PUJOL-SANTIAGO, ALBA (2017) Development of novel catalytic asymmetric diborylation methodologies. Doctoral thesis, Durham University.
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This thesis describes the study of the β-borylation reaction on different types of electron deficient substrates as well as the application of the methodologies herein developed into the synthesis of a key intermediate for cholesterol-lowering drug Atorvastatin.
Within the frame of the use of organoboron compounds in organic synthesis, the literature review presented in the first section after a brief introduction on organoboranes is focused on the different strategies for their synthesis via boron addition, specially the β-borylation reaction. Different aspects of the reaction are covered; enantioselective version, the different methodologies reported for the activation of the diborane reagents or organic electron deficient substrates.
Within the study of the β-borylation reaction on α,β-unsaturated aldehydes via the in situ generated amine-derived aldimine intermediates, and the further application of these synthetically attractive compounds, the relevant challenge of handling β-boryl aldehydes was met. It was confirmed that this type of compound was indeed unstable especially under chromatographic purification conditions, leading to de-borylation. In addition, mechanistic studies were carried out in order to achieve a better understanding of the whole process, but it was not possible to clarify it and avoid the undesired side-process. Hence, the establishment of an efficient derivatisation methodology was required. The solution consisted of a mild, efficient derivatisation process involving an in situ copper(II) sulfate-based imine hydrolysis followed by Wittig trapping of the resulting aldehyde.
Further exploitation of homoallylic boronate carboxylate esters as substrates for a second borylation reaction, led to obtaining versatile 1,3-diborylated esters. A novel methodology was developed which allowed the control of the asymmetry induced in the new stereogenic centre created for a range of substrates, due to the presence of the two boryl units which could subsequently be transformed into other functionalities leading to building blocks for the synthesis of multi-functional, chiral compounds. Therefore, the two boryl units were then examined for transformation into functionalities which would allow unambiguous stereochemical assignment of the two borylation reactions. Specifically, an oxidation/acetal formation sequence was examined showing that 6-membered ring acetonide acetals were ideal compounds for this purpose. Beside aiding the stereochemical analysis, it was confirmed that this dual asymmetric borylation methodology was useful for the synthesis of 3,5-dihydroxy acids (or esters analogous) side-chain present in many natural products or drugs, such as statin-type drugs.
Complementarily, and with the aim of expanding the type of substrates for the β-borylation reaction, structurally varied compounds were examined. Firstly, substrates presenting an additional unsaturation were evaluated under the imine formation/β-borylation reaction sequence conditions paying special attention to the 1,4- vs 1,6-addition selectivity, were examined as a possible alternative for the synthesis of diborylated compounds in a direct manner. This was followed by the study of different unsaturation, and in particular, an alkyne instead of an alkene, i.e. α,β-acetylenic carbonyl compounds, which were envisioned as ideal platforms for the synthesis of vinyl boronates. As well as a brief study on the β-borylation reaction on β-enamino ester substrates which could a priori give rise to valuable α-amino boronate compounds, is reported.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||Organic synthesis, Asymmetric catalysis, Organoboron compounds, Borylation|
|Faculty and Department:||Faculty of Science > Chemistry, Department of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||31 May 2017 12:10|