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Title: Development of new classes of aza-Heck cyclisation for the synthesis of nitrogen heterocycles
Author: Hazelden, Ian
ISNI:       0000 0004 7651 9765
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2019
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Two 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 b-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.
Supervisor: Bower, John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available