The natural product (-)-platencin is a potent antibacterial agent that exerts its effects through a novel mode of action. As such, it is an important lead in the development of next-generation antibacterials that are urgently needed because of the rapidly developing resistance to current therapies. The work reported here concerns the development of a convergent and chemoenzymatic total synthesis of (-)-platencin by methods that should provide access to a range of biologically relevant analogues. The key step involves a thermally promoted and facially selective intramolecular Diels-Alder (IMDA) cycloaddition reaction to give an adduct that embodies the tricarbocyclic core of (-)-platencin. This adduct was elaborated over thirteen steps to the natural product. The substrate for the IMDA reaction was prepared by Stille cross-coupling of a Z-configured alkenylstannane with an iodinated diene obtained in an enantiomerically pure form through the whole-cell biotransformation of iodobenzene.

Nucleoside analogues have long been recognized as prospects for the discovery of direct acting antivirals (DAAs) to treat hepatitis C virus because they have generally exhibited crossgenotype activity and a high barrier to resistance. C-Nucleosides have the potential for improved metabolism and pharmacokinetic properties over their N-nucleoside counterparts due to the presence of a strong carbon−carbon glycosidic bond and a non-natural heterocyclic base. Three 2′CMe-C-adenosine analogues and two 2′CMe-guanosine analogues were synthesized and evaluated for their anti-HCV efficacy. The nucleotide triphosphates of four of these analogues were found to inhibit the NS5B polymerase, and adenosine analogue 1 was discovered to have excellent pharmacokinetic properties demonstrating the potential of this drug class.

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The possibility of intramolecular epoxidation in acyclic unsaturated ketones (via dioxiranes) and oxaziridines (via oxaziridinium species) has been investigated. Treatment of several acyclic unsaturated ketones with Oxone ® led to low levels of regio-and stereocontrol, suggesting that background epoxidation by Oxone ® dominates. However, treatment of unsaturated oxaziridines with methyl trifluoromethanesulfonate led to intramolecular epoxidation. This process allowed regioselective epoxidation of a non-conjugated diene. It also proceeded with a high degree of stereocontrol consistent with a stereoelectronic preference for a spiro-transition state.