Gateway synthesis of daphnane congeners and their protein kinase C affinities and cell-growth activities

The daphnane diterpene orthoesters constitute a structurally fascinating family of natural products that exhibit a remarkable range of potent biological activities. Although partial activity information is available for some natural daphnanes, little information exists for non-natural congeners or on how changes in structure affect mode of action, function, potency or selectivity. A gateway strategy designed to provide general synthetic access to natural and non-natural daphnanes is described and utilized in the synthesis of two novel members of this class. In this study, a commercially available tartrate derivative was elaborated through a key late-stage diversification intermediate into B-ring yuanhuapin analogues to initiate exploration of the structure-function relationships of this class. Protein kinase C was identified as a cellular target for these agents, and their activity against human lung and leukaemia cell lines was evaluated. The natural product and a novel non-natural analogue exhibited significant potency, but the epimeric epoxide was essentially inactive.close151

Synthesis of heterocyclic compounds via gold-catalysed enyne rearrangements

Syntheses of heterocycles using different gold-catalysed rearrangements of enynes are discussed in this chapter. The term skeletal rearrangement has been used in a broad sense to include reactions involving cyclopropyl gold carbene intermediates formed by initial enyne cyclisation, which can undergo many different transformations to give a wide range of heterocyclic structures. Other transformations involving rearrangement of propargylic esters and [3,3]-rearrangement (concerted or stepwise comprising metallic intermediates), as well as special cases, have also been covered. References to earlier work in this area and to recent reviews have been included, but the focus of the chapter is to present recent developments, interesting cases and an overview on how subtle differences in the enyne starting materials, the catalyst used or the reaction conditions can alter the reaction pathway increasing the structural diversity towards complex heterocyclic structures of high value