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“High” temperature asymmetric lithiation of N-Boc heterocycles: synthesis of tetra-substituted pyrrolidines

Gelardi, Giacomo (2014) “High” temperature asymmetric lithiation of N-Boc heterocycles: synthesis of tetra-substituted pyrrolidines. PhD thesis, University of York.

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This thesis describes the study of new methodologies for the asymmetric synthesis of N-Boc heterocycles using lithiation chemistry, with the main focus on N-Boc pyrrolidine. The “high” temperature asymmetric lithiation-trapping of five-membered heterocycles N-Boc pyrrolidine and N-Boc imidazolidine and six-membered heterocycles N-Boc piperidine and N-Boc piperazine is described in Chapter Two. It was found that lithiated N-Boc pyrrolidine is configurationally stable for 1 hour at 40 °C and 30 °C giving high ers (90:10 er). With N-Boc imidazolidine, yields above 50% can be achieved using THF as solvent and are supported by VT 1H NMR spectroscopy studies as well as ReactIR™ spectroscopy studies. In Chapter Three, attempts towards the elucidation of the instability of α-amino sulfoxides are described. The synthetic strategies planned to clarify the possible mechanism causing the elimination of the sulfoxide group were unsuccessful and ultimately, we were unable to understand which process was at the basis of the elimination. As part of these studies, the development of the asymmetric lithiation-trapping of 4-phenyl N-Boc pyrrolidine is also described. Chapter Four describes the development of the asymmetric synthesis of α,α' tri- and tetra-substituted pyrrolidines. The use of ReactIR™ spectroscopy experiments was fundamental for the studies into the interconversion of N-Boc rotamers and to achieve good yields of the trapped products. An interesting match/mismatch mechanism for the formation of tri-substituted pyrrolidines is shown, which can give ers of >99:1 er. Finally, the synthesis of several new tetra-substituted pyrrolidines in 70:30-91:9 dr is presented.

Item Type: Thesis (PhD)
Academic Units: The University of York > Chemistry (York)
Identification Number/EthosID: uk.bl.ethos.605472
Depositing User: Mr Giacomo Gelardi
Date Deposited: 09 Jun 2014 12:59
Last Modified: 08 Sep 2016 13:30
URI: http://etheses.whiterose.ac.uk/id/eprint/6163

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