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Organocatalysis via covalent and non covalent bonding: synthetic applications and mechanistic insights.
Salazar Illera, Diana
<p><strong>For full abstract, see thesis.</strong></p> <p>The present work deals primarily with the development of two new reactions in which scaffold 2 was reacted under organocatalytic conditions.<em>N</em>-heterocyclic carbenes and <em>Cinchona</em>-based phase-transfer catalysts were both employed to promote elaboration of 1.</p> <p>We have shown that 4-nitro-5-styrylisoxazoles <strong>2 (Figure 1) </strong>are excellent Michael acceptors that could be considered as synthetic equivalents to cinnamates. Indeed compound 2 reacted with soft nucleophiles exclusively at electrophilic centre E<sub>2</sub> , while strong nucleophiles such as OH reacted exclusively at reactive centre E<sub>1</sub>. The Adamo group has worked for some time on these scaffolds demonstrating their synthetic utility.</p> <p><strong>Figure 1. </strong>Styrylisoxazole properties.</p> <p>As part of this stream of research (Chapter 2), we have herein demonstrated that compound <strong>2 </strong>reacted with homoenolates allowing access to a number of compounds <strong>4</strong> <strong>(Scheme 1). </strong>The reaction of cinnamaldéhydes under similar conditions gave many compounds, as more than one homoenolate was generated. The use of compound <strong>2 </strong>in this reaction allowed this hurdle to be overcome, and compounds such as <strong>4 </strong>were prepared as a single regioisomer and diastereomer. The synthetic utility of compounds <strong>4</strong> was further demonstrated by elaboration o f the 4-nitroisoxazole core into a carboxylate.</p> <p><strong>Scheme 1. </strong>Planned synthesis of cyclopentanones <strong>4</strong></p> <p>Compounds <strong>2 </strong>are excellent Michael acceptors under phase transfer catalysis which typically provided adducts with <em>ee’s </em>in the range 90-99%. This remarkable level of selectivity prompted us to investigate the mode of molecular recognition operating between <em>Cinchona </em>based PTC 5 <strong>(Figure </strong>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 <em>Cinchona </em>PTCs, <em>i.e. </em><sup>1</sup>H-NMR titration conducted on <em>Cinchona </em>PTC 5 with ligands <strong>6-13</strong> <strong>(Figure 3) </strong>allowed us determine a scale of ligand-PTC affinity <strong>(Table 1) </strong>which correlates with the results obtained by us and others in <em>Cinchona </em>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 <em>Cinchona </em>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 <em>Cinchona </em>PTCs.</p> <p><strong>Figure 2. </strong>//-benzyl cinchoninium chloride PTC.</p> <p><strong>Figure 3. </strong>Substrates used in the <sup>1</sup>H-NMR titration as H-bond acceptors</p> <p>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.</p> <p>The last chapter (Chapter <strong>4) </strong>describes our studies regarding the use of Phase Transfer Catalysis in the preparation of compounds <strong>15a/b (Scheme 2), </strong>which were obtained as two separable diastereomers. An optimized set of conditions was determined to obtain compounds <strong>15a/b </strong>in excellent isolated yields and in <em>ees </em>up to <strong>74%. </strong>Peculiarly, diastereomers <strong>15a </strong>and <strong>15b </strong>were obtained in significantly different enantiomeric excesses. An explanation was provided invoking a base promoted diastereomeric interchange.</p> <p><strong>Scheme 2. </strong>Preparation of γ-butyrolactone containing comp...
Keyword(s): Chemistry; Pharmaceutical; Drug Discovery.; Medicine and Health Sciences
Publication Date:
Type: Doctoral thesis
Peer-Reviewed: No
Institution: Royal College of Surgeons in Ireland
Citation(s): Illera DS. Organocatalysis via covalent and non covalent bonding: synthetic applications and mechanistic insights [PhD Thesis]. Dublin:Royal College of Surgeons in Ireland;2014.
Supervisor(s): Professor Mauro F.A. Adamo
Dr Michele Saviano
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First Indexed: 2015-07-31 15:37:01 Last Updated: 2018-02-13 07:19:22