Steadman, D; (2013) Novel routes towards antibiotics using organocatalytic and biocatalytic approaches. Doctoral thesis , UCL (University College London).

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Abstract

Aromatic ketodiols and 2-amino-1,3-diols are present in many interesting biologically-active molecules. The aminodiol motif itself is present in the broad-spectrum antibiotics chloramphenicol and thiamphenicol. This thesis describes organocatalytic and biocatalytic approaches to this family of compounds, using organocatalysts and transketolase and transaminase enzymes. Transketolase (TK) is a ThDP-dependent enzyme which has been used to prepare aliphatic ketodiols with good yields and high degrees of stereoselectivity. A biomimetic approach to racemic ketodiols has also been reported. Transaminases (TAms) are a broad family of enzymes which stereoselectively form amines from ketone or aldehyde functionalities. A two-step TK/TAm pathway has already been reported which gives access to aliphatic aminodiols, but the preparation of aromatic aminodiols using this combined TK/TAm strategy has yet to be investigated. A literature review of transketolase, transaminase and biocatalysis in general is presented in chapter 1. The substrate scope of the biomimetic TK reaction to prepare racemic aromatic ketodiols has been investigated, and an asymmetric variant developed which was used to transform aromatic aldehydes in water in up to 50% ee (chapter 2). A range of single TK mutants have been used to transform a small range of basic aromatic aldehydes (chapter 3) with low yields but good stereoselectivities (up to 80% ee). In order to create more active combination mutant TKs, a range of mutants were made and tested with aliphatic aldehdyes (chapter 4) to determine what combinations of single mutants could be created without sacrificing enzyme structure and function. With knowledge gained from this and by further study of the TK active-site, a range of combination mutants were then created which accepted a range of functionalised benzaldehydes with excellent yields and stereoselectivities (<98 % ee, <100% yield, chapter 5). With mutant TKs in hand which could transform aromatic aldehydes, the use of two step TK/TAm strategy toward aromatic aldehydes was then investigated (chapter 5). Finally, to assess the substrate range of TK with regards to donor substrate, a range of novel donor substrates was investigated (chapter 6). Mutant TKs were shown to accept several novel donor substrates, giving access to chiral ketols with excellent stereoselectivity (>95% ee). Possible future work is outlined in chapter 7.

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