Medium Ring Heterocycles by Directed C-C Bond Activation

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Our group develops new catalysis platforms that allow the rapid generation of pharmaceuticallyvaluable heterocyclic scaffolds. We have reported a range of (3+1+2) cycloadditions involvingamino-substituted cyclopropanes, where carbonyl directing groups facilitate oxidative insertion ofrhodium and CO to provide rhodacyclopentanone intermediates. These can be trapped by tetheredalkynes or alkenes to deliver the targets. Recently, we have extended this catalysis platform toprovide medium ring systems. Here, carbonyl directed insertion of Rh/CO is followed by alkeneinsertion and fragmentation to the targets. Note that aminocycloprapanes are readily available byCurtius rearrangement of the corresponding cyclopropane carboxylic acid, which in turn can beaccessed directly using a number of established methodologies. Methodologies that provide mediumring heterocycles allow access to unexplored regions of structural space and are therefore highlyvalued by medicinal chemists. In this project we will (a) expand our approach to provide new,distinct medium ring methodologies (Part 1) and (b) apply the chemistry in to a total synthesis of astructurally challenging natural product (Part 2).