Conformational and reactivity studies of lactam esters for their suitability for transannular Dieckmann-type cyclisation towards the azabicyclooctane-scaffold

Weck, Christian (2019) Conformational and reactivity studies of lactam esters for their suitability for transannular Dieckmann-type cyclisation towards the azabicyclooctane-scaffold. PhD thesis, University of Lincoln.

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Conformational and reactivity studies of lactam esters for their suitability for transannular Dieckmann-type cyclisation towards the azabicyclooctane-scaffold
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Item Type:Thesis (PhD)
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Abstract

The following thesis describes a novel Dieckmann-type cyclisation of strategically modified, simple caprolactams to the medicinally interesting 7,8-dioxo-6-azabicyclo[3.2.1]octane scaffold. This scaffold is structurally related to the 1,6-diazabicyclo[3.2.1]octane, the core motif of the β-lactamase inhibitor Avibactam. The presented thesis will outline the considerations and evaluation of crucial concepts of caprolactams, their general chemistry and mechanistic studies of importance to this novel approach towards the bicyclic scaffold. The initial discovery and first attempts at optimisation are presented, which led to a study into the physicochemical behaviour of lactams. During the investigations, it was found that the scarce fundamental research on this long-known group of compounds could not provide enough insight to deliver a comprehensive understanding of the involved mechanism. For that reason, we were additionally interested in the solid-state behaviour of lactams, which led to the first ever published single-crystal structure of free δ-valerolactam without secondary components. This allowed for previously conducted theoretical experiments on the amide bond situation of δ-valerolactam to be disproven and also allowed for the abnormally fast hydrolysis of δ-valerolactam to be explained through empirical evidence. The conclusions drawn from the comparative studies on the homologous series of lactam led to a broader study on the conformational behaviour, leading hydrogen-bonding motifs, general packing in the solid-state and the effects of substitution on the amide bond of selected lactams of various ring sizes. The results from this first ever comprehensive investigation on selected caprolactam esters led to the development of a convenient, one-pot synthesis of the 7,8-dioxo-6-azabicyclo[3.2.1]octane core structure from a simple caprolactam in good yields, with the potential for the preparation of a wide variety of derivatives. This Dieckmann-type cyclisation reaction is discussed in terms of its mechanism and its possibilities for further modifications. Further synthetic effort towards the introduction of specific functional groups for the establishment of water solubility and bioactivity are presented. Parts of the here presented thesis have already been successfully published in influential peer-reviewed journals and it is expected that further such publications will follow.

Divisions:College of Science > School of Pharmacy
ID Code:46820
Deposited On:04 Oct 2021 14:12

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