Date of Award

2014

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Mauro F.A. Adamo

Second Supervisor

Dr Michele Saviano

Keywords

Chemistry, Pharmaceutical, Drug Discovery.

Abstract

For full abstract, see thesis.

The present work deals primarily with the development of two new reactions in which scaffold 2 was reacted under organocatalytic conditions.N-heterocyclic carbenes and Cinchona-based phase-transfer catalysts were both employed to promote elaboration of 1.

We have shown that 4-nitro-5-styrylisoxazoles 2 (Figure 1) are excellent Michael acceptors that could be considered as synthetic equivalents to cinnamates. Indeed compound 2 reacted with soft nucleophiles exclusively at electrophilic centre E2 , while strong nucleophiles such as OH reacted exclusively at reactive centre E1. The Adamo group has worked for some time on these scaffolds demonstrating their synthetic utility.

Figure 1. Styrylisoxazole properties.

As part of this stream of research (Chapter 2), we have herein demonstrated that compound 2 reacted with homoenolates allowing access to a number of compounds 4 (Scheme 1). The reaction of cinnamaldéhydes under similar conditions gave many compounds, as more than one homoenolate was generated. The use of compound 2 in this reaction allowed this hurdle to be overcome, and compounds such as 4 were prepared as a single regioisomer and diastereomer. The synthetic utility of compounds 4 was further demonstrated by elaboration o f the 4-nitroisoxazole core into a carboxylate.

Scheme 1. Planned synthesis of cyclopentanones 4

Compounds 2 are excellent Michael acceptors under phase transfer catalysis which typically provided adducts with ee’s in the range 90-99%. This remarkable level of selectivity prompted us to investigate the mode of molecular recognition operating between Cinchona based PTC 5 (Figure 2) and reagents 2 (Chapter 3). These studies evidenced for the first time the presence of a primary C-H bond donor active in the Cinchona PTCs, i.e. 1H-NMR titration conducted on Cinchona PTC 5 with ligands 6-13 (Figure 3) allowed us determine a scale of ligand-PTC affinity (Table 1) which correlates with the results obtained by us and others in Cinchona mediated enantioselective processes. This study validated many mechanistic proposals put forward to explain the origin of enantioselectivity of PTC catalysed processes and several molecular modelling studies in this area. Importantly we have evidence that the mode by which Cinchona PTC interacts with opportune ligands is strongly dependent on structure, type and number of H-Bond acceptors present in the ligand. Therefore, a single mechanistic rationale explaining all the data available for this class of reagents is unrealistic. The data we have collected are therefore useful to clarify on a case-by-case basis the specific recognition mode available to Cinchona PTCs.

Figure 2. //-benzyl cinchoninium chloride PTC.

Figure 3. Substrates used in the 1H-NMR titration as H-bond acceptors

In order to set a scenario for the abovementioned studies, the first chapter of this present work (Chapter 1) features an in-depth analysis of the intermolecular forces that most lately were invoked to rationalise the origin of enantioselectivity in catalysis. This includes (a) Non classic H-Bonds, (b) π -type interactions and (c) halogen bonds among others.

The last chapter (Chapter 4) describes our studies regarding the use of Phase Transfer Catalysis in the preparation of compounds 15a/b (Scheme 2), which were obtained as two separable diastereomers. An optimized set of conditions was determined to obtain compounds 15a/b in excellent isolated yields and in ees up to 74%. Peculiarly, diastereomers 15a and 15b were obtained in significantly different enantiomeric excesses. An explanation was provided invoking a base promoted diastereomeric interchange.

Scheme 2. Preparation of γ-butyrolactone containing compounds.

In conclusion, this work has provided new procedures for the preparation of compounds useful in drug discovery and production and has shed light on the peculiar mode of interaction of Cinchona based PTC with scaffold 2 and other commonly used reagents.

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Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2014.

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