Resorcylic acid lactones as new lead structures for kinase inhibition

The naturally occurring resorcylic acid lactones LL-Z1640-2 ( 1 ), hypothemycin ( 2 ), L-783277 ( 3 ), radicicol A ( 4 ) and, to a somewhat lesser extent, aigialomycin D ( 5 ) have recently emerged as new lead structures for kinase inhibition. Total syntheses have now been reported for all of these natural products, most of which are based on macrocyclization through ester bond formation. However, RCM-based approaches have also been described and a variety of strategies have been pursued to obtain the requisite seco acids or dienes, respectively, as precursors for macrocyclization.