The design and synthesis of a novel thiamine cofactor for potential biocatalysis

Tinson, Ryan (2016) The design and synthesis of a novel thiamine cofactor for potential biocatalysis. Doctoral thesis, University of East Anglia.

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The design and application of enzyme mimics has received more attention due to requirement of
green chemistry applications within industry and academia. One way of introducing these
modifications is via a cofactor, due to their location within an enzyme’s active site. A number of
crucial biochemical reactions in the cell require not only the enzymes for catalysis, but also the
organic cofactors or metal ions. It is therefore advantageous to utilize this common structural
relationship to model a novel enzyme – cofactor system capable of undergoing chemistry not
commonly undertaken by this enzyme, and which could be beneficial to the synthetic chemist.
Recent research has concentrated on the synthesis of unnatural vitamin B1 motifs containing a
central 1,4 - triazole motif (figure 1) first synthesised by Leeper in 2006.
Figure 1: 1,4 – disubstituted triazole ThDP
Synthesis of a cofactor that could theoretically carry out alternative reaction pathways and invoke
novel enzyme-substrate pathways, whilst regenerating the cofactor in situ was envisaged (figure
2). Structural analogues of this coenzyme could thus be synthesised to tailor different products,
thereby promoting high yields, high stereo/regiochemical control and reduced costs for industrial
Figure 2: Proposed novel bio catalytic pathway based on 1,4 -ThDP scaffold
The multi-step synthesis of some model compounds and their testing in pyruvate decarboxylase
enzyme was successfully completed. Results indicated that only smaller chains are
accommodated in the active site and initial attempts to synthesis a tertiary amine tether proved
difficult because of intramolecular cyclisations. However, a potential novel route to
benzoxyazepines was uncovered by an acid catalysed deprotection, cyclisation, elimination step.
Enantiopure synthesis was also carried out, and an initial high ee% was observed, but conditions
for this require further development. Lastly, the synthesis of a new difluorophosphate isostere for
the diphosphate group was developed in good yield for a potential 1,4-CuAAC of our compound
for further biological evaluation in PDC enzymes.

Item Type: Thesis (Doctoral)
Additional Information: This deposit has been uploaded in two files. It has been embargoed until June 2017.
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: Stacey Armes
Date Deposited: 07 Jun 2016 15:48
Last Modified: 31 May 2017 00:38

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