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Title: Development of aza-Heck cyclisations and cascades for the synthesis of nitrogen heterocycles
Author: Faulkner, Adele
ISNI:       0000 0004 5923 7141
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Palladium- and copper-catalysed aza-Heck cyclisations of oxime esters with pendant olefins, have been developed for the synthesis of chiral nitrogen heterocycles. Initial studies explored palladium-catalysed cyclisations onto 1,1-disubstituted alkenes to afford α,α-disubstituted dihydropyrroles. A wide range of functional groups are tolerated in this process, showcasing the versatility of this approach. A complementary copper-catalysed aza-Heck has also been developed. Mechanistic studies of these two processes revealed two distinct pathways. Cyclisations employing an electron deficient palladium catalyst proceed via oxidative addition of Pd(O) into the N-O bond of the oxime ester to generate a key imino-Pd(II) intermediate. Migratory insertion of the olefin into the Pd-N bond and subsequent β-hydride elimination delivers α,α-disubstituted dihydropyrroles. Under copper-catalysed conditions, cyclisations proceed via a radical type pathway, involving oxidative initiation at the N-O bonds of oxime esters to generate an iminyl radical or radical-like species. After cyclisation, an alkyl-radical is generated which undergoes oxidative elimination to afford the Nheterocyclic products. An enantioselective palladium-catalysed aza-Heck cyclisation is also described herein. Employment of spirocyclic P,N-based SIPHOX ligands is crucial for efficient cyclisation, which delivered enantioemiched α,α-disubstituted dihydropyrroles in high yield and enantioselectivity. In an alternative strategy for achieving alkene 1,2-carboaminations, cascade aza-Heck cyclisations have been developed. Aza-Heck cyclisation of oxime esters enables access to a versatile alkyl-Pd(II) species, which can be trapped with a variety ofnucleophiles. Olefin 1,2-amino-acylation -carboxylation, -arylation, -vinylation and -alkynylation reactions have been established. An ambitious palladium-catalysed aza-Heck cascade cyclisation has been proposed for the total synthesis of (+)-cylindricine C and studies have examined three key aspects: 1) azaHeck spirocyclisation of oxime esters, 2) asymmetric aza-Heck cyclisations and 3) a carbonylative cascade of oxime esters. Proof-of-concept has been achieved on model substrates and fmiher research is ongoing to realise this challenging total synthesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available