AbstractTwo novel classes of aza-Heck reactions have been developed. These processes generate 2-alkenyl-N-heterocycles through the palladium-catalysed cyclisation of substrates containing an activated N–O bond and a pendant olefin. The first of these, based on the cyclisation of N-acyloxysulfonamides, is only the second reported class of aza-Heck reaction and is effective for the synthesis of complex bicyclic N-heterocycles commonly found in the core structures of natural products. Subsequently, an aza-Heck reaction of N-acyloxycarbamates was developed that provides considerable improvements in terms of efficiency compared to the sulfonamide-based reaction. Through the cyclisation of N-acyloxycarbamates, pyrrolidines and piperidines, as well as related 5- and 6-membered N-heterocycles, can be prepared in good to excellent yields. Furthermore, the diastereoselectivities achieved in these processes are generally much greater than those observed with aza-Heck cyclisations of N-acyloxysulfonamides. A number of mechanistic experiments have validated the aza-Heck pathway proposed for these transformations.
A highly asymmetric variant of the aza-Heck reaction was also developed, based on the cyclisation of N-sulfonyloxycarbamates. Through the use of SPINOL-based phosphoramidite ligands, pyrrolidines and piperidines can be prepared in good yields and with high enantioselectivities from substrates containing a diverse range of alkenes.
Additionally, palladium(0)-catalysed cascade reactions using the previously developed N–O bond donors have been demonstrated. These processes initiate with N–O oxidative addition and aminopalladation of a pendant alkene but terminate with trapping of the resulting organopalladium(II) intermediate, as opposed to -hydride elimination. In collaboration with co-workers, a variety of alkene 1,2-aminofunctionalisation cascades have been achieved using this strategy. The application of these cascade reactions to the total synthesis of natural products has also been attempted.
|Date of Award||23 Jan 2019|
|Supervisor||John Bower (Supervisor)|