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Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/3085
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Title: NHCs in organocatalysis : azolium enolate generation and synthetic applications
Authors: Douglas, James J.
Supervisors: Smith, Andrew D.
Keywords: Catalysis
Organocatalysis
N-Heterocyclic carbenes
Ketenes
Issue Date: 30-Nov-2012
Abstract: This thesis details investigations into organocatalytic reactions promoted by N Heterocyclic Carbenes (NHCs) that proceed via an assumed azolium enolate intermediate. Initial research focused on the catalytic asymmetric synthesis of β-lactones via an NHC-catalysed formal [2+2] cycloaddition of alkylarylketenes and chloral. This process operated in good yield (typically >70%) and moderate diastereoselectivity (typically ~75:25 dr, anti:syn) for a range of alkylarylketenes. The enantioselectivity was consistently high for the major anti diastereomer (typically >80% ee) and minor syn diastereomer (typically >70% ee). Interestingly, when a ketene bearing a 2 substituent on the aryl ring, or one that included an α-branched alkyl group was used, an exclusive asymmetric chlorination pathway was accessed. This is, to the best of our knowledge, the first use of chloral as an electrophilic chlorination agent. This methodology was found to be applicable to a range of 2-arylsubstituted alkylarylketenes in good yield and enantioselectivity (typically >70% yield and up to 92% ee). The scope of this reaction with respect to the aldehyde moiety was then analysed with 2-nitrobenzaldehyde providing β-lactone products in excellent dr (up to 94:6 syn:anti) and with good yield and enantioselectivity (typically >60% yield and >80% ee). Importantly these β-lactone products were amenable to further derivatisation with transformation to β-amino- and β-hydroxy acids. Following the identification of an NHC-catalysed chlorination reaction using chloral, the development of a general procedure was undertaken. Following a wide screen of electrophilic chlorination sources, 2,3,4,5,6,6 hexachlorocyclohexa 2,4 dienone was identified as optimal, operating in excellent yield (up to 97%) but in moderate to poor levels of enantioselectivity (21−61% ee). Efforts to expand the practicality of azolium enolate processes focused on the use of α-aroyloxyaldehydes as bench stable mono-substituted ketene surrogates. A range of differentially substituted α-aroyloxyaldehydes allowed access to δ-lactones via the NHC-catalysed [4+2] cycloaddition between azolium enolates and β,γ unsaturated α ketoesters. Following initial optimisation the reaction proceeded in exquisite diastereo- and enantiocontrol (typically >95:5 dr and >99% ee).
URI: http://hdl.handle.net/10023/3085
Type: Thesis
Publisher: University of St Andrews
Appears in Collections:Chemistry Theses



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