Phosphodiester foldamers

Abstract

Phosphodiesters are ubiquitous throughout Nature and underpin many biological processes. Despite their prevalence in biomacromolecules, they themselves do not act as a conformational determinant. Inspired by Nature and foldamer precedent in the literature, this thesis describes the investigation into novel abiotic aromatic phosphodiester architectures in which local conformation control is achieved via intramolecular hydrogen bonds involving the phosphodiester group, behaving in accordance with the foldamer criteria outlined by Gellman. Phosphoramidite chemistry was successfully employed to establish the bond connectivity of phosphodiesters with benzyl alcohols (Figure 2-a). Attempts to establish conformational control began with placing an amide in the ortho-position of the aromatic ring in respect to the phosphodiester in the hope that it would form a strong intramolecular hydrogen bond (Figure 2-b). However, experimental data from hydrogen-deuterium (H-D) exchange and variable temperature (VT) NMR indicated that the designed 8-membered hydrogen bonded ring was not present. The structure was subsequently modified by deleting the sp3 benzylic carbon to reduce the conformational flexibility of the molecule and encourage the formation of a hydrogen bond (Figure 2-b). Synthesis of an exclusively phenyl-based backbone required a departure from phosphoramidite chemistry and so phosphochloridites were used instead. H-D exchange, VT NMR, and 1H-31P HOESY experiments in CDCl3 indicated the presence of a 7-membered hydrogen bonded ring within the phosphotriester compounds. ANMR values were indicative of amide involvement in the hydrogen bond. Computational models in silico predicted the presence of an intramolecular hydrogen bond, and this model was confirmed experimentally by X-ray crystallography (Figure 2-c). For the corresponding phosphodiesters, H-D exchange in DMSO-d6/CDCl3 (20:80) and X-ray crystallography were consistent with the presence of a hydrogen bond, although VT NMR in DMSO-d6/CDCl3 (20:80) was inconclusive. The phenyl phosphodiesters were expanded into larger phosphoresorcinol oligomers whose conformational behaviour was predicted in silico. The oligomers exhibited folding mediated by a series of amide-phosphodiester hydrogen bonds. The synthesis of these foldamers was performed by coupling the amide-bearing phenolic building blocks with phosphochloridites, which allowed access to phosphoresorcinol dimers, trimers, and tetramers (Figure 3). The conformational properties of the dimer were investigated. In DMSO-d6/CDCl3 (20:80), H-D exchange and VT NMR experiments were consistent with the involvement of both amides in intramolecular hydrogen bonds – one of which appeared marginally stronger due to co-operativity from an adjacent hydroxyl-carbonyl hydrogen bond. In DMSO-d6, the NOESY NMR spectrum of the dimer was consistent with a trans relationship between the phosphodiesters which matched further studies in silico (Figure 4). Conformational investigations for the trimer and tetramer are ongoing. Phosphodiesters are a novel class of foldamer which exhibit some promising conformational control from intramolecular hydrogen bonds. There is a lot of potential for future research into this area. Specifically for phosphoresorcinol foldamers, biologically relevant “R” groups can be encoded into a specific sequence to recognise biomacromolecular surfaces and disrupt targeted protein-protein interactions for disease therapeutics. Now that the hydrogen bonding interaction has been established, several further abiotic phosphodiester architectures can be designed to exploit this novel hydrogen bond to influence local conformational control. Alternatively, the phosphodiester might be capable of forming other non-covalent interactions, such as metal chelation, to exert conformational control.

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Identifiers

ORCID for Sam Thompson: orcid.org/0000-0001-6267-5693

ORCID for Eugen Stulz: orcid.org/0000-0002-5302-2276

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