Phosphorylase-mediated dynamic combinatorial chemistry with linear α-1,4-glucans

In this thesis, phosphorylase-mediated dynamic combinatorial chemistry (DCC) is presented as an approach for the selective synthesis of linear α-1,4-glucans (Figure 1). It was shown that the dynamic mixture of different length α-1,4-glucans in phosphorylase-mediated dynamic combinatorial libraries (DCLs) can be shifted by the addition of a carefully chosen template, thus moving towards the selective synthesis of specific lengths of linear α-1,4-glucans.

A deeper understanding of the recognition properties between the linear α-1,4-glucans and a bola-amphiphile template (molecule with two hydrophilic groups linked together with an aliphatic chain) was sought in order to understand the behaviour of the system. This was achieved by studying the mixture of linear α-1,4-glucans in the phosphorylase-mediated DCLs in the absence and presence of template, but also by studying the properties of isolated linear α-1,4-glucans of different lengths. Through NMR experiments and molecular dynamics simulations, it was possible to elucidate that the linear α-1,4-glucans form a left-handed helix around the hydrophobic region of the bola-amphiphile template. It was shown that the amplification factors observed in the phosphorylase-mediated DCLs were related to the binding strength of the interaction between the different length α-1,4-glucans and the template. As an intriguing sidebenefit of having isolated linear α-1,4-glucans in hand, it was possible to show that linear α-1,4-glucans above a certain minimum length can dimerise in aqueous solution.

In the later part of this thesis, it was investigated whether receptors that selectively bind iP over Glc-1-P could be identified, as such a receptor could potentially shift the product distribution in the phosphorylase-mediated DCLs towards the longer α-1,4-glucans.

Lastly, the focus was shifted from polysaccharides to polypeptides. More specifically, the formation of peptidic macrocycles in thiol–disulfide DCLs was explored.