Towards the Total Synthesis of the Polyketide Natural Product DEM30355/A and Associated Crystallisation Studies

Abstract

Due to the continuing rise in drug resistant pathogenic bacteria, there is an urgent need for new Mode of Action antibiotics. We have identified the polyketide natural product DEM30355/A as a potential new Mode of Action antibiotic versus Methicillin-resistant Staphylococcus aureus. This project aims to develop a synthetic route to DEM30355/A and its synthetic analogues to support new antibiotic development. We have shown that the ABC anthracene-like core of DEM30355/A can be constructed by employing a key tandem, Michael-Dieckmann reaction. The functionalised C-ring was synthesised via a stereoselective Michael-Wittig reaction introducing the desired C-4a/C-10a C=C double bond, C-2 methyl and C-3 ethyl ester, followed by a stereoselective Rubottom oxidation to introduce the required hydroxyl group at C-3. A Michael-Dieckmann reaction between the A-ring and C-ring precursors allowed access to the ABC fused ring carbon skeleton of our target DEM30355/A, with a significant number of the required functional groups in place. Future work will focus on lactone ring formation, oxidation of the C-ring and installation of the B-ring C=C double bond between C-10/C-10a (Scheme 1.00). Scheme 1.00: Synthesis of the ABC fused ring core of DEM30355/A via a key Michael-Dieckmann cyclisation. Our synthetic work was supported by crystallographic studies including an investigation into the propensity of shikimate esters to form high Z’ structures and the crystallisation of biologically active small molecules. Our results serve to further confirm the tandem Michael-Dieckmann reaction as a robust method of coupling functionalised aromatic rings for the construction of natural product scaffolds.