Abstract:
Citreoviranol (1) was isolated from the fungus Penicillium citreoviride in 1988 by Yamamura and co-workers. Citreoviranol (1) contains a rare 6,6-spiroketal lactone and is structurally related to the biologically active resorcyclic lactone family of natural products. The interesting molecular architecture and potential therapeutic value of citreoviranol (1) inspired the development of a synthetic approach to this natural product. This thesis describes the first total synthesis of citreoviranol (1). Although there are numerous methods to prepare the spiroketal ring system, gold catalysis has proven to be a mild and efficient method for the synthesis of a variety of heterocycles, motivating us to apply this methodology to the construction of the spiroketal lactone core of citreoviranol (1). The synthesis of citreoviranol was completed in 12 steps from readily available starting materials and features a Sonogashira cross-coupling, gold-catalysed cyclisation, and an unprecedented base-induced ketalisation. The structure and absolute configuration of citreoviranol (1) were confirmed by comprehensive NMR spectroscopy and X-ray crystallography.A major drawback in the total synthesis of citreoviranol (1) was epimerisation of the C4ʹ alcohol during the base-induced ketalisation. To address this issue a second generation synthesis was developed, which focussed on employing a gold-catalysed spiroketalisation of dihydroxyalkyne 197 in order to avoid the formation of a highly stable isocoumarin. However, regiochemical issues were encountered during the cyclisation of alkyne 197, affording a mixture of 5,7- and 6,6- spiroketal products. The third generation synthesis focused on the preparation and cyclisation of dihydroxyalkyne 220. It was envisaged that the propargylic ether of alkyne 220 would direct gold-catalysed spiroketalisation to the desired 6,6-spiroketal ring system. However, cyclisation of 220 also lacked regiocontrol. Although the gold-catalysed spiroketalisation strategy ultimately proved fruitless, the work described herein provides new insights into the intricacies of this valuable synthetic methodology and represents the first total synthesis of citreoviranol (1).