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Application of biocatalysts in the resolution of peptidomimetic compounds from multi-component reactions

A dissertation submitted to the Faculty of Science University of the Witwatersrand
Johannesburg in fulfilment of the requirements for the Degree of Master of Science. May 2017. / A library of potentially bioactive peptidomimetic compounds has been created using the Ugi and
Passerini multi-component reactions. The products were isolated as racemic mixtures which we aimed
to separate by enzymatic means.
The Ugi enantiomers were obtained in exceedingly low yields due to considerable byproduct
formation encountered with the use of ammonia as reactant and methanol as solvent. A threefold
increase in the yields was achieved when employing the less nucleophilic 2,2,2-trifluoroethanol as
solvent. An endeavour to resolve the racemates using proteases and penicillin G acylase proved
unsuccessful, possibly attributable to the poor solubility of the Ugi products in a broad range of organic
Enantiomers obtained from the Passerini reaction were efficaciously hydrolysed by lipase enzymes.
Hence, the enantioselectivity of the hydrolysis reactions was explored by the employment of chiral
HPLC and Mosher ester analysis. The biocatalysts displayed adequate selectivity for one of the
adducts, making prospective separation of the racemic mixture viable.
An investigation into the diastereoselectivity of the Passerini reaction was also performed. The
application of phenylalanine-derived chiral starting materials in the reaction was seen to have a slight
effect on reaction diastereoselectivity, giving on average a 2:1 diastereomeric ratio. Slightly greater
d.r. values were obtained when bulkier isocyanides were employed. The diastereomeric mixtures were effectively separated via preparative HPLC to obtain pure compounds. 13C NMR spectroscopy
indicated a trend in the chemical shift values for the newly formed stereogenic carbon centres for
most of the two separated diastereomers. The C-2 values of most of the minor diastereomers
appeared more downfield in comparison to the major diastereomers. Distinguishing the
stereochemistry of the major and minor diastereomers through X-ray crystallography was not possible
as the compounds were non-crystalline. Thus the configurations of the newly formed stereogenic
centres of the major compounds were assigned by analogy with similar compounds previously
identified in our laboratory. The major compounds were described as R at the newly formed
stereogenic centre when L-phenylalaninal was used, and the minor products S. When D-phenylalaninal
was used, the major diastereomer was assigned an S configuration at the newly formed stereocentre
and the minor one was assigned R. The formation of the major diastereomer could be explained using
a Felkin-Anh chelation controlled model, which has been observed in other reactions of mono
protected amino aldehydes. / XL2018
Date January 2017
CreatorsKola, Fatima
Source SetsSouth African National ETD Portal
Detected LanguageEnglish
FormatOnline resource (156 leaves), application/pdf

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