Organocatalytic synthesis of chiral non-racemic aziridines, labelled with 2H, 15N, 13C stable isotopes

Zdorichenko, Victor (2015) Organocatalytic synthesis of chiral non-racemic aziridines, labelled with 2H, 15N, 13C stable isotopes. Doctoral thesis, University of East Anglia.

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Aziridines are ‘keystone’ synthetic building blocks - relatively reactive, three-membered heterocycles with the potential for generating ‘secondary’ high value entities such as α- or β-amino acids via ring-opening reactions. Within this thesis, a one-pot asymmetric organocatalytic methodology is utilised for the synthesis of enantiomerically enriched cis-N-aryl-3-aryl-aziridine-2-carboxylates, labelled with stable isotopes: 2H, 13C and 15N. The reactions were catalysed by (S)-BINOL derived N-triflylphosphoramide Brønsted acid and stable isotopes were selectively introduced within an aziridine ring with > 95% isotopic enrichment. The desired compounds were generated in yields of up to 81% and up to 87% e.e. Furthermore optically active β-bromo-α-amino acid derivatives were generated via aziridine ring-opening methodology without loss of the isotopic label or e.e.
α-Arylglycinols are α-amino-β-alcohols, that can be found as structural motifs in synthetic and natural compounds or used as building blocks to access other functional groups. When oxidised, α-arylglycinols are converted to the α-arylglycines - a class of α-amino acids found in a wide range of bioactive compounds such as vancomycin and teicoplanin glycopeptide antibiotics. Successful incorporation of 2H or 13C stable isotopes at α- or β-positions of enantiomerically enriched N-Cbz protected α-arylglycinols is reported with > 95% isotopic enrichment, yields of up to 73% and up to 98% e.e.
Teicoplanin is a glycopeptide antibiotic, used against methicillin-resistant Staphylococcus aureus (MRSA), but the emerging bacterial resistance has escalated the search for new antibiotics. The synthesis of a non-labelled model fragment of the glycopeptide antibiotic teicoplanin is reported. The fragment is synthesised via an aziridination reaction and can be used as a template to generate teicoplanin analogues, both non-labelled and labelled with stable isotopes.
It is anticipated that the stable isotope incorporating methodologies described within this thesis will be applicable not only to the synthesis of novel glycopeptide antibiotics, but also to other biologically active compounds. The installation of stable isotopes affords compounds with highly valuable properties that can be used to study drug metabolism, toxicology, pharmacokinetics and reaction mechanisms.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: Users 2259 not found.
Date Deposited: 29 Jan 2016 11:18
Last Modified: 29 Jan 2016 11:18


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