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Synthesis and pharmacology of monosubstituted 8-oxatropanes and the development of new ligands for the catalytic asymmetric hydrogenation of ketones

posted on 24.01.2017, 00:53 by Walker, Ashley John
In Chapter 1, the synthesis of a series of monosubstituted 8-oxatropanes, which consist of an eight-membered oxabicyclic core bearing either a carboxylic acid or a methyl ester, and a study of their biological activity is described. The oxabicyclic structures were prepared via the (4+3)-cycloaddition of tetrabromoacetone with furan or suitably substituted derivatives thereof, and an asymmetric synthesis of the C2-substituted compounds was achieved using a homochiral lithium amide-mediated desymmetrisation of a meso-oxabicyclic ketone intermediate. Whilst the majority of the target compounds were prepared successfully, difficulties in manipulation of the relative stereochemistry precluded the synthesis of the 2β-carboxylic acids. Primary high-throughput screening of the compounds at a range of common cellular receptors led to the identification of three compounds which displayed affinity for the H₂ histamine or M₅ muscarinic receptors, although in more sensitive secondary assays these were found to be false positives. Despite failing to exhibit binding in the primary assays, a number of other compounds were also subjected to secondary examination. Two of these compounds were found to exhibit micromolar affinity for the dopamine transporter or the M4 muscarinic receptor, and may be useful as leads for the development of more potent analogues. Chapter 2 describes the synthesis of a series of β³-amino acid-derived benzazoles and the evaluation of their usefulness as diamine ligands in the ruthenium-catalysed asymmetric hydrogenation of ketones. A series of six benzimidazoles were prepared in three steps from Boc-protected β-alanine, β³-homoalanine, β³-homophenylalanine, β³-homovaline (1R,2R)-2-aminocyclopentane carboxylic acid or (1R,2R)-2-aminocyclohexane carboxylic acid and o-phenylenediamine; starting from o-aminophenol, an analogous series of benzoxazoles was also prepared. Methods were developed for the preparation of a number of [RuCl₂(phosphine)(diamine)] complexes, and the catalytic activity of these complexes was then examined. It was shown that complexes bearing the achiral benzimidazole prepared from β-alanine and one of several phosphine ligands were highly effective for the hydrogenation of acetophenone, giving (S)-1-phenylethanol in up to 97.5%e.e.; they were also effective for the hydrogenation of a variety of other ketones, although there were some indications that the scope of the catalysts may have certain limitations. The hydrogenation of acetophenone using complexes bearing the chiral benzimidazole ligands was also examined – these ligands led to improved enantioselectivity when used in combination with DIOP, although no notable improvement was observed when they were used in combination with SegPhos. Complexes containing a benzoxazole ligand failed to display any catalytic activity. Finally, one of the active benzimidazole-containing complexes was applied to the asymmetric synthesis of a key intermediate for the synthesis of the important anti-emetic drug aprepitant, and it was found that the chiral alcohol could be obtained in 95%e.e. – comparable to the best results obtained by the industrially used methods and with significant operational advantages over those processes.


Campus location


Principal supervisor

Patrick Perlmutter

Year of Award


Department, School or Centre



Doctor of Philosophy

Degree Type



Faculty of Science