Skeletal reorganisation has emerged in recent years as an approach enabling precise multi-bond modification of small molecule substrates. These processes enable efficient access to challenging architectures for natural product and drug target synthesis, or rapid diversification of parent scaffolds for pharmaceutical applications. While recent efforts pay homage to classical ring-contraction reactions, or focus on heteroarene construction, reconceptualisation as skeletal editing has also led to significant new advances in the efficient construction of complex sp3 carbon frameworks.
In recent years our group has uncovered a manifold of skeletal reorganisation reactions based on azide-enolate (3+2) cycloaddition-rearrangement processes. A diverse range of product structures are accessible in a single step, depending on the choice of parent carbonyl compound and the azide cycloaddition partner. The lithium, sodium or potassium enolates of aldehydes, esters, lactones, amides and ketones have all been demonstrated to undergo facile (3+2) cycloaddition with aryl or vinyl azides, with conserved azide addition regiochemistry across all substrate classes. The initial hydroxy triazoline cycloadducts undergo formal extrusion of nitrogen and rearrangement, in a substrate-dependent manner, to afford a highly diverse range of product species. Computational studies of the underlying mechanisms have revealed unexpected aspects of these transformations, including the stereochemical outcome, the specific role of coordinated metal counterions and the importance of protonation for key intermediates.