Thesis-1997-Lewis.pdf (5.08 MB)
Stereoselective synthesis using aminyl radicals derived from [alpha]-amino acids
thesisposted on 2018-05-15, 11:11 authored by Kirk A. Lewis
Chapter 1 is the introduction to the thesis. It contains an overview of amino acids and aminyl radicals. The amino acids section includes material on their synthesis through traditional methods and asymmetric syntheses, as well as the use of radical reactions in their formation. The aminyl radical section gives a description of the nature of the radical and then proceeds with general techniques for aminyl radical formation. A more detailed account of our own group's use of sulfenamides and imines in aminyl radical formation is ·covered and the chapter is ended with a look at the work of aminyl radicals in amino acid synthesis and my subsequent intentions in this area. The preparation and cyclisation of sulfenamide precursors derived from [alpha]-amino acids is discussed in chapter 2. Both the cyclisations of aminyl and urethanyl (introduction of benzyloxycarbonyl and tosyl protecting groups onto amine) radicals onto suitably placed alkenyl substituents were investigated. 5-Exo-trig cyclisation reactions successfully afforded the cyclic products in moderate yield with reasonable diastereoselectivity. The effects of the [alpha]-CO2R (where R = Me or tBu), the size of the amino acid side chain and placement of alkenyl substituent (N-substituted or sidechain containing alkene) are discussed. The use of imines as aminyl radical precursors is explored in chapter 3. [Alpha]-amino acids and aldehydes were condensed and the cyclisation products isolated. The formation of aminyl radicals by 5-exo-trig cyclisation and subsequent H-atom abstraction gave moderate to good yields of N-cyclopentyl substituted a-amino acids. Preparation of the aldehydes is discussed. Tandem cyclisations involving aspects of chapters 2 and 3 are looked at in chapter 4. The preparation of the unnatural a-amino acids required for tandem cyclisation and subsequent formation of the sulfenamide or imine is reported. 5-Exo, 6-exo cyclisation of the sulfenamide derivative gave the tandem product in low yield and with moderate diastereoselectivity. This was in contrast to the imine derived reaction which proved unsuccessful. The remaining chapters incorporate the detailing of experimental relevant to the discussion and the presentation of references quoted throughout the thesis.
Roche Holding AG, Roche Discovery (Welwyn Garden City).
Publisher© Kirk Lewis
Publisher statementThis work is made available according to the conditions of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. Full details of this licence are available at: https://creativecommons.org/licenses/by-nc-nd/4.0/
NotesA Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy at Loughborough University.