to represent a privileged template for SAR studies. Efficient new methodology, based particularly around the novel doubly tethered intramolecular Michael approach , but also utilising alkene metathesis and Stille coupling, has been designed to provide rapid access to key tricyclic core of these compounds. This methodology will be optimised and employed to prepare key templates which will be elaborated to give a range of novel, simplified analogues for SAR studies. The same methodology will also used as the cornerstone of total syntheses of dictyosphaeric acid A and dictyosphaeric acid B. Similarly, the methodology will then be applied to prepare the colletofragarones A1 and A2 (and so enable the stereochemistry of these natural products to be confirmed).