Quaternary centres bearing a nitrogen atom are found in natural products and therapeutic agents but they represent a remarkably challenging synthetic motif to access when stereochemical control is required. This thesis details investigations into the development of an innovative approach that - by combining biocatalysis with organolithium chemistry - allows the synthesis of enantioenriched α-tertiary amines. The strategy relies on the initial enzymatic asymmetric synthesis of amines. Two complementary pathways were identified: deracemisation with amine oxidases or enantioselective reduction with imine reductases. The enantioenriched amines were converted to the corresponding N-benzyl-N'-aryl ureas and subsequent organolithium-mediated stereospecific aryl migration developed in the Clayden group were carried out to obtain α-tertiary amines. Various scaffold were investigated: 1,1-disubstituted 1,2,3,4-tetrahydroisoquinoline, 2,2-disubstituted azepane and 1,1-disubstituted 2,3,4,5-tetrahydro-1H-benzo[c]azepine derivatives were successfully synthesised. The methodology was extended to acyclic systems, giving 3-pyridyl-derived α-tertiary amines.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:764521 |
| Date | January 2017 |
| Creators | Zawodny, Wojciech |
| Contributors | Turner, Nicholas |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/asymmetric-synthesis-of-itertiary-amines-by-combination-of-biocatalysis-and-organolithiummediated-rearrangements-of-ureas(395c9e72-0b5f-4441-9ef0-ae8447c8d80c).html |
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