Medium Ring Heterocycles by Directed C-C Bond Activation

Our group develops new catalysis platforms that allow the rapid generation of pharmaceutically
valuable heterocyclic scaffolds. We have reported a range of (3+1+2) cycloadditions involving
amino-substituted cyclopropanes, where carbonyl directing groups facilitate oxidative insertion of
rhodium and CO to provide rhodacyclopentanone intermediates. These can be trapped by tethered
alkynes or alkenes to deliver the targets. Recently, we have extended this catalysis platform to
provide medium ring systems. Here, carbonyl directed insertion of Rh/CO is followed by alkene
insertion and fragmentation to the targets. Note that aminocycloprapanes are readily available by
Curtius rearrangement of the corresponding cyclopropane carboxylic acid, which in turn can be
accessed directly using a number of established methodologies. Methodologies that provide medium
ring heterocycles allow access to unexplored regions of structural space and are therefore highly
valued 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 a
structurally challenging natural product (Part 2).