Research in the group ranges across the total synthesis of biologically active natural products and structural analogues to the discovery and development of new synthetic methods.
Stereocontrolled Synthesis of Bioactive Natural Products and Structural Analogues. Current targets include rare anticancer agents of marine origin such as 1-4 below. For example, dictyostatin (1) has a promising antitumour profile and shares the same microtubule-stabilising mechanism as the clinically important drug Taxol, while spirastrellolide A (2) is a potent inhibitor of protein phosphatase 2A. Likewise, peloruside A (3) and reidispongiolide A (4) are novel antimitotic macrolides of marine origin, which also represent challenging synthetic targets. The initial uncertainty over the stereochemistry, combined with the lack of material from the natural source, has adversely affected their preclinical development. Efficient and flexible synthetic routes for the construction of these polyoxygenated structures are being developed to establish their full configurations and provide material for biological evaluation. A parallel objective is to design simplified analogues that retain the exceptional cancer cell growth inhibitory properties whilst increasing their synthetic accessibility.
New Synthetic Methods. There is a need for new and more efficient methods of synthesis, particularly ones that achieve high levels of stereocontrol, where the development of asymmetric aldol methodology is of particular interest. These new methods are being applied to the synthesis of a wide variety of important natural products.
Selected Publications
Synthetic studies towards spirastrellolide A. Angew. Chem. Int. Ed. 2008, 47, 3016 and 3021
Total synthesis of reidispongiolide A and tail analogues as actin-targeted drugs. Chem. Biol. 2008, 15, 287; Angew. Chem. Int. Ed. 2007, 46, 6167; Proc. Natl. Acad. Sci. USA 2004, 101, 11986
Synthetic studies towards spirangien A. Angew. Chem. Int. Ed. 2007, 46, 6699
Total synthesis of dictyostatin and analogues, and hybrids with discodermolide. Chem. Commun. 2008, in press, and 2007, 49; Bioorg. Med. Chem. Lett. 2007, 17, 2443; Angew. Chem. Int. Ed. 2004, 43, 4629
Total synthesis of spongistatin and analogues. Org. Biomol. Chem. 2005, 3, 2399, 2410, 2420, and 2431