Rhodium-catalysed allylic substitution with an acyl anion equivalent: asymmetric construction of acyclic quaternary carbon stereogenic centres

Oliver, Samuel
Rhodium-catalysed allylic substitution with an acyl anion equivalent: asymmetric construction of acyclic quaternary carbon stereogenic centres. PhD thesis, University of Liverpool.

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The asymmetric construction of substituted carbonyl compounds, particularly those containing α-quaternary carbon stereogenic centres, remains a significant area of interest in organic chemistry. This can largely be attributed to the ubiquity and versatility of these compounds as synthetic intermediates, and the presence of such motifs in a range of biologically active pharmaceutical agents and natural products. In this context, the transition metal-catalysed allylic substitution provides an extremely powerful tool for the asymmetric construction of a range of C-C, C-N and C-O bonds, and has found significant application in the synthesis of substituted carbonyl compounds. The overall utility of these methods is described in the introductory review, which seeks to compare and contrast two alternative bond forming strategies for the asymmetric construction of these units via allylic substitution. While this work is generally dominated by the asymmetric allylic alkylation of unstabilised enolates, these reactions are often limited by the numerous challenges associated with the regio- and stereoselective formation of an enolate nucleophile, product racemisation and polyalkylation, and their relatively narrow substrate scope. In contrast, the transition metal-catalysed allylic substitution with an acyl anion equivalent has the potential to provide a range of α-substituted carbonyl compounds via a fundamentally different bond forming event, in which the acyl functionality is installed directly into the allylic framework. Despite the numerous potential advantages that are afforded by this approach, a general method for the regio- and stereoselective transition-metal catalysed allylic acylation of substituted electrophiles has yet to be reported. Chapter 2 describes the development of a novel regio- and stereospecific rhodium-catalysed allylic substitution reaction, which utilises a trialkylsilyl-protected cyanohydrin as a convenient acyl anion equivalent. Following a brief introduction to the rhodium-catalysed allylic substitution reaction, this chapter is organised into three distinct sections. The first of these outlines the identification of a suitable nucleophile, and the subsequent development of reaction conditions for the regioselective alkylation of tertiary allylic carbonates with a range of stabilised aryl cyanohydrins. The stereospecific variant of this transformation, which involves the direct conversion of an enantiomerically enriched acyclic tertiary allylic alcohol to the corresponding α-quaternary substituted aryl ketone, is then described. Finally, the expansion of this methodology to the preparation of more synthetically useful α,β-unsaturated ketones, and preliminary investigations towards the application of secondary allylic carbonates, are outlined. Overall, this method provides a fundamentally novel bond construction towards the synthesis of α-quaternary substituted carbonyl compounds, and circumvents many of the problems associated with conventional enolate alkylation reactions. Thus, we anticipate that the methodology outlined herein will find significant application in target directed synthesis, particularly in the preparation of complex bioactive pharmaceuticals and natural products that contain quaternary carbon stereogenic centres.

Item Type: Thesis (PhD)
Additional Information: Date: 2012-08 (completed)
Subjects: ?? Q1 ??
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Divisions: Faculty of Science and Engineering > School of Physical Sciences
Depositing User: Symplectic Admin
Date Deposited: 21 Jan 2013 10:11
Last Modified: 16 Dec 2022 04:37
DOI: 10.17638/00008433
URI: https://livrepository.liverpool.ac.uk/id/eprint/8433