ETD Collection

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Author: search.filters.author.Juma, Wanyama PeterSubject: search.filters.subject.Organic compounds--Synthesis

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    An investigation of the enzymatic kinetic resolution of Morita-Baylis-Hillman adducts and their further functionalisation
    (2019) Juma, Wanyama Peter
    The Morita-Baylis-Hillman reaction (MBHR) is a carbon-carbon bond forming reaction that affords multifunctional Morita-Baylis-Hillman adducts (MBHA) with various synthetic applications. Unfortunately, many of the synthetic applications of these adducts cannot be realised because these adducts are formed in racemic form. This thesis has investigated functionalisation of enantiopure MBHA obtained using biocatalytic methods. The first part of the thesis describes the use of enantiopure aldehydes N-Boc-L-phenylalaninal and N-Boc-D-phenylalaninal to synthesize several Morita-Baylis-Hillman adducts in order to obtain diastereomers that would be separable by chromatographic methods. Unfortunately, this approach proved unsuccessful due to racemization of the aldehydes or MBHA under the reaction conditions applied. The second approach described is the resolution of racemic MBH acetates and esters using different enzymes. This exercise led to the identification of several lipases that were able to resolve racemic MBH acetates with excellent enantiomeric excess (ee) values and enantiomeric ratios (E). Racemic MBH adducts derived from the reaction of acrylonitrile with benzaldehyde, cinnamaldehyde and hydrocinnamaldehyde were successfully resolved. In each case the (+)-alcohol products were isolated in 94 - 97% ee after lipase-mediated enzymatic kinetic resolution of the corresponding acetates. Mosher’s ester derivatisation protocol was used to determine the absolute configuration of the resolved adducts, which was found to be (S). A lipase from Pseudomonas fluorescens, and Candida antarctica type B were found to be the best-performing enzymes. The last part of the thesis investigated the use of nitrogen nucleophiles for Michael addition to MBH adducts. The process confirmed that the use of nitrogen nucleophiles on TBS protected MBH adducts afforded nucleophilic addition products of high diastereoselectivity. The use of one of the enantiopure isolated MBH adducts in a diastereoselective Michael addition reaction with benzylamine led to a significantly enantio-enriched final product.